[ { "pmid": "16357751", "text": "Selective costimulation modulators: a novel approach for the treatment of rheumatoid arthritis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "T cells have a central role in the orchestration of the immune pathways that contribute to the inflammation and joint destruction characteristic of rheumatoid arthritis (RA).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "The requirement for a dual signal for T-cell activation and the construction of a fusion protein that prevents engagement of the costimulatory molecules required for this activation has led to a new approach to RA therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "This approach is mechanistically distinct from other currently used therapies; it targets events early rather than late in the immune cascade, and it results in immunomodulation rather than complete immunosuppression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "The fusion protein abatacept is a selective costimulation modulator that avidly binds to the CD80/CD86 ligands on an antigen-presenting cell, resulting in the inability of these ligands to engage the CD28 receptor on the T cell.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "Abatacept dose-dependently reduces T-cell proliferation, serum concentrations of acute-phase reactants, and other markers of inflammation, including the production of rheumatoid factor by B cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "Recent studies have provided consistent evidence that treatment with abatacept results in a rapid onset of efficacy that is maintained over the course of treatment in patients with inadequate response to methotrexate and anti-tumor necrosis factor therapies.", "type": "CHEMICAL", "entities": [ "methotrexate" ], "offsets": [ [ 204, 216 ] ] }, { "pmid": "16357751", "text": "This efficacy includes patient-centered outcomes and radiographic measurement of disease progression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "Abatacept has also demonstrated a very favorable safety profile to date.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "This article reviews the rationale for this therapeutic approach and highlights some of the recent studies that demonstrate the benefits obtained by using abatacept.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16357751", "text": "This clinical experience indicates that abatacept is a significant addition to the therapeutic armamentarium for the management of patients with RA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate.", "type": "CHEMICAL", "entities": [ "platinum" ], "offsets": [ [ 76, 84 ] ] }, { "pmid": "14967461", "text": "Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer.", "type": "CHEMICAL", "entities": [ "taxanes", "vinorelbine", "gemcitabine", "irinotecan" ], "offsets": [ [ 28, 35 ], [ 37, 48 ], [ 50, 61 ], [ 67, 77 ] ] }, { "pmid": "14967461", "text": "Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux).", "type": "CHEMICAL", "entities": [ "gefitinib", "Iressa", "ZD1839", "erlotinib", "Tarceva", "OSI-774", "cetuximab", "IMC-225", "Erbitux" ], "offsets": [ [ 102, 111 ], [ 113, 119 ], [ 121, 127 ], [ 133, 142 ], [ 144, 151 ], [ 153, 160 ], [ 204, 213 ], [ 215, 222 ], [ 224, 231 ] ] }, { "pmid": "14967461", "text": "Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2).", "type": "CHEMICAL", "entities": [ "CI-1033", "tyrosine", "PKI166", "GW572016" ], "offsets": [ [ 67, 74 ], [ 101, 109 ], [ 132, 138 ], [ 143, 151 ] ] }, { "pmid": "14967461", "text": "Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "However, serious clinical challenges persist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14967461", "text": "Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.", "type": "CHEMICAL", "entities": [ "gefitinib", "erlotinib", "gefitinib" ], "offsets": [ [ 5, 14 ], [ 19, 28 ], [ 173, 182 ] ] }, { "pmid": "23468099", "text": "Effects of chronic social defeat stress on behavior and choline acetyltransferase, 78-kDa glucose-regulated protein, and CCAAT/enhancer-binding protein (C/EBP) homologous protein in adult mice.\n", "type": "CHEMICAL", "entities": [ "choline", "glucose" ], "offsets": [ [ 56, 63 ], [ 90, 97 ] ] }, { "pmid": "23468099", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "Social defeat stress induces physiological and behavioral symptoms, including anxiety, anhedonia, immune deficits, and altered expression of key brain genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "The present study investigated the effects of social defeat stress on the behaviors and expressions of Chat, Grp78, and chop in the brains of adult mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "In experiment 1, behavioral tests were conducted, and brains were processed for Western blotting at day 27 after stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "In experiment 2, social avoidance tests were conducted, and brains were processed for Western blotting at day 12 after stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "The results indicate decreased and increased locomotion and anxiety behavior in all defeated mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "Decrease in social interaction, increased immobility, and impaired memory performance were only observed in susceptible mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "A decrease in the Chat level at days 12 and 27 was noted in the prefrontal cortex (PFC), amygdala (Amyg), and dorsal hippocampus (HIP) in defeated mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "The expression levels of Grp78 and chop measured on days 12 and 27 were significantly greater in the Amyg of susceptible mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "In the PFC and HIP, defeated mice displayed different patterns in the levels of Grp78 and chop expressions measured on days 12 and 27.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "The present study demonstrated that chronic social defeat stress in mice produces stress-related behaviors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23468099", "text": "Different response patterns were noted for Grp78 and chop expression among the groups in terms of brain regions and time-course effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "Matriptase-2, a recently identified cell surface protease, is the key enzyme of iron homoeostasis modulating the expression of the liver peptide hormone hepcidin.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 80, 84 ] ] }, { "pmid": "23293962", "text": "HAI (hepatocyte growth factor activator inhibitor) types 1 and 2 (HAI-1 and HAI-2 respectively) have been shown to inhibit the close homologue, i.e. matriptase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "By co-expressing matriptase-2 and the inhibitor HAI-2 we have identified HAI-2 displaying high inhibitory potential against matriptase-2 at the cell surface as well as in conditioned medium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "Accordingly, complex formation between matriptase-2 and HAI-2 was demonstrated by isolation of the complex via immobilizing either HAI-2 or matriptase-2 from lysates and conditioned medium of co-expressing cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "Furthermore, HAI-2 indirectly influences the expression of the hepcidin-encoding gene HAMP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "The inhibitor abrogates the matriptase-2-mediated suppression of HAMP expression, presumably by inhibiting the supposed potential of matriptase-2 to cleave membrane-bound HJV (haemojuvelin).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293962", "text": "Taken together, the results of the present study have characterized HAI-2 as an inhibitor of matriptase-2 that modulates the synthesis of hepcidin and provides new insights into the regulatory mechanism of iron homoeostasis, with clinical importance for a treatment of iron overload diseases.", "type": "CHEMICAL", "entities": [ "iron", "iron" ], "offsets": [ [ 206, 210 ], [ 269, 273 ] ] }, { "pmid": "7678677", "text": "Alprenolol and bromoacetylalprenololmenthane are competitive slowly reversible antagonists at the beta 1-adrenoceptors of rat left atria.\n", "type": "CHEMICAL", "entities": [ "Alprenolol", "bromoacetylalprenololmenthane" ], "offsets": [ [ 0, 10 ], [ 15, 44 ] ] }, { "pmid": "7678677", "text": "We studied the effects of alprenolol and bromoacetylalprenololmenthane (BAAM) on rat left atria.", "type": "CHEMICAL", "entities": [ "alprenolol", "bromoacetylalprenololmenthane", "BAAM" ], "offsets": [ [ 26, 36 ], [ 41, 70 ], [ 72, 76 ] ] }, { "pmid": "7678677", "text": "Alprenolol and BAAM at 10(-7), 3 x 10(-7), and 10(-6)", "type": "CHEMICAL", "entities": [ "BAAM", "Alprenolol" ], "offsets": [ [ 15, 19 ], [ 0, 10 ] ] }, { "pmid": "7678677", "text": "M inhibited the cardiac stimulation response slightly, which is indicative of membrane-stabilizing activity independent of beta-adrenoceptor blockade.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7678677", "text": "This membrane-stabilizing activity was readily reversible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7678677", "text": "Alprenolol and BAAM also caused surmountable antagonism of isoprenaline responses, and this beta 1-adrenoceptor antagonism was slowly reversible.", "type": "CHEMICAL", "entities": [ "Alprenolol", "BAAM", "isoprenaline" ], "offsets": [ [ 0, 10 ], [ 15, 19 ], [ 59, 71 ] ] }, { "pmid": "7678677", "text": "Inhibition of the isoprenaline responses with alprenolol and BAAM at 10(-6)", "type": "CHEMICAL", "entities": [ "isoprenaline", "alprenolol", "BAAM" ], "offsets": [ [ 18, 30 ], [ 46, 56 ], [ 61, 65 ] ] }, { "pmid": "7678677", "text": "M was at equilibrium after 60 min, which is indicative of reversible antagonism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7678677", "text": "We conclude that alprenolol and BAAM are competitive slowly reversible beta 1-adrenoceptor antagonists on rat left atria.", "type": "CHEMICAL", "entities": [ "alprenolol", "BAAM" ], "offsets": [ [ 17, 27 ], [ 32, 36 ] ] }, { "pmid": "16554356", "text": "Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds.", "type": "CHEMICAL", "entities": [ "polysorbates" ], "offsets": [ [ 26, 38 ] ] }, { "pmid": "16554356", "text": "Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug.", "type": "CHEMICAL", "entities": [ "Loperamide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16554356", "text": "Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP.", "type": "CHEMICAL", "entities": [ "loperamide" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "16554356", "text": "This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554356", "text": "These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16789740", "text": "Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.\n", "type": "CHEMICAL", "entities": [ "anthranilic acid sulfonamides", "methionine" ], "offsets": [ [ 30, 59 ], [ 77, 87 ] ] }, { "pmid": "16789740", "text": "Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy.", "type": "CHEMICAL", "entities": [ "Methionine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16789740", "text": "As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening.", "type": "CHEMICAL", "entities": [ "anthranilic acid sulfonamides" ], "offsets": [ [ 92, 121 ] ] }, { "pmid": "16789740", "text": "These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16789740", "text": "Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 272, 282 ] ] }, { "pmid": "7526860", "text": "Keratinocyte growth factor and acidic fibroblast growth factor are mitogens for primary cultures of mammary epithelium.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Mammary epithelial cells derived from the entire mammary parenchyma or only end buds were isolated by collagenase digestion of mammary glands from virgin mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Cells were cultured within collagen gels in serum-free medium containing insulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Keratinocyte growth factor (KGF or FGF-7) and acidic fibroblast growth factor (aFGF or FGF-1) stimulated multifold proliferation when added alone to this medium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Growth occurred as three-dimensional colonies within the collagen gel matrix.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "KGF stimulated growth was unaffected by adding heparin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Conversely, multifold growth stimulation by acidic FGF required heparin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "Since end buds are the actively proliferating cell population of ductal glands, organ cultures of these structures were prepared.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7526860", "text": "KGF stimulated 3H-thymidine incorporation in these end buds in the absence and presence of epidermal growth factor.", "type": "CHEMICAL", "entities": [ "3H-thymidine" ], "offsets": [ [ 15, 27 ] ] }, { "pmid": "7526860", "text": "These data suggest that acidic FGF and KGF may represent in vivo stromal factors capable of regulating mammary gland development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17199504", "text": "Configuration of a scintillation proximity assay for the activity assessment of recombinant human adenine phosphoribosyltransferase.\n", "type": "CHEMICAL", "entities": [ "adenine" ], "offsets": [ [ 98, 105 ] ] }, { "pmid": "17199504", "text": "Adenine phosphoribosyltransferase plays a role in purine salvage by catalyzing the direct conversion of adenine to adenosine monophosphate.", "type": "CHEMICAL", "entities": [ "Adenine", "adenine", "adenosine monophosphate", "purine" ], "offsets": [ [ 0, 7 ], [ 104, 111 ], [ 115, 138 ], [ 50, 56 ] ] }, { "pmid": "17199504", "text": "The involvement of the purine salvage pathway in tumor proliferation and angiogenesis makes adenine phosphoribosyltransferase a potential target for oncology drug discovery.", "type": "CHEMICAL", "entities": [ "purine", "adenine" ], "offsets": [ [ 23, 29 ], [ 92, 99 ] ] }, { "pmid": "17199504", "text": "We have expressed and characterized recombinant, N-terminally His-tagged human adenine phosphoribosyltransferase.", "type": "CHEMICAL", "entities": [ "N", "His", "adenine" ], "offsets": [ [ 49, 50 ], [ 62, 65 ], [ 79, 86 ] ] }, { "pmid": "17199504", "text": "Two assay formats were assessed for use in a high throughput screen: a spectrophotometric-based enzyme-coupled assay system and a radiometric ionic capture scintillation proximity bead assay format.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17199504", "text": "Ultimately, the scintillation proximity assay format was chosen because of automated screening compatibility limitations of the coupled assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17199504", "text": "We describe here the biochemical characterization of adenine phosphoribosyltransferase and the development of a robust, homogeneous, 384-well assay suitable for high throughput screening.", "type": "CHEMICAL", "entities": [ "adenine" ], "offsets": [ [ 53, 60 ] ] }, { "pmid": "16437532", "text": "Cholinesterase inhibitors for Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "BACKGROUND: Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "donepezil", "galantamine", "rivastigmine" ], "offsets": [ [ 170, 179 ], [ 181, 192 ], [ 197, 209 ] ] }, { "pmid": "16437532", "text": "The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 111, 124 ] ] }, { "pmid": "16437532", "text": "The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "donepezil", "galantamine", "rivastigmine" ], "offsets": [ [ 25, 34 ], [ 36, 47 ], [ 52, 64 ] ] }, { "pmid": "16437532", "text": "SEARCH STRATEGY:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, \"ENA 713\" and ENA-713 on 12 June 2005.", "type": "CHEMICAL", "entities": [ "donepezil", "E2020", "Aricept", "galanthamin", "galantamin", "reminyl", "rivastigmine", "exelon", "ENA 713", "ENA-713" ], "offsets": [ [ 107, 116 ], [ 120, 125 ], [ 130, 137 ], [ 141, 152 ], [ 154, 164 ], [ 166, 173 ], [ 175, 187 ], [ 189, 195 ], [ 198, 205 ], [ 211, 218 ] ] }, { "pmid": "16437532", "text": "This Register contains up-to-date records of all major health care databases and many ongoing trial databases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "SELECTION CRITERIA: All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "DATA COLLECTION AND ANALYSIS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "MAIN RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale.", "type": "CHEMICAL", "entities": [ "donepezil", "galantamine", "rivastigmine" ], "offsets": [ [ 140, 149 ], [ 151, 162 ], [ 166, 178 ] ] }, { "pmid": "16437532", "text": "Study clinicians blind to other measures rated global clinical state more positively in treated patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Benefits of treatment were also seen on measures of activities of daily living and behaviour.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "None of these treatment effects are large.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine.", "type": "CHEMICAL", "entities": [ "donepezil", "galantamine", "donepezil", "rivastigmine" ], "offsets": [ [ 127, 136 ], [ 151, 162 ], [ 175, 184 ], [ 199, 211 ] ] }, { "pmid": "16437532", "text": "In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event.", "type": "CHEMICAL", "entities": [ "donepezil", "galantamine" ], "offsets": [ [ 79, 88 ], [ 93, 104 ] ] }, { "pmid": "16437532", "text": "There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years.", "type": "CHEMICAL", "entities": [ "donepezil", "rivastigmine" ], "offsets": [ [ 69, 78 ], [ 83, 95 ] ] }, { "pmid": "16437532", "text": "Fewer patients suffer adverse events on donepezil than rivastigmine.", "type": "CHEMICAL", "entities": [ "donepezil", "rivastigmine" ], "offsets": [ [ 40, 49 ], [ 55, 67 ] ] }, { "pmid": "16437532", "text": "AUTHORS' CONCLUSIONS: The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "It is not possible to identify those who will respond to treatment prior to treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There is no evidence that treatment with a ChEI is not cost effective.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16437532", "text": "There appears to be less adverse effects associated with donepezil compared with rivastigmine.", "type": "CHEMICAL", "entities": [ "donepezil", "rivastigmine" ], "offsets": [ [ 57, 66 ], [ 81, 93 ] ] }, { "pmid": "16437532", "text": "It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used.", "type": "CHEMICAL", "entities": [ "galantamine", "rivastigmine", "donepezil" ], "offsets": [ [ 15, 26 ], [ 31, 43 ], [ 50, 59 ] ] }, { "pmid": "16437532", "text": "Titration with donepezil is more straightforward and the lower dose may be worth consideration.", "type": "CHEMICAL", "entities": [ "donepezil" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "11716850", "text": "The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide.\n", "type": "CHEMICAL", "entities": [ "sulfonylureas", "mitiglinide", "nateglinide", "KAD-1229" ], "offsets": [ [ 137, 150 ], [ 15, 26 ], [ 155, 166 ], [ 28, 36 ] ] }, { "pmid": "11716850", "text": "Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells.", "type": "CHEMICAL", "entities": [ "Mitiglinide", "ATP", "K+", "K", "ATP", "KAD-1229" ], "offsets": [ [ 0, 11 ], [ 107, 110 ], [ 121, 123 ], [ 125, 126 ], [ 127, 130 ], [ 13, 21 ] ] }, { "pmid": "11716850", "text": "However, its selectivity for the various K(ATP) channels is not known.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 41, 42 ], [ 43, 46 ] ] }, { "pmid": "11716850", "text": "In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide.", "type": "CHEMICAL", "entities": [ "mitiglinide", "K", "ATP", "meglitinide", "nateglinide" ], "offsets": [ [ 42, 53 ], [ 72, 73 ], [ 74, 77 ], [ 193, 204 ], [ 223, 234 ] ] }, { "pmid": "11716850", "text": "Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM).", "type": "CHEMICAL", "entities": [ "mitiglinide" ], "offsets": [ [ 74, 85 ] ] }, { "pmid": "11716850", "text": "Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM).", "type": "CHEMICAL", "entities": [ "Nateglinide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11716850", "text": "Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site.", "type": "CHEMICAL", "entities": [ "[3H]glibenclamide", "mitiglinide", "nateglinide", "repaglinide", "glibenclamide", "mitiglinide", "nateglinide", "repaglinide" ], "offsets": [ [ 140, 157 ], [ 180, 191 ], [ 201, 212 ], [ 224, 235 ], [ 283, 296 ], [ 23, 34 ], [ 36, 47 ], [ 53, 64 ] ] }, { "pmid": "11716850", "text": "The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment.", "type": "CHEMICAL", "entities": [ "glucose", "mitiglinide", "tolbutamide", "glibenclamide", "mitiglinide", "nateglinide", "repaglinide", "tolbutamide", "glibenclamide" ], "offsets": [ [ 25, 32 ], [ 34, 45 ], [ 47, 58 ], [ 64, 77 ], [ 106, 117 ], [ 119, 130 ], [ 135, 146 ], [ 196, 207 ], [ 212, 225 ] ] }, { "pmid": "11716850", "text": "These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.", "type": "CHEMICAL", "entities": [ "sulfonylureas", "mitiglinide", "K", "ATP", "mitiglinide" ], "offsets": [ [ 44, 57 ], [ 59, 70 ], [ 149, 150 ], [ 151, 154 ], [ 182, 193 ] ] }, { "pmid": "23487168", "text": "A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23487168", "text": "Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23487168", "text": "Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan].", "type": "CHEMICAL", "entities": [ "azilsartan", "candesartan", "eprosartan", "irbesartan", "losartan", "olmesartan", "telmisartan", "valsartan" ], "offsets": [ [ 37, 47 ], [ 49, 60 ], [ 62, 72 ], [ 74, 84 ], [ 86, 94 ], [ 96, 106 ], [ 108, 119 ], [ 121, 130 ] ] }, { "pmid": "23487168", "text": "Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites.", "type": "CHEMICAL", "entities": [ "Azilsartan", "candesartan", "olmesartan" ], "offsets": [ [ 0, 10 ], [ 32, 43 ], [ 49, 59 ] ] }, { "pmid": "23487168", "text": "On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23487168", "text": "The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23487168", "text": "Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23487168", "text": "Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 96, 107 ] ] }, { "pmid": "23487168", "text": "Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "Diuretic effects of cannabinoids.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "Direct-acting CB1 agonists, including Δ(9)-tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate], AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol], and AM4054", "type": "CHEMICAL", "entities": [ "Δ(9)-tetrahydrocannabinol", "WIN 55,212", "R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate", "AM2389", "9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol", "AM4054" ], "offsets": [ [ 38, 63 ], [ 65, 75 ], [ 77, 198 ], [ 201, 207 ], [ 209, 265 ], [ 272, 278 ] ] }, { "pmid": "23019138", "text": "[9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED(50) values for diuresis than for hypothermia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019138", "text": "The highest doses of cannabinoid drugs yielded, on average, 26-32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488).", "type": "CHEMICAL", "entities": [ "furosemide", "trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide", "U50-488" ], "offsets": [ [ 122, 132 ], [ 147, 227 ], [ 229, 236 ] ] }, { "pmid": "23019138", "text": "Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241", "type": "CHEMICAL", "entities": [ "AM1241" ], "offsets": [ [ 87, 93 ] ] }, { "pmid": "23019138", "text": "[1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects.", "type": "CHEMICAL", "entities": [ "anandamide", "AM404", "rimonabant" ], "offsets": [ [ 67, 77 ], [ 98, 103 ], [ 127, 137 ] ] }, { "pmid": "23019138", "text": "In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)].", "type": "CHEMICAL", "entities": [ "AM4054", "rimonabant", "vanilloid", "capsazepine", "WIN 55,212", "AM630", "(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)" ], "offsets": [ [ 57, 63 ], [ 218, 228 ], [ 245, 254 ], [ 282, 293 ], [ 319, 329 ], [ 364, 369 ], [ 371, 457 ] ] }, { "pmid": "23019138", "text": "These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor gamma in rheumatoid synovial cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce apoptosis in a variety of cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "In this study, we examined the effect of NSAIDs on the growth and apoptosis of synovial cells from patients with rheumatoid arthritis and analyzed the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) as a possible mechanism of action of NSAIDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "Cell proliferation and viability were assessed from 5-bromo-2'-deoxyuridine incorporation and by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay, respectively.", "type": "CHEMICAL", "entities": [ "5-bromo-2'-deoxyuridine", "4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate", "WST-1" ], "offsets": [ [ 52, 75 ], [ 97, 175 ], [ 177, 182 ] ] }, { "pmid": "12065695", "text": "The apoptosis of synovial cells was identified by DNA fragmentation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "Indometacin, diclofenac, oxaprozin, and zaltoprofen reduced cell proliferation and induced apoptotic cell death in synovial cells, whereas ketoprofen and acetaminophen did not.", "type": "CHEMICAL", "entities": [ "Indometacin", "diclofenac", "oxaprozin", "zaltoprofen", "ketoprofen", "acetaminophen" ], "offsets": [ [ 0, 11 ], [ 13, 23 ], [ 25, 34 ], [ 40, 51 ], [ 139, 149 ], [ 154, 167 ] ] }, { "pmid": "12065695", "text": "N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, also inhibited cell proliferation, whereas it did not cause apoptosis.", "type": "CHEMICAL", "entities": [ "N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide", "NS-398" ], "offsets": [ [ 0, 55 ], [ 57, 63 ] ] }, { "pmid": "12065695", "text": "Rheumatoid synovial cells expressed PPARgamma mRNA, and the PPARgamma ligands 15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone reduced the proliferation and induced apoptosis in synovial cells.", "type": "CHEMICAL", "entities": [ "15-deoxy-Delta(12,14)-prostaglandin J(2)", "troglitazone" ], "offsets": [ [ 78, 118 ], [ 123, 135 ] ] }, { "pmid": "12065695", "text": "Luciferase reporter assay demonstrated that not only PPARgamma ligands but also NSAIDs, which could induce apoptosis, increased the activation of PPARgamma in synovial cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "Furthermore, the ability of NSAIDs and PPARgamma ligands to stimulate the activation of PPARgamma correlated with their ability to decrease cell viability(r = 0.92, p < 0.01) and ability to induce DNA fragmentation (r = 0.97, p < 0.001) in synovial cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12065695", "text": "These results suggest that PPARgamma is an attractive target for induction of apoptosis in rheumatoid synovial cells and that the activation of the PPARgamma pathway is associated with the apoptotic action of NSAIDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23214423", "text": "Anisotropy of chemical bonding in semifluorinated graphite C2F revealed with angle-resolved X-ray absorption spectroscopy.\n", "type": "CHEMICAL", "entities": [ "graphite", "C2F" ], "offsets": [ [ 50, 58 ], [ 59, 62 ] ] }, { "pmid": "23214423", "text": "Highly oriented pyrolytic graphite characterized by a low misorientation of crystallites is fluorinated using a gaseous mixture of BrF(3) with Br(2) at room temperature.", "type": "CHEMICAL", "entities": [ "BrF(3)", "Br(2)", "graphite" ], "offsets": [ [ 131, 137 ], [ 143, 148 ], [ 26, 34 ] ] }, { "pmid": "23214423", "text": "The golden-colored product, easily delaminating into micrometer-size transparent flakes, is an intercalation compound where Br(2) molecules are hosted between fluorinated graphene layers of approximate C(2)F composition.", "type": "CHEMICAL", "entities": [ "Br(2)", "graphene", "C(2)F" ], "offsets": [ [ 124, 129 ], [ 171, 179 ], [ 202, 207 ] ] }, { "pmid": "23214423", "text": "To unravel the chemical bonding in semifluorinated graphite, we apply angle-resolved near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and quantum-chemical modeling.", "type": "CHEMICAL", "entities": [ "graphite" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23214423", "text": "The strong angular dependence of the CK and FK edge NEXAFS spectra on the incident radiation indicates that room-temperature-produced graphite fluoride is a highly anisotropic material, where half of the carbon atoms are covalently bonded with fluorine, while the rest of the carbon atoms preserve π electrons.", "type": "CHEMICAL", "entities": [ "graphite fluoride", "carbon", "fluorine" ], "offsets": [ [ 134, 151 ], [ 204, 210 ], [ 244, 252 ] ] }, { "pmid": "23214423", "text": "Comparison of the experimental CK edge spectrum with theoretical spectra plotted for C(2)F models reveals that fluorine atoms are more likely to form chains.", "type": "CHEMICAL", "entities": [ "C(2)F", "fluorine" ], "offsets": [ [ 84, 89 ], [ 110, 118 ] ] }, { "pmid": "23214423", "text": "This conclusion agrees with the atomic force microscopy observation of a chain-like pattern on the surface of graphite fluoride layers.", "type": "CHEMICAL", "entities": [ "graphite fluoride" ], "offsets": [ [ 109, 126 ] ] }, { "pmid": "16840830", "text": "Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "We describe 2 families with MEN1 with novel mutations in the MEN1 gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "There was also a prolactinoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16840830", "text": "The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid.", "type": "CHEMICAL", "entities": [ "lysine", "glutamic acid" ], "offsets": [ [ 165, 171 ], [ 175, 188 ] ] }, { "pmid": "16840830", "text": "The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine.", "type": "CHEMICAL", "entities": [ "aspartic acid", "tyrosine" ], "offsets": [ [ 147, 160 ], [ 164, 172 ] ] }, { "pmid": "16840830", "text": "In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15736931", "text": "Mutation of arginine 228 to lysine enhances the glucosyltransferase activity of bovine beta-1,4-galactosyltransferase I.\nBeta-1,4-galactosyltransferase I (beta4Gal-T1) normally transfers Gal from UDP-Gal to GlcNAc in the presence of Mn(2+) ion (Gal-T activity) and also transfers Glc from UDP-Glc to GlcNAc (Glc-T activity), albeit at only 0.3% efficiency.", "type": "CHEMICAL", "entities": [ "Mn(2+)", "Gal", "Glc", "UDP-Glc", "GlcNAc", "Glc", "Gal", "UDP-Gal", "GlcNAc", "arginine", "lysine" ], "offsets": [ [ 233, 239 ], [ 245, 248 ], [ 280, 283 ], [ 289, 296 ], [ 300, 306 ], [ 308, 311 ], [ 187, 190 ], [ 196, 203 ], [ 207, 213 ], [ 12, 20 ], [ 28, 34 ] ] }, { "pmid": "15736931", "text": "In addition, alpha-lactalbumin (LA) enhances this Glc-T activity more than 25 times.", "type": "CHEMICAL", "entities": [ "Glc" ], "offsets": [ [ 50, 53 ] ] }, { "pmid": "15736931", "text": "Comparison of the crystal structures of UDP-Gal- and UDP-Glc-bound beta4Gal-T1 reveals that the O4 hydroxyl group in both Gal and Glc moieties forms a hydrogen bond with the side chain carboxylate group of Glu317.", "type": "CHEMICAL", "entities": [ "UDP-Gal", "UDP-Glc", "O4 hydroxyl", "Gal", "Glc", "hydrogen", "carboxylate" ], "offsets": [ [ 40, 47 ], [ 53, 60 ], [ 96, 107 ], [ 122, 125 ], [ 130, 133 ], [ 151, 159 ], [ 185, 196 ] ] }, { "pmid": "15736931", "text": "The orientation of the O4 hydroxyl of glucose causes a steric hindrance to the side chain carboxylate group of Glu317, accounting for the enzyme's low Glc-T activity.", "type": "CHEMICAL", "entities": [ "O4 hydroxyl of glucose", "carboxylate", "Glc" ], "offsets": [ [ 23, 45 ], [ 90, 101 ], [ 151, 154 ] ] }, { "pmid": "15736931", "text": "In this study, we show that mutation of Arg228, a residue in the vicinity of Glu317, to lysine (R228K-Gal-T1) results in a 15-fold higher Glc-T activity, which is further enhanced by LA to nearly 25% of the Gal-T activity of the wild type.", "type": "CHEMICAL", "entities": [ "lysine", "Gal", "Glc", "Gal" ], "offsets": [ [ 88, 94 ], [ 102, 105 ], [ 138, 141 ], [ 207, 210 ] ] }, { "pmid": "15736931", "text": "The kinetic parameters indicate that the main effect of the mutation of Arg228 to lysine is on the k(cat) of Glc-T, which increases 3-4-fold, both in the absence and in the presence of LA; simultaneously, the k(cat) for the Gal-T reaction is reduced 30-fold.", "type": "CHEMICAL", "entities": [ "lysine", "Glc", "Gal" ], "offsets": [ [ 82, 88 ], [ 109, 112 ], [ 224, 227 ] ] }, { "pmid": "15736931", "text": "The crystal structure of R228K-Gal-T1 complexed with LA, UDP-Gal, and Mn(2+) determined at 1.9 A resolution shows that the Asp318 side chain exhibits a minor alternate conformation, compared to that in the wild type.", "type": "CHEMICAL", "entities": [ "Gal", "UDP-Gal", "Mn(2+)" ], "offsets": [ [ 31, 34 ], [ 57, 64 ], [ 70, 76 ] ] }, { "pmid": "15736931", "text": "This alternate conformation now causes a steric hindrance to the O4 hydroxyl group of the Gal moiety of UDP-Gal, probably causing the dissociation of UDP-Gal and the reduced k(cat) of the Gal-T reaction.", "type": "CHEMICAL", "entities": [ "O4 hydroxyl", "Gal", "UDP-Gal", "UDP-Gal", "Gal" ], "offsets": [ [ 65, 76 ], [ 90, 93 ], [ 104, 111 ], [ 150, 157 ], [ 188, 191 ] ] }, { "pmid": "23414802", "text": "Discovery of novel 2-hydroxydiarylamide derivatives as TMPRSS4 inhibitors.\n", "type": "CHEMICAL", "entities": [ "2-hydroxydiarylamide" ], "offsets": [ [ 19, 39 ] ] }, { "pmid": "23414802", "text": "TMPRSS4 is a novel type II transmembrane serine protease that has been implicated in the invasion and metastasis of colon cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23414802", "text": "In this study, a novel series of 2-hydroxydiarylamide derivatives were synthesized and evaluated for inhibiting TMPRSS4 serine protease activity and suppressing cancer cell invasion.", "type": "CHEMICAL", "entities": [ "2-hydroxydiarylamide", "serine" ], "offsets": [ [ 33, 53 ], [ 120, 126 ] ] }, { "pmid": "23414802", "text": "These derivatives demonstrated good inhibitory activity against TMPRSS4 serine protease, which correlated with the promising anti-invasive activity of colon cancer cells overexpressing TMPRSS4.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 72, 78 ] ] }, { "pmid": "23578689", "text": "Conformationally restricted homotryptamines.", "type": "CHEMICAL", "entities": [ "homotryptamines" ], "offsets": [ [ 28, 43 ] ] }, { "pmid": "23578689", "text": "Part 6: Indole-5-cycloalkyl methylamines as selective serotonin reuptake inhibitors.\n", "type": "CHEMICAL", "entities": [ "Indole-5-cycloalkyl methylamines", "serotonin" ], "offsets": [ [ 8, 40 ], [ 54, 63 ] ] }, { "pmid": "23578689", "text": "Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors.", "type": "CHEMICAL", "entities": [ "Racemic 5-(trans-2-aminomethylcyclopropyl)indoles", "serotonin", "5-(trans-2-aminomethylcyclopentyl) indoles", "5-(cis-2-aminomethylcyclopentyl)indoles" ], "offsets": [ [ 0, 49 ], [ 183, 192 ], [ 51, 93 ], [ 99, 138 ] ] }, { "pmid": "23578689", "text": "These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles.", "type": "CHEMICAL", "entities": [ "3-cycloalkyl substituted indoles" ], "offsets": [ [ 75, 107 ] ] }, { "pmid": "23578689", "text": "The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "Beta1 adrenergic receptor-mediated enhancement of hippocampal CA3 network activity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain.", "type": "CHEMICAL", "entities": [ "Norepinephrine" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "15908512", "text": "In higher cortical structures such as the hippocampus, norepinephrine, via beta adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory.", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 55, 69 ] ] }, { "pmid": "15908512", "text": "In this study, we investigated the effect of beta1AR activation on hippocampal cornu ammonis 3 (CA3) network activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "AR expression was first determined using immunocytochemistry with antibodies against beta1ARs, which were found to be exceptionally dense in hippocampal CA3 pyramidal neurons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "CA3 network activity was then examined in vitro using field potential recordings in rat brain slices.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "The selective betaAR agonist isoproterenol caused an enhancement of hippocampal CA3 network activity, as measured by an increase in frequency of spontaneous burst discharges recorded in the CA3 region.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 29, 42 ] ] }, { "pmid": "15908512", "text": "In the presence of alphaAR blockade, concentration-response curves for isoproterenol, norepinephrine, and epinephrine suggested that a beta1AR was involved in this response, and the rank order of potency was isoproterenol > norepinephrine = epinephrine.", "type": "CHEMICAL", "entities": [ "isoproterenol", "norepinephrine", "epinephrine", "isoproterenol", "norepinephrine", "epinephrine" ], "offsets": [ [ 208, 221 ], [ 224, 238 ], [ 241, 252 ], [ 71, 84 ], [ 86, 100 ], [ 106, 117 ] ] }, { "pmid": "15908512", "text": "Finally, equilibrium dissociation constants (pK(b)) of subtype-selective betaAR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15908512", "text": "The selective beta1AR antagonists atenolol and metoprolol blocked isoproterenol-induced enhancement, with apparent K(b) values of 85 +/- 36 and 3.9 +/- 1.7 nM, respectively.", "type": "CHEMICAL", "entities": [ "atenolol", "metoprolol", "isoproterenol" ], "offsets": [ [ 34, 42 ], [ 47, 57 ], [ 66, 79 ] ] }, { "pmid": "15908512", "text": "In contrast, the selective beta2AR antagonists ICI-118,551 and butoxamine inhibited isoproterenol-mediated enhancement with apparent low affinities (K(b) of 222 +/- 61 and 9268 +/- 512 nM, respectively).", "type": "CHEMICAL", "entities": [ "ICI-118,551", "butoxamine", "isoproterenol" ], "offsets": [ [ 47, 58 ], [ 63, 73 ], [ 84, 97 ] ] }, { "pmid": "15908512", "text": "Together, this pharmacological profile of subtype-selective betaAR antagonists indicates that in this model, beta1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 206, 219 ] ] }, { "pmid": "14507899", "text": "P2Y(2) receptor agonist INS37217 enhances functional recovery after detachment caused by subretinal injection in normal and rds mice.\n", "type": "CHEMICAL", "entities": [ "INS37217" ], "offsets": [ [ 24, 32 ] ] }, { "pmid": "14507899", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "To evaluate the effects of INS37217 on the recovery of retinal function after experimental retinal detachment induced by subretinal injection.", "type": "CHEMICAL", "entities": [ "retinal", "INS37217", "retinal" ], "offsets": [ [ 91, 98 ], [ 27, 35 ], [ 55, 62 ] ] }, { "pmid": "14507899", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "Subretinal injections of 1 micro L of fluorescent microbeads, saline, or INS37217 (1-200 micro M) were made by the transvitreal method in normal (C57BL/6) mice and in mice heterozygous for the retinal degeneration slow (rds) gene.", "type": "CHEMICAL", "entities": [ "INS37217", "retinal" ], "offsets": [ [ 73, 81 ], [ 193, 200 ] ] }, { "pmid": "14507899", "text": "Control, mock-injected animals underwent corneal puncture without injection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "Histologic and ERG evaluations were made at 0 to 1 and 8 hours, and 1, 3, 7, 10, 14, and 60 days post injection (PI).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "DNA fragmentation was evaluated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL).", "type": "CHEMICAL", "entities": [ "deoxynucleotidyl", "uridine 5'-triphosphate-biotin" ], "offsets": [ [ 44, 60 ], [ 82, 112 ] ] }, { "pmid": "14507899", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "A single subretinal injection of saline solution containing fluorescent beads caused a histologically evident retinal detachment and distributed the microbeads to almost all the subretinal space.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "Spontaneous reattachment occurred within 24 hours after injection and was accompanied by evident retinal folding that appeared largely resolved by 6 days later.", "type": "CHEMICAL", "entities": [ "retinal" ], "offsets": [ [ 97, 104 ] ] }, { "pmid": "14507899", "text": "Relative to controls, injection of saline resulted in approximately 40% recovery of dark-adapted a-wave amplitude at 24 hours PI and gradually improved to approximately 90% of controls at 2 months PI.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "Subretinal injection of saline containing INS37217 (10 micro M) significantly increased rod and cone ERG of normal and rds(+/-) mice at 1 and 10 days PI, when compared with injection of saline alone.", "type": "CHEMICAL", "entities": [ "INS37217" ], "offsets": [ [ 42, 50 ] ] }, { "pmid": "14507899", "text": "Additionally, INS37217 reduced the number of TUNEL-positive photoreceptors and the enhanced rate of reattachment.", "type": "CHEMICAL", "entities": [ "INS37217" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "14507899", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507899", "text": "Enhancement of ERG recovery by INS37217 is likely due to reduced retinal folding and cell death associated with detachment.", "type": "CHEMICAL", "entities": [ "INS37217", "retinal" ], "offsets": [ [ 31, 39 ], [ 65, 72 ] ] }, { "pmid": "14507899", "text": "These results support the use of INS37217 to help restore function after therapies that involve subretinal administration of drugs in animal models of retinal diseases.", "type": "CHEMICAL", "entities": [ "INS37217", "retinal" ], "offsets": [ [ 33, 41 ], [ 151, 158 ] ] }, { "pmid": "12904467", "text": "Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons.\n", "type": "CHEMICAL", "entities": [ "kainate", "topiramate" ], "offsets": [ [ 30, 37 ], [ 77, 87 ] ] }, { "pmid": "12904467", "text": "Topiramate is a widely used antiepileptic agent whose mechanism of action is poorly understood.", "type": "CHEMICAL", "entities": [ "Topiramate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12904467", "text": "The drug has been reported to interact with various ion channel types, including AMPA/kainate receptors.", "type": "CHEMICAL", "entities": [ "AMPA", "kainate" ], "offsets": [ [ 81, 85 ], [ 86, 93 ] ] }, { "pmid": "12904467", "text": "In whole-cell voltage-clamp recordings from principal neurons of the rat basolateral amygdala, topiramate at low concentrations (IC50, approximately 0.5 microm) selectively inhibited pharmacologically isolated excitatory synaptic currents mediated by kainate receptors containing the GluR5 subunit.", "type": "CHEMICAL", "entities": [ "topiramate", "kainate" ], "offsets": [ [ 95, 105 ], [ 251, 258 ] ] }, { "pmid": "12904467", "text": "Topiramate also partially depressed predominantly AMPA-receptor-mediated EPSCs, but with lower efficacy.", "type": "CHEMICAL", "entities": [ "Topiramate", "AMPA" ], "offsets": [ [ 0, 10 ], [ 50, 54 ] ] }, { "pmid": "12904467", "text": "Topiramate did not alter the degree of facilitation in paired-pulse experiments, and it reduced the amplitude of miniature EPSCs without affecting their frequency, demonstrating that the block of synaptic responses occurs postsynaptically.", "type": "CHEMICAL", "entities": [ "Topiramate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12904467", "text": "Inhibition of GluR5 kainate receptors could represent a key mechanism underlying the anticonvulsant activity of topiramate.", "type": "CHEMICAL", "entities": [ "kainate", "topiramate" ], "offsets": [ [ 20, 27 ], [ 112, 122 ] ] }, { "pmid": "12904467", "text": "Moreover, these results support the concept that GluR5 kainate receptors represent a novel target for antiepileptic drug development.", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 55, 62 ] ] }, { "pmid": "23210783", "text": "From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23210783", "text": "The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23210783", "text": "In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23210783", "text": "Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example.", "type": "CHEMICAL", "entities": [ "Galanthamine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23210783", "text": "The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23210783", "text": "Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD.", "type": "CHEMICAL", "entities": [ "Galanthamine" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "10606746", "text": "Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.\n", "type": "CHEMICAL", "entities": [ "(-)-galanthamine" ], "offsets": [ [ 49, 65 ] ] }, { "pmid": "10606746", "text": "(-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity.", "type": "CHEMICAL", "entities": [ "(-)-Galanthamine", "GAL" ], "offsets": [ [ 0, 16 ], [ 18, 21 ] ] }, { "pmid": "10606746", "text": "This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10606746", "text": "We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10606746", "text": "The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290).", "type": "CHEMICAL", "entities": [ "choline", "Trp", "acyl", "Phe", "Phe" ], "offsets": [ [ 94, 101 ], [ 116, 119 ], [ 132, 136 ], [ 153, 156 ], [ 162, 165 ] ] }, { "pmid": "10606746", "text": "The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring.", "type": "CHEMICAL", "entities": [ "tertiary amine", "Trp", "cyclohexene", "indole" ], "offsets": [ [ 4, 18 ], [ 63, 66 ], [ 102, 113 ], [ 138, 144 ] ] }, { "pmid": "10606746", "text": "The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge.", "type": "CHEMICAL", "entities": [ "hydrogen", "N-methyl", "Asp" ], "offsets": [ [ 54, 62 ], [ 77, 85 ], [ 96, 99 ] ] }, { "pmid": "10606746", "text": "The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199.", "type": "CHEMICAL", "entities": [ "hydroxyl", "hydrogen", "Glu" ], "offsets": [ [ 4, 12 ], [ 51, 59 ], [ 78, 81 ] ] }, { "pmid": "10606746", "text": "The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16851960", "text": "Methyl transfer in glycine N-methyltransferase.", "type": "CHEMICAL", "entities": [ "Methyl", "glycine", "N" ], "offsets": [ [ 0, 6 ], [ 19, 26 ], [ 27, 28 ] ] }, { "pmid": "16851960", "text": "A theoretical study.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16851960", "text": "Density functional theory calculations using the hybrid functional B3LYP have been performed to study the methyl transfer step in glycine N-methyltransferase (GNMT).", "type": "CHEMICAL", "entities": [ "methyl", "glycine", "N" ], "offsets": [ [ 106, 112 ], [ 130, 137 ], [ 138, 139 ] ] }, { "pmid": "16851960", "text": "This enzyme catalyzes the S-adenosyl-L-methionine (SAM)-dependent methylation of glycine to form sarcosine.", "type": "CHEMICAL", "entities": [ "S-adenosyl-L-methionine", "SAM", "glycine", "sarcosine" ], "offsets": [ [ 26, 49 ], [ 51, 54 ], [ 81, 88 ], [ 97, 106 ] ] }, { "pmid": "16851960", "text": "The starting point for the calculations is the recent X-ray crystal structure of GNMT complexed with SAM and acetate.", "type": "CHEMICAL", "entities": [ "SAM" ], "offsets": [ [ 101, 104 ] ] }, { "pmid": "16851960", "text": "Several quantum chemical models with different sizes, employing up to 98 atoms, were used.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16851960", "text": "The calculations demonstrate that the suggested mechanism, where the methyl group is transferred in a single S(N)2 step, is thermodynamically plausible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16851960", "text": "By adding or eliminating various groups at the active site, it was furthermore demonstrated that hydrogen bonds to the amino group of the glycine substrate lower the reaction barrier, while hydrogen bonds to the carboxylate group raise the barrier.", "type": "CHEMICAL", "entities": [ "hydrogen", "amino", "glycine", "hydrogen", "carboxylate" ], "offsets": [ [ 97, 105 ], [ 119, 124 ], [ 138, 145 ], [ 190, 198 ], [ 212, 223 ] ] }, { "pmid": "23643542", "text": "Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "ETHNOPHARMACOLOGICAL RELEVANCE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Licorice (Glycyrrhiza uralensis Fisch., Leguminosae) has been used in herbal medicine and food supplement worldwide for centuries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Licorice is a common ingredient of several prescriptions of traditional Chinese medicine which have been proved to inhibit infection of human respiratory syncytial virus (HRSV).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "There are two preparations of licorice, Radix Glycyrrhizae and Radix Glycyrrhizae Preparata.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "However, it is unknown whether licorice or which preparation of licorice is effective against HRSV, nor is its active constituent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "AIM OF THE STUDY: We tested the hypothesis that Radix Glycyrrhizae can effectively decrease HRSV-induced plaque formation in respiratory mucosal cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "We also tried to find out the active constituent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "MATERIALS AND METHODS: Anti-HRSV activities of hot water extracts of preparations of licorice, glycyrrhizin and 18β-glycyrrhetinic acid (18β-GA), the active constituents of licorice, were examined by plaque reduction assay in both human upper (HEp-2) and low (A549) respiratory tract cell lines.", "type": "CHEMICAL", "entities": [ "glycyrrhizin", "18β-glycyrrhetinic acid", "18β-GA" ], "offsets": [ [ 95, 107 ], [ 112, 135 ], [ 137, 143 ] ] }, { "pmid": "23643542", "text": "Abilities of crude licorice to inhibit viral replication and to stimulate IFN-β were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Radix Glycyrrhizae and Radix Glycyrrhizae Preparata dose-dependently inhibited HRSV-induced plaque formation in both HEp-2 and A549 cell lines (p<0.0001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "The effect of Radix Glycyrrhizae was better than that of Radix Glycyrrhizae Preparata on HEp-2 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "However, there was no difference of their anti-HRSV effects on A549 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Besides, glycyrrhizin was ineffective at all.", "type": "CHEMICAL", "entities": [ "glycyrrhizin" ], "offsets": [ [ 6, 18 ] ] }, { "pmid": "23643542", "text": "Nevertheless, 18β-GA showed a potent anti-HRSV activity.", "type": "CHEMICAL", "entities": [ "18β-GA" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "23643542", "text": "Radix Glycyrrhizae was more effective when given before viral inoculation (p<0.0001) which may be due to its inhibition of viral attachment on (p<0.0001) and penetration (p<0.0001) into the host cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "The anti-HRSV activity of Radix Glycyrrhizae was further confirmed by RT-PCR and qRT-PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "300μg/ml Radix Glycyrrhizae markedly decreased the viral amounts within the cells and in the suspension.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Radix Glycyrrhizae might further stimulate mucosal cells to secrete IFN-β to counteract viral infection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "CONCLUSIONS: Both Radix Glycyrrhizae and Radix Glycyrrhizae Preparata are effective against HRSV infection on airway epithelial cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "Radix Glycyrrhizae inhibited HRSV mainly by preventing viral attachment, internalization, and by stimulating IFN secretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643542", "text": "18β-GA may be one of its active constituents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "Parental exposure to natural mixtures of POPs reduced embryo production and altered gene transcription in zebrafish embryos.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "Determination of toxicity of complex mixtures has been proposed to be one of the most important challenges for modern toxicology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "In this study we performed genome wide transcriptome profiling to assess potential toxicant induced changes in gene regulation in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POPs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "The mixtures used were extracted from burbot (Lota lota) liver originating from two lakes (Lake Mjøsa and Lake Losna) belonging to the same freshwater system in Norway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "The dominating groups of contaminants were polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane metabolites (DDTs).", "type": "CHEMICAL", "entities": [ "polybrominated diphenyl ethers", "PBDEs", "polychlorinated biphenyls", "PCBs", "dichlorodiphenyltrichloroethane" ], "offsets": [ [ 42, 72 ], [ 74, 79 ], [ 82, 107 ], [ 109, 113 ], [ 119, 150 ] ] }, { "pmid": "23063069", "text": "Because both mixtures used in the present study induced similar effects, it is likely that the same toxicants are involved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "The Mjøsa mixture contains high levels of PBDEs while this group of pollutants is low in the Losna mixture.", "type": "CHEMICAL", "entities": [ "PBDEs" ], "offsets": [ [ 41, 46 ] ] }, { "pmid": "23063069", "text": "However, both mixtures contain substantial concentrations of PCB and DDT suggesting these contaminants as the predominant contributors to the toxicity observed.", "type": "CHEMICAL", "entities": [ "PCB", "DDT" ], "offsets": [ [ 59, 62 ], [ 67, 70 ] ] }, { "pmid": "23063069", "text": "The observed effects included phenotypic traits, like embryo production and survival, and gene transcription changes corresponding with disease and biological functions such as cancer, reproductive system disease, cardiovascular disease, lipid and protein metabolism, small molecule biochemistry and cell cycle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "The changes in gene transcription included genes regulated by HNF4A, insulin, LH, FSH and NF-κB which are known to be central regulators of endocrine signaling, metabolism, metabolic homeostasis, immune functions, cancer development and reproduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063069", "text": "The results suggest that relative low concentrations of the natural mixtures of POPs used in the present study might pose a threat to wild freshwater fish living in the lakes from which the POPs mixtures originated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511858", "text": "Complexities of androgen action.\n", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "11511858", "text": "Androgens mediate a wide range of processes during embryogenesis and in the adult.", "type": "CHEMICAL", "entities": [ "Androgens" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11511858", "text": "In mammals, the principal androgens are testosterone and its 5alpha-reduced metabolite, 5alpha-dihydrotestosterone (DHT).", "type": "CHEMICAL", "entities": [ "androgens", "testosterone", "5alpha-dihydrotestosterone", "DHT" ], "offsets": [ [ 26, 35 ], [ 40, 52 ], [ 88, 114 ], [ 116, 119 ] ] }, { "pmid": "11511858", "text": "Although these androgenic hormones are diverse in character, it is believed that their effects are mediated via the protein products of a single androgen receptor gene encoded on the X-chromosome.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 145, 153 ] ] }, { "pmid": "11511858", "text": "A great deal of information has now accumulated pertaining to the mechanisms by which nuclear receptors, such as the androgen receptor, modulate the activity of responsive genes.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 117, 125 ] ] }, { "pmid": "11511858", "text": "The studies have demonstrated the participation of a number of ancillary proteins in modulating activation or repression by nuclear receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511858", "text": "In addition to studies focused on the mechanisms of nuclear receptor function, additional work has illuminated the mechanism by which androgens are metabolized in selected tissues.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 134, 143 ] ] }, { "pmid": "11511858", "text": "This information provides a perspective on the number of levels of complexity by which differential gene regulation by androgens may occur in different tissues and in different cell types.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 119, 128 ] ] }, { "pmid": "23207409", "text": "Combining QSAR classification models for predictive modeling of human monoamine oxidase inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc.", "type": "CHEMICAL", "entities": [ "chromones", "coumarins", "chalcones", "thiazolylhydrazones" ], "offsets": [ [ 94, 103 ], [ 105, 114 ], [ 116, 125 ], [ 127, 146 ] ] }, { "pmid": "23207409", "text": "These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "This work also showed how several QSAR models can be combined to make better predictions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207409", "text": "The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature.", "type": "CHEMICAL", "entities": [ "coumarins" ], "offsets": [ [ 266, 275 ] ] }, { "pmid": "16434489", "text": "Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis.\n", "type": "CHEMICAL", "entities": [ "Dasatinib", "BMS-354825", "imatinib" ], "offsets": [ [ 0, 9 ], [ 11, 21 ], [ 45, 53 ] ] }, { "pmid": "16434489", "text": "Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16434489", "text": "This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML).", "type": "CHEMICAL", "entities": [ "imatinib", "Dasatinib", "BMS-354825", "imatinib" ], "offsets": [ [ 41, 49 ], [ 160, 169 ], [ 171, 181 ], [ 267, 275 ] ] }, { "pmid": "16434489", "text": "Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "16434489", "text": "In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "16434489", "text": "Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "16434489", "text": "Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "16434489", "text": "Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib.", "type": "CHEMICAL", "entities": [ "imatinib", "dasatinib" ], "offsets": [ [ 129, 137 ], [ 197, 206 ] ] }, { "pmid": "16434489", "text": "Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "16434489", "text": "Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23411259", "text": "A water-alcohol extract of Citrus grandis whole fruits has beneficial metabolic effects in the obese Zucker rats fed with high fat/high cholesterol diet.\n", "type": "CHEMICAL", "entities": [ "cholesterol", "alcohol" ], "offsets": [ [ 136, 147 ], [ 8, 15 ] ] }, { "pmid": "23411259", "text": "Epidemiological studies suggest that citrus fruits and compounds such as flavonoids, limonoids and pectins have health promoting effects.", "type": "CHEMICAL", "entities": [ "flavonoids" ], "offsets": [ [ 73, 83 ] ] }, { "pmid": "23411259", "text": "Our aim was to study the effects of Citrus grandis (L.)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "Osbeck var.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "tomentosa hort.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "fruit extract on the energy metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "A whole fruit powder from dry water and alcohol extracts of C. grandis containing 19% naringin flavonoid was prepared.", "type": "CHEMICAL", "entities": [ "alcohol", "naringin" ], "offsets": [ [ 40, 47 ], [ 86, 94 ] ] }, { "pmid": "23411259", "text": "The effects of the citrus extract were followed in the obese Zucker rats fed with the HFD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "The circulatory levels of GLP-1 decreased significantly by the extract in comparison to the HFD group, whereas the decreased ghrelin levels were reversed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "The levels of PYY were decreased in all HFD groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "The leptin amounts decreased but not significantly whereas insulin and amylin were unchanged.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411259", "text": "The cholesterol and glucose levels were somewhat but not systematically improved in the HFD fed rats.", "type": "CHEMICAL", "entities": [ "cholesterol", "glucose" ], "offsets": [ [ 4, 15 ], [ 20, 27 ] ] }, { "pmid": "23411259", "text": "Further studies are needed to identify the active compounds and their mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12110374", "text": "Dopamine D(2) receptor-induced COX-2-mediated production of prostaglandin E(2) in D(2)-transfected Chinese hamster ovary cells without simultaneous administration of a Ca(2+)-mobilizing agent.\n", "type": "CHEMICAL", "entities": [ "Dopamine", "Ca(2+)", "prostaglandin E(2)" ], "offsets": [ [ 0, 8 ], [ 168, 174 ], [ 60, 78 ] ] }, { "pmid": "12110374", "text": "We have earlier demonstrated that dopamine stimulates the liberation of the prostaglandin E(2)", "type": "CHEMICAL", "entities": [ "prostaglandin E(2)" ], "offsets": [ [ 76, 94 ] ] }, { "pmid": "12110374", "text": "(PGE(2)) precursor, arachidonic acid, in Chinese hamster ovary cells transfected with the rat dopamine D(2) receptor (long isoform), also without concomitant administration of a Ca(2+)-releasing agent [Nilsson et al., Br J Pharmacol 1998;124:1651-8].", "type": "CHEMICAL", "entities": [ "arachidonic acid", "dopamine", "Ca(2+)", "PGE(2)" ], "offsets": [ [ 20, 36 ], [ 94, 102 ], [ 178, 184 ], [ 1, 7 ] ] }, { "pmid": "12110374", "text": "In the present report, we show that dopamine, under the same conditions, also induces a concentration-dependent increase in the production of PGE(2), with a maximal effect of 235% at approximately 100 microM, and with an EC(50) of 794 nM. The effect was counteracted by the D(2) antagonist eticlopride, pertussis toxin, the inhibitor of intracellular Ca(2+) release TMB-8, incubation in Ca(2+)-free experimental medium, and PKC desensitization obtained by chronic pretreatment with the phorbol ester TPA.", "type": "CHEMICAL", "entities": [ "dopamine", "PGE(2)", "eticlopride", "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 36, 44 ], [ 142, 148 ], [ 290, 301 ], [ 351, 357 ], [ 387, 393 ] ] }, { "pmid": "12110374", "text": "It was also antagonized by the non-specific cyclooxygenase (COX) inhibitor, indomethacin, and by the selective COX-2 inhibitor, NS-398, but not by the specific COX-1 inhibitor, valeryl salicylate.", "type": "CHEMICAL", "entities": [ "valeryl salicylate", "indomethacin", "NS-398" ], "offsets": [ [ 177, 195 ], [ 76, 88 ], [ 128, 134 ] ] }, { "pmid": "12110374", "text": "Both the non-specific phospholipase A(2) inhibitor, quinacrine, and an inhibitor of cPLA(2) and iPLA(2), AACOF3, counteracted the effect; in contrast, a selective iPLA(2) inhibitor, BEL, and a selective sPLA(2) inhibitor, TAPC, were ineffective.", "type": "CHEMICAL", "entities": [ "quinacrine" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "12110374", "text": "No effects of dopamine were obtained in control cells mock-transfected with the p3C vector only.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "12110374", "text": "The results reinforce previous assumptions that dopamine may interact with eicosanoid metabolism by means of D(2) receptor activation, and implicate an involvement of cPLA(2) and COX-2 in this effect.", "type": "CHEMICAL", "entities": [ "dopamine", "eicosanoid" ], "offsets": [ [ 48, 56 ], [ 75, 85 ] ] }, { "pmid": "12110374", "text": "It is suggested that measurement of dopamine-induced PGE(2) production may serve as a convenient way to study D(2) receptor function in vitro.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 36, 44 ] ] }, { "pmid": "23551063", "text": "A high throughput assay for the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin by recombinant human UDP-glucuronosyltransferases and liver microsomes.\n", "type": "CHEMICAL", "entities": [ "UDP", "7-hydroxy-4-trifluoromethylcoumarin" ], "offsets": [ [ 108, 111 ], [ 51, 86 ] ] }, { "pmid": "23551063", "text": "Abstract 1.  UDP-glucuronosyltransferases (UGTs) are versatile and important conjugation enzymes in the metabolism of drugs and other xenobiotics.", "type": "CHEMICAL", "entities": [ "UDP" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23551063", "text": "2. ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551063", "text": "We have developed a convenient quantitative multi-well plate assay to measure the glucuronidation rate of 7-hydroxy-4-trifluoromethylcoumarin (HFC) for several UGTs.", "type": "CHEMICAL", "entities": [ "7-hydroxy-4-trifluoromethylcoumarin", "HFC" ], "offsets": [ [ 102, 137 ], [ 139, 142 ] ] }, { "pmid": "23551063", "text": "3. ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551063", "text": "We have used this method to screen 11 recombinant human UGTs for HFC glucuronidation activity and studied the reaction kinetics with the most active enzymes.", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 59, 62 ] ] }, { "pmid": "23551063", "text": "We have also examined the HFC glucuronidation activity of liver microsomes from human, pig, rabbit and rat. 4. ", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 20, 23 ] ] }, { "pmid": "23551063", "text": "At a substrate concentration of 20 µM, the most active HFC glucuronidation catalysts were UGT1A10 followed by UGT1A6 >UGT1A7 >UGT2A1, whereas at 300 µM UGT1A6 was about 10 times better catalyst than the other recombinant UGTs.", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23551063", "text": "The activities of UGTs 1A3, 1A8, 1A9, 2B4 and 2B7 were low, whereas UGT1A1 and UGT2B17 exhibited no HFC glucuronidation activity.", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 86, 89 ] ] }, { "pmid": "23551063", "text": "UGT1A6 exhibited a significantly higher Vmax and Km values toward both HFC and UDP-glucuronic acid than the other UGTs.", "type": "CHEMICAL", "entities": [ "HFC", "UDP", "glucuronic acid" ], "offsets": [ [ 57, 60 ], [ 65, 68 ], [ 69, 84 ] ] }, { "pmid": "23551063", "text": "5.  Human, pig and rabbit, but not rat liver microsomes, catalyzed HFC glucuronidation at high rates.", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 53, 56 ] ] }, { "pmid": "23551063", "text": "6. ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551063", "text": "This new method is particularly suitable for fast activity screenings of UGTs 1A6, 1A7, 1A10 and 2A1 and HFC glucuronidation activity determination from various samples.", "type": "CHEMICAL", "entities": [ "HFC" ], "offsets": [ [ 87, 90 ] ] }, { "pmid": "23474889", "text": "Influence of the novel histamine H3 receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice.\n", "type": "CHEMICAL", "entities": [ "ethanol", "histamine", "alcohol" ], "offsets": [ [ 100, 107 ], [ 23, 32 ], [ 76, 83 ] ] }, { "pmid": "23474889", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "Growing evidence supports a role for the central histaminergic system to have a modulatory influence on drug addiction in general and alcohol-use disorders in particular through histamine H3 receptors (H3R).", "type": "CHEMICAL", "entities": [ "alcohol", "histamine" ], "offsets": [ [ 134, 141 ], [ 178, 187 ] ] }, { "pmid": "23474889", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "In the present study, the effects of systemic injection of the newly synthesized H3R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated.", "type": "CHEMICAL", "entities": [ "ethanol", "EtOH", "EtOH" ], "offsets": [ [ 106, 113 ], [ 115, 119 ], [ 142, 146 ] ] }, { "pmid": "23474889", "text": "METHODS: Oral EtOH, saccharin, and quinine intake was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol or tastant solutions.", "type": "CHEMICAL", "entities": [ "EtOH", "saccharin", "quinine", "alcohol" ], "offsets": [ [ 14, 18 ], [ 20, 29 ], [ 35, 42 ], [ 130, 137 ] ] }, { "pmid": "23474889", "text": "EtOH-induced place preference (CPP), EtOH-induced locomotor activity, and blood ethanol concentration (BEC) were also measured.", "type": "CHEMICAL", "entities": [ "EtOH", "EtOH", "ethanol" ], "offsets": [ [ 0, 4 ], [ 37, 41 ], [ 80, 87 ] ] }, { "pmid": "23474889", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "Following administration of the H3R antagonist (2.5, 5, and 10 mg/kg, i.p.), there was a significant dose-dependent decrease in alcohol consumption and preference.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 128, 135 ] ] }, { "pmid": "23474889", "text": "Importantly, vehicle- and ST1283 (5 mg/kg)-treated mice showed similar consumption and preference to increasing concentration of both sweet and bitter tastes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "More interestingly, systemic administration of ST1283 inhibited EtOH-CPP and EtOH-enhanced locomotion.", "type": "CHEMICAL", "entities": [ "EtOH", "EtOH" ], "offsets": [ [ 62, 66 ], [ 75, 79 ] ] }, { "pmid": "23474889", "text": "This inhibition was blocked when mice were pretreated with the selective H3R agonist R-(alpha)-methyl-histamine (10 mg/kg).", "type": "CHEMICAL", "entities": [ "R-(alpha)-methyl-histamine" ], "offsets": [ [ 83, 109 ] ] }, { "pmid": "23474889", "text": "Finally, vehicle- and ST1283-treated mice had similar BECs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474889", "text": "Our results show that ST1283 may decrease voluntary EtOH consumption and EtOH-CPP by altering its reinforcing effects, suggesting a novel role for histamine signaling in regulation of alcoholism.", "type": "CHEMICAL", "entities": [ "EtOH", "EtOH", "histamine" ], "offsets": [ [ 49, 53 ], [ 70, 74 ], [ 144, 153 ] ] }, { "pmid": "23474889", "text": "Lastly, the results add to the growing literature on H3R modulation in the pharmacotherapy of EtOH addiction.", "type": "CHEMICAL", "entities": [ "EtOH" ], "offsets": [ [ 91, 95 ] ] }, { "pmid": "14501155", "text": "The tricyclic antidepressant clomipramine increases plasma glucose levels of mice.\n", "type": "CHEMICAL", "entities": [ "clomipramine", "tricyclic", "glucose" ], "offsets": [ [ 29, 41 ], [ 4, 13 ], [ 59, 66 ] ] }, { "pmid": "14501155", "text": "Effects of the tricyclic antidepressant clomipramine on plasma glucose levels in mice were studied.", "type": "CHEMICAL", "entities": [ "tricyclic", "clomipramine", "glucose" ], "offsets": [ [ 15, 24 ], [ 40, 52 ], [ 63, 70 ] ] }, { "pmid": "14501155", "text": "Clomipramine at doses ranging 5 - 20 mg/kg elicited significant hyperglycemia in mice.", "type": "CHEMICAL", "entities": [ "Clomipramine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14501155", "text": "Hyperglycemia elicited by clomipramine was not reduced by pretreatment with the 5-hydroxytryptamine (5-HT) depleter p-chlorophenylalanine.", "type": "CHEMICAL", "entities": [ "clomipramine", "5-hydroxytryptamine", "5-HT", "p-chlorophenylalanine" ], "offsets": [ [ 26, 38 ], [ 80, 99 ], [ 101, 105 ], [ 116, 137 ] ] }, { "pmid": "14501155", "text": "The 5-HT(1/2/5/7)-receptor antagonist methysergide and the 5-HT(2A/2B/2C)-receptor antagonist LY 53857 enhanced clomipramine-induced hyperglycemia, while the 5-HT(1A/1B)-receptor antagonist (-)-propranolol and the 5-HT(3/4)-receptor antagonist tropisetron did not affect it.", "type": "CHEMICAL", "entities": [ "LY 53857", "clomipramine", "(-)-propranolol", "tropisetron" ], "offsets": [ [ 94, 102 ], [ 112, 124 ], [ 190, 205 ], [ 244, 255 ] ] }, { "pmid": "14501155", "text": "The 5-HT(2B/2C)-receptor antagonist SB 206553 facilitated hyperglycemia induced by clomipramine, although the 5-HT(2A)-receptor antagonist ketanserin was without effect.", "type": "CHEMICAL", "entities": [ "SB 206553", "clomipramine", "ketanserin" ], "offsets": [ [ 36, 45 ], [ 83, 95 ], [ 139, 149 ] ] }, { "pmid": "14501155", "text": "Clomipramine-induced hyperglycemia was reduced by prior adrenalectomy.", "type": "CHEMICAL", "entities": [ "Clomipramine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14501155", "text": "These results suggest that clomipramine induces hyperglycemia in mice by blocking the 5-HT(2B )and/or 5-HT(2C) receptors, which results in facilitation of adrenaline release.", "type": "CHEMICAL", "entities": [ "clomipramine", "adrenaline" ], "offsets": [ [ 27, 39 ], [ 155, 165 ] ] }, { "pmid": "23307557", "text": "p300-mediated acetylation of TRF2 is required for maintaining functional telomeres.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23307557", "text": "The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23307557", "text": "Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly(ADP-ribosyl)ation have been shown to play important roles in telomere function.", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 116, 119 ] ] }, { "pmid": "23307557", "text": "Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 116, 122 ] ] }, { "pmid": "23307557", "text": "We also report that p300-mediated acetylation stabilizes the TRF2 protein by inhibiting its ubiquitin-dependent proteolysis and is required for efficient telomere binding of TRF2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23307557", "text": "Furthermore, overexpression of the acetylation-deficient mutant, K293R, induces DNA-damage response foci at telomeres, thereby leading to induction of impaired cell growth, cellular senescence and altered cell cycle distribution.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23307557", "text": "A small but significant number of metaphase chromosomes show no telomeric signals at chromatid ends, suggesting an aberrant telomere structure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23307557", "text": "These findings demonstrate that acetylation of TRF2 by p300 plays a crucial role in the maintenance of functional telomeres as well as in the regulation of the telomere-associated DNA-damage response, thus providing a new route for modulating telomere protection function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14984733", "text": "Externalization of phosphatidylserine during apoptosis does not specifically require either isoform of phosphatidylserine synthase.\n", "type": "CHEMICAL", "entities": [ "phosphatidylserine", "phosphatidylserine" ], "offsets": [ [ 103, 121 ], [ 19, 37 ] ] }, { "pmid": "14984733", "text": "Phosphatidylserine (PtdSer) is made in mammalian cells by two PtdSer synthases, PSS1 and PSS2.", "type": "CHEMICAL", "entities": [ "Phosphatidylserine", "PtdSer", "PtdSer" ], "offsets": [ [ 0, 18 ], [ 20, 26 ], [ 62, 68 ] ] }, { "pmid": "14984733", "text": "In the plasma membrane PtdSer is normally localized on the inner leaflet but undergoes transbilayer movement during apoptosis and becomes exposed on the cell surface.", "type": "CHEMICAL", "entities": [ "PtdSer" ], "offsets": [ [ 23, 29 ] ] }, { "pmid": "14984733", "text": "We induced apoptosis with staurosporine in four Chinese hamster ovary (CHO) cell lines that are deficient in PSS1 and/or", "type": "CHEMICAL", "entities": [ "staurosporine" ], "offsets": [ [ 26, 39 ] ] }, { "pmid": "14984733", "text": "PSS2 to determine if PtdSer generated by either of these enzymes is required for externalization on the cell surface during apoptosis.", "type": "CHEMICAL", "entities": [ "PtdSer" ], "offsets": [ [ 21, 27 ] ] }, { "pmid": "14984733", "text": "The onset of apoptosis was confirmed by the appearance of morphological changes and DNA fragmentation while the plasma membrane remained largely intact.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14984733", "text": "In all cell lines, regardless of their content of PSS1 and/or PSS2, apoptosis occurred to approximately the same extent, and within approximately the same time frame, as in parental CHO-K1 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14984733", "text": "The exposure of PtdSer on the cell surface was assessed by annexin V labeling and flow cytometry.", "type": "CHEMICAL", "entities": [ "PtdSer" ], "offsets": [ [ 16, 22 ] ] }, { "pmid": "14984733", "text": "Cells that were deficient in either PSS1 or PSS2, as well as cells that were deficient in both PSS1 and PSS2, externalized normal amounts of PtdSer.", "type": "CHEMICAL", "entities": [ "PtdSer" ], "offsets": [ [ 141, 147 ] ] }, { "pmid": "14984733", "text": "Our study demonstrates, that reduction of in vitro serine-exchange activity, even by 97%, does not restrict the externalization of PtdSer during apoptosis.", "type": "CHEMICAL", "entities": [ "serine", "PtdSer" ], "offsets": [ [ 51, 57 ], [ 131, 137 ] ] }, { "pmid": "14984733", "text": "Moreover, a normal level of expression of PSS1 and/or PSS2 is not required for generating the pool of PtdSer externalized during apoptosis.", "type": "CHEMICAL", "entities": [ "PtdSer" ], "offsets": [ [ 102, 108 ] ] }, { "pmid": "15126366", "text": "Characterization of the interaction of ingenol 3-angelate with protein kinase C.\nIngenol 3-angelate (I3A) is one of the active ingredients in Euphorbia peplus, which has been used in traditional medicine.", "type": "CHEMICAL", "entities": [ "Ingenol 3-angelate", "I3A", "ingenol 3-angelate" ], "offsets": [ [ 81, 99 ], [ 101, 104 ], [ 39, 57 ] ] }, { "pmid": "15126366", "text": "Here, we report the initial characterization of I3A as a protein kinase C (PKC) ligand.", "type": "CHEMICAL", "entities": [ "I3A" ], "offsets": [ [ 48, 51 ] ] }, { "pmid": "15126366", "text": "I3A bound to PKC-alpha in the presence of phosphatidylserine with high affinity; however, under these assay conditions, little PKC isoform selectivity was observed.", "type": "CHEMICAL", "entities": [ "I3A", "phosphatidylserine" ], "offsets": [ [ 0, 3 ], [ 42, 60 ] ] }, { "pmid": "15126366", "text": "PKC isoforms did show different sensitivity and selectivity for down-regulation by I3A and phorbol 12-myristate 13-acetate (PMA) in WEHI-231, HOP-92, and Colo-205 cells.", "type": "CHEMICAL", "entities": [ "I3A", "phorbol 12-myristate 13-acetate", "PMA" ], "offsets": [ [ 83, 86 ], [ 91, 122 ], [ 124, 127 ] ] }, { "pmid": "15126366", "text": "In all of the three cell types, I3A inhibited cell proliferation with somewhat lower potency than did PMA.", "type": "CHEMICAL", "entities": [ "I3A", "PMA" ], "offsets": [ [ 32, 35 ], [ 102, 105 ] ] }, { "pmid": "15126366", "text": "In intact CHO-K1 cells, I3A was able to translocate different green fluorescent protein-tagged PKC isoforms, visualized by confocal microscopy, with equal or higher potency than PMA.", "type": "CHEMICAL", "entities": [ "I3A", "PMA" ], "offsets": [ [ 24, 27 ], [ 178, 181 ] ] }, { "pmid": "15126366", "text": "PKC-delta in particular showed a different pattern of translocation in response to I3A and PMA.", "type": "CHEMICAL", "entities": [ "I3A", "PMA" ], "offsets": [ [ 83, 86 ], [ 91, 94 ] ] }, { "pmid": "15126366", "text": "I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction.", "type": "CHEMICAL", "entities": [ "PMA", "I3A" ], "offsets": [ [ 97, 100 ], [ 0, 3 ] ] }, { "pmid": "15126366", "text": "I3A was unable to cause the same extent of association of the C1b domain of PKC-delta with lipids, compared with PMA or the physiological regulator diacylglycerol, and was able to partially block the association induced by these agents, measured by surface plasmon resonance.", "type": "CHEMICAL", "entities": [ "I3A", "PMA", "diacylglycerol" ], "offsets": [ [ 0, 3 ], [ 113, 116 ], [ 148, 162 ] ] }, { "pmid": "15126366", "text": "The in vitro kinase activity of PKC-alpha induced by I3A was lower than that induced by PMA.", "type": "CHEMICAL", "entities": [ "I3A", "PMA" ], "offsets": [ [ 53, 56 ], [ 88, 91 ] ] }, { "pmid": "15126366", "text": "The novel pattern of behavior of I3A makes it of great interest for further evaluation.", "type": "CHEMICAL", "entities": [ "I3A" ], "offsets": [ [ 33, 36 ] ] }, { "pmid": "23629516", "text": "In ovo effects of two organophosphate flame retardants, TCPP and TDCPP, on pipping success, development, mRNA expression and thyroid hormone levels in chicken embryos.\n", "type": "CHEMICAL", "entities": [ "organophosphate", "TCPP", "TDCPP" ], "offsets": [ [ 22, 37 ], [ 56, 60 ], [ 65, 70 ] ] }, { "pmid": "23629516", "text": "Tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are organic flame retardants detected in the environment and biota for which toxicological data for avian species are limited.", "type": "CHEMICAL", "entities": [ "Tris(1-chloro-2-propyl) phosphate", "TCPP", "tris(1,3-dichloro-2-propyl) phosphate", "TDCPP" ], "offsets": [ [ 0, 33 ], [ 35, 39 ], [ 45, 82 ], [ 84, 89 ] ] }, { "pmid": "23629516", "text": "In this study, domestic chicken eggs were injected with TCPP or TDCPP (maximum dose = 51600 and 45000 ng/g egg, respectively) to determine dose-dependent effects on pipping success, development, hepatic messenger RNA (mRNA) expression levels of genes associated with xenobiotic metabolism and the thyroid hormone (TH) pathway, and TH levels following 20-22 days of incubation.", "type": "CHEMICAL", "entities": [ "TCPP", "TDCPP" ], "offsets": [ [ 56, 60 ], [ 64, 69 ] ] }, { "pmid": "23629516", "text": "Neither compound reduced pipping success; however, TCPP significantly delayed pipping at 9240 and 51600 ng/g and reduced tarsus length at 51600 ng/g. TDCPP exposure resulted in significant decreases in head plus bill length, embryo mass and gallbladder size at 45000 ng/g and reduced plasma free T4 levels at 7640 ng/g. Type I deiodinase, liver fatty-acid binding protein and cytochrome P450 (CYP)", "type": "CHEMICAL", "entities": [ "TCPP", "TDCPP" ], "offsets": [ [ 51, 55 ], [ 150, 155 ] ] }, { "pmid": "23629516", "text": "3A37 mRNA levels were significantly induced by TCPP, while TDCPP induced CYP3A37 and CYP2H1.", "type": "CHEMICAL", "entities": [ "TCPP", "TDCPP" ], "offsets": [ [ 47, 51 ], [ 59, 64 ] ] }, { "pmid": "23629516", "text": "Chemical analysis of egg contents at incubation days 0, 5, 11, 18, and 19 revealed that >92% of the injected TCPP or TDCPP concentration was detectable up to day 5; however, <1% was detected by day 19.", "type": "CHEMICAL", "entities": [ "TCPP", "TDCPP" ], "offsets": [ [ 109, 113 ], [ 117, 122 ] ] }, { "pmid": "23629516", "text": "The observed phenotypic responses to TCPP and TDCPP exposure may be associated with disruption of the TH-axis, which is critical for normal growth and development in birds.", "type": "CHEMICAL", "entities": [ "TCPP", "TDCPP" ], "offsets": [ [ 37, 41 ], [ 46, 51 ] ] }, { "pmid": "23629516", "text": "The effects of TDCPP on the gallbladder indicate that the disturbance of lipid metabolism is a likely target in its mechanism of toxicity.", "type": "CHEMICAL", "entities": [ "TDCPP" ], "offsets": [ [ 15, 20 ] ] }, { "pmid": "23188819", "text": "Insulin-degrading enzyme (IDE): a novel heat shock-like protein.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23188819", "text": "Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase that is ubiquitously distributed in human tissues, and particularly abundant in the brain, liver, and muscles.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "23188819", "text": "IDE activity has been historically associated with insulin and β-amyloid catabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23188819", "text": "However, over the last decade, several experimental findings have established that IDE is also involved in a wide variety of physiopathological processes, including ubiquitin clearance and Varicella Zoster Virus infection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23188819", "text": "In this study, we demonstrate that normal and malignant cells exposed to different stresses markedly up-regulate IDE in a heat shock protein (HSP)-like fashion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23188819", "text": "Additionally, we focused our attention on tumor cells and report that (i) IDE is overexpressed in vivo in tumors of the central nervous system (CNS); (ii) IDE-silencing inhibits neuroblastoma (SHSY5Y) cell proliferation and triggers cell death; (iii) IDE inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23188819", "text": "In this work, we propose a novel role for IDE as a heat shock protein with implications in cell growth regulation and cancer progression, thus opening up an intriguing hypothesis of IDE as an anticancer target.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "Development of a cell-based high-throughput peroxisome proliferator-activated receptors (PPARs) screening model and its application for evaluation of the extracts from Rhizoma Coptis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "To date, peroxisome proliferator-activated receptors (PPARs) are becoming the new therapeutic targets for the treatment of metabolic diseases, such as Type 2 diabetes, obesity, and cardiovascular disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "In this study, a cell-based high-throughput PPARs (PPARα/β/γ) model was developed for the screening of PPARs agonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "The screening conditions were evaluated through analyzing the expression value of luciferase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "Finally, 24 h of drug acting time, 5 times of the dilution factor of luciferase zymolyte, and about 2 × 10(4) cells/ well on HeLa cells in 96-well plates were used, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "Furthermore, the quality of high-throughput screening (HTS) in stability and reliability was evaluated by the Z'-factor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418674", "text": "Additionally, different extracts of Rhizoma Coptis and berberine were tested by the developed method.", "type": "CHEMICAL", "entities": [ "berberine" ], "offsets": [ [ 48, 57 ] ] }, { "pmid": "23418674", "text": "The results suggested that both the EtOAc extract and berberine were able to activate PPARα/β/γ, and Rhizoma Coptis contains potential natural agonists of PPARs besides berberine.", "type": "CHEMICAL", "entities": [ "EtOAc", "berberine", "berberine" ], "offsets": [ [ 29, 34 ], [ 47, 56 ], [ 162, 171 ] ] }, { "pmid": "23418674", "text": "In conclusion, the developed HTS assay is a simple, rapid, stable, and specific method for the screening of PPARs natural agonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23347684", "text": "Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH₄-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity.\n", "type": "CHEMICAL", "entities": [ "2-(4-chloro-2-cyano-2-phenylbutyl)aziridines", "2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes", "LiAlH₄" ], "offsets": [ [ 108, 152 ], [ 13, 63 ], [ 68, 74 ] ] }, { "pmid": "23347684", "text": "2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol.", "type": "CHEMICAL", "entities": [ "endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes", "azaheterobicyclic", "LiAlH(4)" ], "offsets": [ [ 111, 175 ], [ 183, 200 ], [ 224, 232 ] ] }, { "pmid": "23347684", "text": "Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures.", "type": "CHEMICAL", "entities": [ "1-azabicyclo[2.2.1]heptanes" ], "offsets": [ [ 33, 60 ] ] }, { "pmid": "23347684", "text": "Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10583449", "text": "Pretreatment renal vascular tone predicts the effect of specific renin inhibition on natriuresis in essential hypertension.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10583449", "text": "BACKGROUND: In essential hypertension an elevated renal vascular resistance (RVR) may be a marker of renin-angiotensin-aldosterone system-mediated impairment of renal sodium excretion.", "type": "CHEMICAL", "entities": [ "angiotensin", "aldosterone", "sodium" ], "offsets": [ [ 107, 118 ], [ 119, 130 ], [ 167, 173 ] ] }, { "pmid": "10583449", "text": "This hypothesis was tested by investigating whether, in subjects with essential hypertension, the natriuretic response to specific renin-angiotensin-aldosterone system (RAAS) blockade by renin-inhibitor remikiren could be predicted from pretreatment renal vascular tone.", "type": "CHEMICAL", "entities": [ "angiotensin", "aldosterone", "remikiren" ], "offsets": [ [ 137, 148 ], [ 149, 160 ], [ 203, 212 ] ] }, { "pmid": "10583449", "text": "MATERIALS AND METHODS: Renal hemodynamics, and the effects of single (n = 17) and multiple doses (n = 8, 8 days) of remikiren (600 mg day-1) on sodium excretion were studied under conditions of carefully controlled sodium balance.", "type": "CHEMICAL", "entities": [ "remikiren", "sodium", "sodium" ], "offsets": [ [ 116, 125 ], [ 144, 150 ], [ 215, 221 ] ] }, { "pmid": "10583449", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10583449", "text": "Pretreatment renal vascular tone showed considerable individual differences: filtration fraction (FF) ranged from 21.2 to 30.3% and RVR from 18.8 to 33.5 10-2 mmHg min mL-1 in the single dose study, and FF from 20.8 to 24.9% and RVR from 14.8 to 28.8 10-2 mmHg min mL-1 in the multiple dose study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10583449", "text": "Remikiren induced a fall in blood pressure, FF and RVR, with considerable interindividual variability in natriuretic response.", "type": "CHEMICAL", "entities": [ "Remikiren" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10583449", "text": "During single dose, cumulative sodium loss was 5.1 mmol per 5 h (-8.8 to +24.6), whereas after 8 days treatment cumulative sodium loss was 72 +/- 30 mmol (-46 to +187).", "type": "CHEMICAL", "entities": [ "sodium", "sodium" ], "offsets": [ [ 31, 37 ], [ 123, 129 ] ] }, { "pmid": "10583449", "text": "The natriuretic response to remikiren during single as well as multiple dose significantly correlated with pretreatment renal vascular tone (estimated from FF and RVR) but not with remikiren-induced changes in renal hemodynamics or in hormonal parameters.", "type": "CHEMICAL", "entities": [ "remikiren", "remikiren" ], "offsets": [ [ 28, 37 ], [ 181, 190 ] ] }, { "pmid": "10583449", "text": "Cumulative sodium loss was largest in patients with a higher pretreatment FF and RVR (r = 0.74, P < 0.001 and r = 0.52, P < 0.05, respectively, single dose; and r = 0.75, P < 0.05 and r = 0.73, P < 0.05, respectively, multiple dose).", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "10583449", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10583449", "text": "These data support the hypothesis that in essential hypertension an elevated renal vascular tone is a marker of RAAS-mediated impairment of sodium excretion.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 140, 146 ] ] }, { "pmid": "9003761", "text": "Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel.\n", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 98, 100 ] ] }, { "pmid": "9003761", "text": "Human TWIK-1, which has been cloned recently, is a new structural type of weak inward rectifier K+ channel.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 96, 98 ] ] }, { "pmid": "9003761", "text": "Here we report the structural and functional properties of TREK-1, a mammalian TWIK-1-related K+ channel.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 94, 96 ] ] }, { "pmid": "9003761", "text": "Despite a low amino acid identity between TWIK-1 and TREK-1 (approximately 28%), both channel proteins share the same overall structural arrangement consisting of two pore-forming domains and four transmembrane segments (TMS).", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "9003761", "text": "This structural similarity does not give rise to a functional analogy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9003761", "text": "K+ currents generated by TWIK-1 are inwardly rectifying while K+ currents generated by TREK-1 are outwardly rectifying.", "type": "CHEMICAL", "entities": [ "K+", "K+" ], "offsets": [ [ 0, 2 ], [ 62, 64 ] ] }, { "pmid": "9003761", "text": "These channels have a conductance of 14 pS. TREK-1 currents are insensitive to pharmacological agents that block TWIK-1 activity such as quinine and quinidine.", "type": "CHEMICAL", "entities": [ "quinine", "quinidine" ], "offsets": [ [ 137, 144 ], [ 149, 158 ] ] }, { "pmid": "9003761", "text": "Extensive inhibitions of TREK-1 activity are observed after activation of protein kinases A and C. TREK-1 currents are sensitive to extracellular K+ and Na+.", "type": "CHEMICAL", "entities": [ "K+", "Na+" ], "offsets": [ [ 146, 148 ], [ 153, 156 ] ] }, { "pmid": "9003761", "text": "TREK-1 mRNA is expressed in most tissues and is particularly abundant in the lung and in the brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9003761", "text": "Its localization in this latter tissue has been studied by in situ hybridization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9003761", "text": "TREK-1 expression is high in the olfactory bulb, hippocampus and cerebellum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9003761", "text": "These results provide the first evidence for the existence of a K+ channel family with four TMS and two pore domains in the nervous system of mammals.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 64, 66 ] ] }, { "pmid": "9003761", "text": "They also show that different members in this structural family can have totally different functional properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17059881", "text": "Dopamine D2 receptor occupancy by risperidone: implications for the timing and magnitude of clinical response.\n", "type": "CHEMICAL", "entities": [ "Dopamine", "risperidone" ], "offsets": [ [ 0, 8 ], [ 34, 45 ] ] }, { "pmid": "17059881", "text": "The objective of the study is to investigate whether dopamine D2 receptor occupancy by risperidone and plasma levels over time can account for therapeutic efficacy and the latency period to response.", "type": "CHEMICAL", "entities": [ "dopamine", "risperidone" ], "offsets": [ [ 53, 61 ], [ 87, 98 ] ] }, { "pmid": "17059881", "text": "Thirty-eight examinations with (123)I-IBZM single photon emission computed tomography were performed on 22 patients with schizophrenia, at diagnosis, 48 h after starting risperidone treatment and at a stable dose.", "type": "CHEMICAL", "entities": [ "(123)I-IBZM", "risperidone" ], "offsets": [ [ 31, 42 ], [ 170, 181 ] ] }, { "pmid": "17059881", "text": "Risperidone plasma levels were determined and psychopathologic evaluations (Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale) were carried out.", "type": "CHEMICAL", "entities": [ "Risperidone" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17059881", "text": "No differences in the striatal/occipital (S/O) ratio or plasma levels were found between examinations at the 48-h time point and when a stable dose level had been established, so these parameters could not account for the latency period required for clinical response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17059881", "text": "D2 receptor occupancy at 48 h correlated positively with clinical improvement after 2 weeks of treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17059881", "text": "Therefore, if these results are confirmed, D2 receptor occupancy at the beginning of treatment with risperidone may be a predictor of subsequent clinical response.", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 100, 111 ] ] }, { "pmid": "14757703", "text": "Overexpression of beta 1-adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for 'putative' beta 4-adrenoceptor pharmacology.\n", "type": "CHEMICAL", "entities": [ "CGP 12177A" ], "offsets": [ [ 82, 92 ] ] }, { "pmid": "14757703", "text": "1. CGP 12177A mediates cardiostimulation by activation of the 'putative' beta(4)-adrenoceptor; however, it has recently been reported that disruption of the beta(1)-adrenoceptor gene abolishes this effect.", "type": "CHEMICAL", "entities": [ "CGP 12177A" ], "offsets": [ [ 3, 13 ] ] }, { "pmid": "14757703", "text": "We have adenovirally overexpressed beta(1)-adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 microm propranolol).", "type": "CHEMICAL", "entities": [ "isoprenaline", "CGP 12177A", "propranolol" ], "offsets": [ [ 154, 166 ], [ 171, 181 ], [ 211, 222 ] ] }, { "pmid": "14757703", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14757703", "text": "Isoprenaline was a full inotropic agonist at rat ventricular myocytes (pD(2) 7.69+/-0.12).", "type": "CHEMICAL", "entities": [ "Isoprenaline" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14757703", "text": "CGP 12177A was a nonconventional partial agonist (pD(2) 6.34+/-0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol.", "type": "CHEMICAL", "entities": [ "CGP 12177A", "bupranolol" ], "offsets": [ [ 0, 10 ], [ 159, 169 ] ] }, { "pmid": "14757703", "text": "3. beta(1)-adrenoceptor", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14757703", "text": "overexpression enhanced the inotropic potency of isoprenaline by 11.7-fold (pD(2) 8.76+/-0.14) and CGP 12177A by 5.9-fold (7.11+/-0.10), respectively.", "type": "CHEMICAL", "entities": [ "isoprenaline" ], "offsets": [ [ 49, 61 ] ] }, { "pmid": "14757703", "text": "Green fluorescent protein (GFP) overexpression did not alter the potency of isoprenaline or CGP 12177A (pD(2) 7.41+/-0.24 and pD(2) 6.60+/-0.50, respectively).", "type": "CHEMICAL", "entities": [ "isoprenaline" ], "offsets": [ [ 76, 88 ] ] }, { "pmid": "14757703", "text": "4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14757703", "text": "The cardiostimulant effects of CGP 12177A were enhanced by IBMX (phosphodiesterase inhibitor) and decreased by Rp-cAMPS (cAMP antagonist).", "type": "CHEMICAL", "entities": [ "CGP 12177A", "Rp-cAMPS", "cAMP" ], "offsets": [ [ 31, 41 ], [ 111, 119 ], [ 121, 125 ] ] }, { "pmid": "14757703", "text": "CGP 12177A also increased cAMP levels.", "type": "CHEMICAL", "entities": [ "CGP 12177A", "cAMP" ], "offsets": [ [ 0, 10 ], [ 26, 30 ] ] }, { "pmid": "14757703", "text": "CGP 12177A but not isoprenaline initiated arrhythmias at lower concentrations following beta(1)-adrenoceptor overexpression.", "type": "CHEMICAL", "entities": [ "CGP 12177A", "isoprenaline" ], "offsets": [ [ 0, 10 ], [ 19, 31 ] ] }, { "pmid": "14757703", "text": "5. (125)I-Cyanopindolol saturation binding in Adv.beta(1) myocytes demonstrated approximately 18-fold increase in beta(1)-adrenoceptors.", "type": "CHEMICAL", "entities": [ "(125)I-Cyanopindolol" ], "offsets": [ [ 3, 23 ] ] }, { "pmid": "14757703", "text": "(3)H-CGP 12177A saturation binding, in the presence of propranolol, increased approximately 5-fold following overexpression of beta(1)-adrenoceptors.", "type": "CHEMICAL", "entities": [ "(3)H-CGP 12177A", "propranolol" ], "offsets": [ [ 0, 15 ], [ 55, 66 ] ] }, { "pmid": "14757703", "text": "6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14757703", "text": "This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing beta(1)-adrenoceptors, mediated by a Gs/cAMP signalling pathway.", "type": "CHEMICAL", "entities": [ "CGP 12177A", "propranolol", "cAMP" ], "offsets": [ [ 54, 64 ], [ 85, 96 ], [ 181, 185 ] ] }, { "pmid": "14757703", "text": "'Putative' beta(4)-adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the beta(1)-adrenoceptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "Antithrombin binding of low molecular weight heparins and inhibition of factor Xa.\nFluorescence and stopped flow methods were used to compare clinically used heparins with regard to their ability to bind to antithrombin and to accelerate the inactivation of factor Xa.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "Titration of antithrombin with both low molecular weight heparin (LMWH) (enoxaparin, fragmin and ardeparin) and unfractionated heparin (UFH) produced an equivalent fluorescence increase and indicates similar affinity of all heparin preparations to antithrombin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "However, relative to UFH enoxaparin, the LMWH with the smallest average molecular mass, contained only 12% material with high affinity for antithrombin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "The rate of factor Xa inhibition by antithrombin increased with the concentration of the examined heparins to the same limiting value, but the concentration required for maximal acceleration depended on the preparation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "According to these data the high affinity fraction of the heparin preparations increased the intrinsic fluorescence and inhibitory activity equally without additional effects by variations in chain length and chemical composition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "In contrast, in the presence of Ca UFH accelerated the inhibition of factor Xa by antithrombin 10-fold more efficiently than comparable concentrations of the high affinity fractions of enoxaparin and fragmin.", "type": "CHEMICAL", "entities": [ "Ca" ], "offsets": [ [ 32, 34 ] ] }, { "pmid": "11287128", "text": "The bell-shaped dependence of this accelerating effect suggests simultaneous binding of both proteins to heparin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "In conclusion, under physiologic conditions the anti-factor Xa activity of heparin results from a composite effect of chain length and the content of material with high affinity to antithrombin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11287128", "text": "Thus, the reduced antithrombotic activity of LMWH relative to UFH results from a smaller content of high affinity material and the absence of a stimulating effect of calcium.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 166, 173 ] ] }, { "pmid": "15673388", "text": "Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG.\n", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "15673388", "text": "INTRODUCTION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15673388", "text": "The principal aim of this study was to assess the efficacy of quinidine in suppressing IKr in vitro and in modulating the rate dependence of the QT interval in the \"SQT1\" form of the short QT syndrome.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "15673388", "text": "METHODS AND RESULTS: Graded-intensity bicycle exercise testing was performed off drug in three patients and during oral quinidine in two patients with short QT syndrome and compared to a control group of healthy normal subjects.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 120, 129 ] ] }, { "pmid": "15673388", "text": "The in vitro effects of quinidine on currents in patch clamp technique were investigated.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "15673388", "text": "Off drugs QTpV3/heart rate correlation is much weaker in patients with short QT syndrome, and QTpV3 shortens less with heart rate increase compared to normal subjects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15673388", "text": "In addition to prolonging the QT interval into the normal range, quinidine restored the heart rate dependence of the QT interval toward a range of adaptation reported for normal subjects.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "15673388", "text": "Data from heterologous expression of wild-type and mutant HERG genes indicate the mutation causes a 20-fold increase in IC50 of d-sotalol but only a 5.8-fold increase in IC50 of quinidine.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 178, 187 ] ] }, { "pmid": "15673388", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15673388", "text": "Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.", "type": "CHEMICAL", "entities": [ "quinidine" ], "offsets": [ [ 5, 14 ] ] }, { "pmid": "23386780", "text": "Apoptotic cell death in rat epididymis following epichlorohydrin treatment.\n", "type": "CHEMICAL", "entities": [ "epichlorohydrin" ], "offsets": [ [ 49, 64 ] ] }, { "pmid": "23386780", "text": "Epichlorohydrin (ECH) is an antifertility agent that acts both as an epididymal toxicant and an agent capable of directly affecting sperm motility.", "type": "CHEMICAL", "entities": [ "Epichlorohydrin", "ECH" ], "offsets": [ [ 0, 15 ], [ 17, 20 ] ] }, { "pmid": "23386780", "text": "This study identified the time course of apoptotic cell death in rat epididymides after ECH treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386780", "text": "Rats were administrated with a single oral dose of ECH (50 mg/kg).", "type": "CHEMICAL", "entities": [ "ECH" ], "offsets": [ [ 51, 54 ] ] }, { "pmid": "23386780", "text": "ECH-induced apoptotic changes were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and its related mechanism was confirmed by Western blot analysis and colorimetric assay.", "type": "CHEMICAL", "entities": [ "dUTP" ], "offsets": [ [ 85, 89 ] ] }, { "pmid": "23386780", "text": "The TUNEL assay showed that the number of apoptotic cells increased at 8 h, reached a maximum level at 12 h, and then decreased progressively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386780", "text": "The Western blot analysis demonstrated no significant changes in proapoptotic Bcl-2-associated X (Bax) and anti-apoptotic Bcl-2 expression during the time course of the study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386780", "text": "However, phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and phospho-c-Jun amino-terminal kinase (p-JNK) expression increased at 8-24 h. Caspase-3 and caspase-8 activities also increased at 8-48 h and 12-48 h, respectively, in the same manner as p-p38 MAPK and p-JNK expression.", "type": "CHEMICAL", "entities": [ "amino" ], "offsets": [ [ 82, 87 ] ] }, { "pmid": "23386780", "text": "These results indicate that ECH induced apoptotic changes in rat epididymides and that the apoptotic cell death may be related more to the MAPK pathway than to the mitochondrial pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "Effects of an ethanolic salix extract on the release of selected inflammatory mediators in vitro.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "Salix extracts are in current use for the treatment of pain and inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "In order to obtain an insight into the mechanism(s) of action of the ethanolic Salix extract 1520L--which is essentially similar to an extract for which clinical studies have demonstrated analgesic effectiveness--its effects were evaluated in an established in vitro assay test system using primary human monocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "The IC50-values obtained for the inhibition of lipopolysaccharide (LPS)-induced release of prostaglandin E2 (PGE2) reflecting cyclooxygenase (COX)-2-mediated PGE2 release were 47 microg/ml and 0.6 microg/ml, for the Salix extract 1520L and rofecoxib-like research compound L745337, respectively.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2", "PGE2", "rofecoxib", "L745337" ], "offsets": [ [ 91, 107 ], [ 109, 113 ], [ 158, 162 ], [ 240, 249 ], [ 273, 280 ] ] }, { "pmid": "15070163", "text": "There was no effect on COX-1 and COX-2 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "The Salix extract inhibited the LPS-induced release of tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 with IC50-values of 180.0, 33.0 and 86.0 microg/ml, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15070163", "text": "Both, salicin and salicylate, had no effect in any of the parameters.", "type": "CHEMICAL", "entities": [ "salicin", "salicylate" ], "offsets": [ [ 6, 13 ], [ 18, 28 ] ] }, { "pmid": "15070163", "text": "Our results indicate that Salix extract 1520L inhibits COX-2-mediated PGE2 release through compounds other than salicin or salicylate.", "type": "CHEMICAL", "entities": [ "PGE2", "salicin", "salicylate" ], "offsets": [ [ 70, 74 ], [ 112, 119 ], [ 123, 133 ] ] }, { "pmid": "15070163", "text": "Our data further suggest that the proprietary Salix extract is a weak inhibitor of proinflammatory cytokines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11299519", "text": "Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11299519", "text": "Follicle-stimulating hormone (FSH), a dimeric glycoprotein synthesized in the anterior pituitary gland, is important for the production of sex steroids and gametes.", "type": "CHEMICAL", "entities": [ "steroids" ], "offsets": [ [ 143, 151 ] ] }, { "pmid": "11299519", "text": "FSH-beta (FSH beta) and FSH receptor (FSHR) knockout mice display impaired ovarian follicular development and infertility in females and small testes, oligospermia, and fertility in males.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11299519", "text": "Humans with FSH beta gene mutations tend to have a more severe phenotype than those with FSHR gene mutations, although infertility and varying degrees of impaired sex steroid production occur in both types of mutations.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 167, 174 ] ] }, { "pmid": "11299519", "text": "Data from human and mouse mutations in the FSH beta and FSHR genes suggest that FSH is necessary for normal pubertal development and fertility in males and females.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17333137", "text": "Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme.\n", "type": "CHEMICAL", "entities": [ "rolipram" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "17333137", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17333137", "text": "Recent studies provide evidence for reduced phosphodiesterase-4B (PDE4B) as a genetic susceptibility factor as well as suggesting an association of several single nucleotide polymorphisms (SNPs) in PDE4B that are associated with an increased incidence of schizophrenia.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 163, 173 ] ] }, { "pmid": "17333137", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17333137", "text": "The aim of the current study was to assess the activity of rolipram, a nonsubtype-selective PDE4 inhibitor, in several animal models predictive of antipsychotic-like efficacy and side-effect liability and to use PDE4B wild-type and knockout mice to begin to understand the subtypes involved in the activity of rolipram.", "type": "CHEMICAL", "entities": [ "rolipram", "rolipram" ], "offsets": [ [ 59, 67 ], [ 310, 318 ] ] }, { "pmid": "17333137", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17333137", "text": "In rats, rolipram antagonized both phencyclidine hydrochloride- and D-amphetamine-induced hyperactivity and inhibited conditioned avoidance responding (CAR).", "type": "CHEMICAL", "entities": [ "rolipram", "phencyclidine hydrochloride", "D-amphetamine" ], "offsets": [ [ 9, 17 ], [ 35, 62 ], [ 68, 81 ] ] }, { "pmid": "17333137", "text": "In PDE4B wild-type mice, rolipram dose-dependently suppressed CAR (ED(50) = 2.4 mg/kg); however, in knockout mice, their sensitivity to rolipram at the higher doses (1.0 and 3.2 mg/kg) was reduced, resulting in a threefold shift in the ED(50) (7.3 mg/kg), suggesting PDE4B is involved, at least in part, with the activity of rolipram.", "type": "CHEMICAL", "entities": [ "rolipram", "rolipram", "rolipram" ], "offsets": [ [ 325, 333 ], [ 25, 33 ], [ 136, 144 ] ] }, { "pmid": "17333137", "text": "Only the highest dose of rolipram (3.2 mg/kg) produced a modest but significant degree of catalepsy.", "type": "CHEMICAL", "entities": [ "rolipram" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "17333137", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17333137", "text": "Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability.", "type": "CHEMICAL", "entities": [ "Rolipram" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "17333137", "text": "These results suggest that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis.", "type": "CHEMICAL", "entities": [ "rolipram", "cyclic adenosine monophosphate" ], "offsets": [ [ 71, 79 ], [ 116, 146 ] ] }, { "pmid": "15963006", "text": "Improving the tolerability of anticholinergic agents in the treatment of overactive bladder.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "Pharmacological treatment for overactive bladder has centred around the interruption of the detrusor activity that is central to urge and incontinence symptoms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "The majority of patients with this disorder are treated with antimuscarinic agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "These drugs have been demonstrated to improve urgency, frequency of micturition and urge incontinence, all of which are primary symptoms of overactive bladder; however, they are also commonly associated with anticholinergic adverse effects, most notably dry mouth.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "Attempts to increase tolerability have included the development of advanced formulations that regulate release of the active ingredient and the development of pharmacological agents that target the desired bladder receptors more specifically and accurately.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "Although all agents provide good efficacy, tolerability is greatly affected by the formulation used to deliver the active pharmacological agent, as well as the specificity of the targeted receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963006", "text": "Clinical trials involving a transdermal formulation of oxybutynin have shown that this delivery method may be associated with a lower incidence of anticholinergic adverse events compared with both the immediate-release and the extended-release oral formulations of traditional agents, as well as the most recently approved agents - trospium chloride, solifenacin and darifenacin.", "type": "CHEMICAL", "entities": [ "oxybutynin", "trospium chloride", "solifenacin", "darifenacin" ], "offsets": [ [ 55, 65 ], [ 332, 349 ], [ 351, 362 ], [ 367, 378 ] ] }, { "pmid": "15963006", "text": "Much is still being learned about the function and specificity of muscarinic receptors, which will support the development of agents with sustained efficacy and enhanced tolerability compared with the available formulations to date.", "type": "CHEMICAL", "entities": [ "muscarinic" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "15963006", "text": "These include the S-isomer of oxybutynin, as well as selective muscarinic M2 receptor antagonists.", "type": "CHEMICAL", "entities": [ "S-isomer of oxybutynin" ], "offsets": [ [ 18, 40 ] ] }, { "pmid": "16441928", "text": "Intradialytic parenteral nutrition: comparison of olive oil versus soybean oil-based lipid emulsions.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16441928", "text": "Lipid, oxidative and inflammatory parameters are frequently altered in dialysis patients and may be worsened by intravenous lipid emulsions (ILE).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16441928", "text": "We assessed the efficacy and tolerance of olive as compared with standard soybean oil-based ILE during intradialytic parenteral nutrition (IDPN).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16441928", "text": "IDPN mixtures containing amino acids, glucose, and either olive oil (OO group, n 17) or soybean oil-based ILE (SO group, n 18) were administered in a 5-week randomized, double-blind study.", "type": "CHEMICAL", "entities": [ "amino acids", "glucose" ], "offsets": [ [ 25, 36 ], [ 38, 45 ] ] }, { "pmid": "16441928", "text": "On days 0 and 35, patients' nutritional status was assessed by BMI, normalized protein catabolic rate, predialytic creatinine, serum albumin and transthyretin; lipid metabolism by plasma LDL- and HDL-cholesterol, triacylglycerols, phospholipids, apo A-I, A-II, B, C-II, C-III, E and lipoprotein (a); oxidative status by alpha-tocopherol, retinol, selenium, glutathione peroxidase, malondialdehyde and advanced oxidized protein products; inflammatory status by serum C-reactive protein, orosomucoid, IL-2 and IL-6.", "type": "CHEMICAL", "entities": [ "creatinine", "cholesterol", "triacylglycerols", "alpha-tocopherol", "retinol", "selenium", "glutathione", "malondialdehyde" ], "offsets": [ [ 115, 125 ], [ 200, 211 ], [ 213, 229 ], [ 320, 336 ], [ 338, 345 ], [ 347, 355 ], [ 357, 368 ], [ 381, 396 ] ] }, { "pmid": "16441928", "text": "No serious adverse event was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16441928", "text": "Significant changes were observed from day 0 to day 35 (P<0.05): nutritional criteria improved (albumin in OO; albumin, transthyretin and creatinine in SO); LDL-cholesterol, apo B, C-II, C-III and apo A-I/A-II ratio increased in both groups.", "type": "CHEMICAL", "entities": [ "creatinine", "cholesterol" ], "offsets": [ [ 138, 148 ], [ 161, 172 ] ] }, { "pmid": "16441928", "text": "HDL-cholesterol decreased in OO; apo E increased and lipoprotein (a) decreased in SO; alpha-tocopherol/cholesterol ratio increased in OO; malondialdehyde decreased in both groups; IL-2 increased in both groups.", "type": "CHEMICAL", "entities": [ "cholesterol", "alpha-tocopherol", "cholesterol", "malondialdehyde" ], "offsets": [ [ 4, 15 ], [ 86, 102 ], [ 103, 114 ], [ 138, 153 ] ] }, { "pmid": "16441928", "text": "The between-group comparison only showed the following differences: alpha-tocopherol/cholesterol increased in OO; lipoprotein (a) decreased in SO.", "type": "CHEMICAL", "entities": [ "alpha-tocopherol", "cholesterol" ], "offsets": [ [ 68, 84 ], [ 85, 96 ] ] }, { "pmid": "16441928", "text": "From these data, it was concluded that OO- and SO-based IDPNs similarly improved nutritional status and influenced plasma lipid, oxidative, inflammatory and immune parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "Transcriptional control of the arginine/lysine transporter, cat-1, by physiological stress.\n", "type": "CHEMICAL", "entities": [ "arginine", "lysine" ], "offsets": [ [ 31, 39 ], [ 40, 46 ] ] }, { "pmid": "14523001", "text": "Cells respond to physiological stress by phosphorylating the alpha subunit of the translation initiation factor eIF2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "This adaptive response inhibits protein synthesis and up-regulates genes essential for cell survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "Cat-1, the transporter for the essential amino acids, arginine and lysine, is one of the up-regulated genes.", "type": "CHEMICAL", "entities": [ "amino acids", "arginine", "lysine" ], "offsets": [ [ 41, 52 ], [ 54, 62 ], [ 67, 73 ] ] }, { "pmid": "14523001", "text": "We previously showed that stress increases cat-1 expression by coordinated stabilization of the mRNA and increased mRNA translation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "This induction is triggered by amino acid depletion and the unfolded protein response (UPR), which is caused by unfolded proteins in the endoplasmic reticulum.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 31, 41 ] ] }, { "pmid": "14523001", "text": "We show here that cat-1 gene transcription is also increased by cellular stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "Our studies demonstrate that the cat-1 gene promoter/regulatory region is TATA-less and is located in a region that includes 94 bases of the first exon.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "Transcription from this promoter is stimulated 8-fold by cellular stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "An amino acid response element within the first exon is shown to be required for the response to amino acid depletion but not to the UPR.", "type": "CHEMICAL", "entities": [ "amino acid", "amino acid" ], "offsets": [ [ 97, 107 ], [ 3, 13 ] ] }, { "pmid": "14523001", "text": "The stimulation of transcription by amino acid depletion requires activation of GCN2 kinase, which phosphorylates eIF2alpha.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "14523001", "text": "This phosphorylation also induces translation of the cat-1 mRNA, demonstrating that stress-induced transcriptional and translational control of cat-1 are downstream targets of a signaling pathway initiating with eIF2alpha phosphorylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14523001", "text": "Our studies show that the increase in cat-1 gene expression by cellular stress involves at least three types of coordinate regulation: regulation of transcription, regulation of mRNA stability, and regulation of mRNA translation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Hypoxia has been suspected to trigger transdifferentiation of renal tubular cells into myofibroblasts in an epithelial-to-mesenchymal transition (EMT) process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "To determine the functional networks potentially altered by hypoxia, rat renal tubule suspensions were incubated under three conditions of oxygenation ranging from normoxia (lactate uptake) to severe hypoxia (lactate production).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Transcriptome changes after 4 h were analyzed on a high scale by restriction fragment differential display.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Among 1,533 transcripts found, 42% were maximally expressed under severe hypoxia and 8% under mild hypoxia (Po(2) = 48 mmHg), suggesting two different levels of oxygen sensing.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 161, 167 ] ] }, { "pmid": "16597615", "text": "Normoxia was required for full expression of the proximal tubule-specific transcripts 25-hydroxyvitamin D 1-hydroxylase (Cyp27b1) and l-pyruvate kinase (Pklr), transcripts involved in tissue cohesion such as fibronectin (Fn1) and N-cadherin (Cdh2), and non-muscle-type myosin transcripts.", "type": "CHEMICAL", "entities": [ "25-hydroxyvitamin D", "l-pyruvate" ], "offsets": [ [ 86, 105 ], [ 134, 144 ] ] }, { "pmid": "16597615", "text": "Mild hypoxia increased myogenin transcript level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Conversely, severe hypoxia increased transcripts involved in extracellular matrix remodeling, those of muscle-type myosins, and others involved in creatine phosphate synthesis and lactate transport (Slc16a7).", "type": "CHEMICAL", "entities": [ "phosphate" ], "offsets": [ [ 156, 165 ] ] }, { "pmid": "16597615", "text": "Accordingly, microscopy showed loss of tubule aggregation under hypoxia, without tubular disruption.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "Hypoxia also increased the levels of kidney-specific transcripts normally restricted to the less oxygenated medullary zone and others specific for the distal part of the nephron.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16597615", "text": "We conclude that extensive oxygen supply to the kidney tubule favors expression of its differentiated functions specifically in the proximal tubule, whose embryonic origin is mesenchymal.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 27, 33 ] ] }, { "pmid": "16597615", "text": "The phenotype changes could potentially permit transient adaptation to hypoxia but also favor pathological processes such as tissue invasion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "A human hemi-cornea model for eye irritation testing: quality control of production, reliability and predictive capacity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "We have developed a 3-dimensional human hemi-cornea which comprises an immortalized epithelial cell line and keratocytes embedded in a collagen stroma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "In the present study, we have used MTT reduction of the whole tissue to clarify whether the production of this complex 3-D-model is transferable into other laboratories and whether these tissues can be constructed reproducibly.", "type": "CHEMICAL", "entities": [ "MTT" ], "offsets": [ [ 35, 38 ] ] }, { "pmid": "22902307", "text": "Our results demonstrate the reproducible production of the hemi-cornea model according to standard operation procedures using 15 independent batches of reconstructed hemi-cornea models in two independent laboratories each.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "Furthermore, the hemi-cornea tissues have been treated with 20 chemicals of different eye-irritating potential under blind conditions to assess the performance and limitations of our test system comparing three different prediction models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "The most suitable prediction model revealed an overall in vitro-in vivo concordance of 80% and 70% in the participating laboratories, respectively, and an inter-laboratory concordance of 80%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "Sensitivity of the test was 77% and specificity was between 57% and 86% to discriminate classified from non-classified chemicals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22902307", "text": "We conclude that additional physiologically relevant endpoints in both epithelium and stroma have to be developed for the reliable prediction of all GHS classes of eye irritation in one stand alone test system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "Steroidal glycosides from the bulbs of Easter lily (Lilium longiflorum Thunb.)", "type": "CHEMICAL", "entities": [ "Steroidal glycosides" ], "offsets": [ [ 0, 20 ] ] }, { "pmid": "23644411", "text": "promote dermal fibroblast migration in vitro.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "ETHNOPHARMACOLOGICAL RELEVANCE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "Preparations derived from bulbs of various Lilium species have been used to promote the healing of skin abrasions, sores and burns and to aid in healing wounds in Traditional Chinese and Greco-Roman Medicine.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "AIM OF THE STUDY: To evaluate fractionated Easter lily bulb extracts and their steroidal glycosides (1-5) for the promotion of dermal fibroblast migration in vitro, as a model for the early events in wound healing.", "type": "CHEMICAL", "entities": [ "steroidal glycosides" ], "offsets": [ [ 79, 99 ] ] }, { "pmid": "23644411", "text": "MATERIALS AND METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "An activity-guided screening approach was used by coupling sequential solvent extraction, gel permeation chromatography (GPC), and semi-preparative reverse-phase high performance liquid chromatography (RP-HPLC) with an in vitro dermal fibroblast migration assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "Cytotoxicity was evaluated with methyl thiazole tetrazolium (MTT).", "type": "CHEMICAL", "entities": [ "methyl thiazole tetrazolium", "MTT" ], "offsets": [ [ 32, 59 ], [ 61, 64 ] ] }, { "pmid": "23644411", "text": "To gain insight into the mode of action of the steroidal glycosides, nitric oxide (NO) production, and expression of genes for transforming growth factor beta-1 (TGF-β) and its receptors were evaluated.", "type": "CHEMICAL", "entities": [ "steroidal glycosides", "nitric oxide", "NO" ], "offsets": [ [ 47, 67 ], [ 69, 81 ], [ 83, 85 ] ] }, { "pmid": "23644411", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "Fractionated bulb extracts and the two isolated steroidal glycoalkaloids (1) and (2) induced NO production and TGF-β receptor I mRNA expression in fibroblast cell culture.", "type": "CHEMICAL", "entities": [ "steroidal glycoalkaloids", "NO" ], "offsets": [ [ 47, 71 ], [ 92, 94 ] ] }, { "pmid": "23644411", "text": "In a cytotoxicity assay, steroidal glycosides (1) and (3) had IC50 values of 8.2 and 8.7µM, but the natural acetylation of the C-6″' hydroxy of the terminal glucose unit in (2) resulted in a 3-fold decrease in cell cytotoxicity when compared with (1).", "type": "CHEMICAL", "entities": [ "steroidal glycosides", "hydroxy", "glucose" ], "offsets": [ [ 23, 43 ], [ 131, 138 ], [ 155, 162 ] ] }, { "pmid": "23644411", "text": "Results from the dermal fibroblast migration assay revealed that the steroidal glycoalkaloids (1) and (2), and the furostanol saponin (3) promoted fibroblast migration from the range of 23.7±5.7 to 37.7±5.1%, as compared with the control.", "type": "CHEMICAL", "entities": [ "steroidal glycoalkaloids", "furostanol saponin" ], "offsets": [ [ 64, 88 ], [ 110, 128 ] ] }, { "pmid": "23644411", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23644411", "text": "Collectively, our data demonstrate that the steroidal glycosides present in Easter lily bulbs induce, at least in part, the observed dermal fibroblast migration activity of the bulb extracts.", "type": "CHEMICAL", "entities": [ "steroidal glycosides" ], "offsets": [ [ 37, 57 ] ] }, { "pmid": "23644411", "text": "This is the first evidence that steroidal glycosides from L. longiflorum may potentially play a role in the wound healing process and may provide a scientific basis for the historical use of lily bulbs for this purpose.", "type": "CHEMICAL", "entities": [ "steroidal glycosides" ], "offsets": [ [ 25, 45 ] ] }, { "pmid": "10988273", "text": "Species-specific pharmacological properties of human alpha(2A)-adrenoceptors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10988273", "text": "On the basis of data obtained in rabbits, the imidazoline receptor ligand rilmenidine has been suggested to decrease blood pressure in humans by activating central alpha(2A)-adrenoceptors.", "type": "CHEMICAL", "entities": [ "imidazoline", "rilmenidine" ], "offsets": [ [ 46, 57 ], [ 74, 85 ] ] }, { "pmid": "10988273", "text": "A prerequisite for this hypothesis was the unproved assumption that rabbit and human alpha(2A)-adrenoceptors are equally activated by rilmenidine.", "type": "CHEMICAL", "entities": [ "rilmenidine" ], "offsets": [ [ 134, 145 ] ] }, { "pmid": "10988273", "text": "Because alpha(2A)-adrenoceptors in the brain and on cardiovascular sympathetic nerve terminals are identical, the latter were used as a model for the former to confirm or disprove this assumption.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10988273", "text": "Human atrial appendages and rabbit pulmonary arteries were used to determine the potencies of alpha(2)-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10988273", "text": "[(3)H]norepinephrine release and of antagonists in counteracting the alpha(2)-adrenoceptor-mediated inhibition induced by moxonidine.", "type": "CHEMICAL", "entities": [ "[(3)H]norepinephrine", "moxonidine" ], "offsets": [ [ 0, 20 ], [ 122, 132 ] ] }, { "pmid": "10988273", "text": "In the rabbit pulmonary artery, rilmenidine and oxymetazoline are potent full agonists, whereas in the human atrial appendages they are antagonists at the alpha(2)-autoreceptors, sharing this property with rauwolscine, phentolamine, and idazoxan.", "type": "CHEMICAL", "entities": [ "rauwolscine", "phentolamine", "idazoxan", "rilmenidine", "oxymetazoline" ], "offsets": [ [ 206, 217 ], [ 219, 231 ], [ 237, 245 ], [ 32, 43 ], [ 48, 61 ] ] }, { "pmid": "10988273", "text": "In contrast, prazosin is ineffective.", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "10988273", "text": "In addition, a partial nucleotide and amino acid sequence of the rabbit alpha(2A)-adrenoceptor (a region known to substantially influence the pharmacological characteristics of the alpha(2)-adrenoceptor) revealed marked differences between the rabbit and the human alpha(2A)-adrenoceptor.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "10988273", "text": "The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with alpha(2A)-autoreceptors, at which, however, both rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively).", "type": "CHEMICAL", "entities": [ "rilmenidine", "oxymetazoline" ], "offsets": [ [ 153, 164 ], [ 169, 182 ] ] }, { "pmid": "10988273", "text": "The antagonistic property of rilmenidine at human alpha(2A)-adrenoceptors indicates that in contrast to the suggestion based on rabbit data, the hypotensive property of the drug in humans is not due to activation of alpha(2A)-adrenoceptors but other, presumably I(1)-imidazoline receptors, are probably involved.", "type": "CHEMICAL", "entities": [ "rilmenidine", "imidazoline" ], "offsets": [ [ 29, 40 ], [ 267, 278 ] ] }, { "pmid": "12606421", "text": "Gonadotropin-releasing hormone receptor gene expression during pubertal development of male rats.\n", "type": "CHEMICAL", "entities": [ "Gonadotropin-releasing hormone" ], "offsets": [ [ 0, 30 ] ] }, { "pmid": "12606421", "text": "Appropriate expression of the GnRH receptor (GnRH-R) in gonadotropes is critical for GnRH signaling and hence for gonadotropin secretion and sexual development.", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH", "GnRH" ], "offsets": [ [ 30, 34 ], [ 45, 49 ], [ 85, 89 ] ] }, { "pmid": "12606421", "text": "In the present work, we have studied the ontogeny of the steady-state GnRH-R mRNA levels in pituitaries of male rats from Day 5 to Day 55, when sexual maturity is attained.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 70, 74 ] ] }, { "pmid": "12606421", "text": "Developmental changes of gonadotropin subunit (alpha, FSHbeta, and LHbeta) mRNA levels were also assessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "In addition, the role of the endogenous GnRH on the maturational changes of GnRH-R and gonadotropin subunit gene expression was investigated.", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH" ], "offsets": [ [ 40, 44 ], [ 76, 80 ] ] }, { "pmid": "12606421", "text": "Messenger RNA levels were determined by Northern blot analysis of total RNA from anterior pituitaries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "Amounts of the most abundant (5.0 kb) GnRH-R mRNA increased slowly from Day 5 through the infantile and the juvenile periods, to peak at Day 35 (12-fold increase vs. Day 5).", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 38, 42 ] ] }, { "pmid": "12606421", "text": "Thereafter, the levels of the GnRH-R mRNA decline slightly until Day 55 (33% decrease vs. Day 35).", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 30, 34 ] ] }, { "pmid": "12606421", "text": "Parallel changes were observed on the 4.5-kb transcript of the GnRH-R gene.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 63, 67 ] ] }, { "pmid": "12606421", "text": "Alpha subunit mRNA was easily detected at Day 5, and its levels increased progressively through the infantile period (2.5-fold increase) and peaked at Day 25 (3.3-fold increase vs. Day 5) with a smooth nonstatistically significant increment until Day 35; then it decreased by 41.5% at Day 55.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "FSHbeta and LHbeta mRNA levels rose slowly until Day 25.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "A sharp rise occurred thereafter to reach maximum levels at Day 35 (5.8-fold for FSHbeta and 3.8-fold for LHbeta vs. Day 25).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "Thereafter, the levels of both mRNAs fell until Day 55 (44.1% decrease for FSHbeta and 37.1% decrease for LHbeta vs. Day 35).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "To ascertain whether developmental activation of the GnRH-R and gonadotropin subunit gene expression is GnRH dependent, we have studied the effect of blocking the endogenous GnRH action by treating developing male rats with the specific GnRH antagonist cetrorelix (1.5 mg/kg body weight/week, s.c.)", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH", "GnRH", "GnRH" ], "offsets": [ [ 53, 57 ], [ 104, 108 ], [ 174, 178 ], [ 237, 241 ] ] }, { "pmid": "12606421", "text": "through the infantile (Days 5-20) and the juvenile periods (Days 20-35).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "Cetrorelix completely blocked the rise of levels of the two most abundant species, 5.0 kb and 4.5 kb, of the GnRH-R mRNA, during both the infantile and the juvenile periods.", "type": "CHEMICAL", "entities": [ "Cetrorelix", "GnRH" ], "offsets": [ [ 0, 10 ], [ 109, 113 ] ] }, { "pmid": "12606421", "text": "Cetrorelix also abolished the developmental rise of the gonadotropin beta subunit mRNAs during the two periods of the study.", "type": "CHEMICAL", "entities": [ "Cetrorelix" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12606421", "text": "In contrast, the alpha subunit gene expression was not altered by cetrorelix treatment during any of the two periods.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12606421", "text": "These data demonstrate that sexual maturation of male rats is accompanied by a progressive and concerted induction of GnRH-R and gonadotropin subunit gene expression.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 118, 122 ] ] }, { "pmid": "12606421", "text": "Developmental activation of GnRH-R and gonadotropin beta subunit genes is GnRH dependent.", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH" ], "offsets": [ [ 28, 32 ], [ 74, 78 ] ] }, { "pmid": "12606421", "text": "The apparent GnRH-independent regulation of the alpha-glycoprotein subunit mRNA levels may be due to the contribution of thyrotropes and perhaps to the presence of exclusive regulatory signals for this gene.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 13, 17 ] ] }, { "pmid": "2568212", "text": "Nonsedating histamine H1-receptor antagonists.\n", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "2568212", "text": "The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosages of the nonsedating histamine H1-receptor antagonists terfenadine, astemizole, loratadine, and acrivastine are reviewed.", "type": "CHEMICAL", "entities": [ "histamine", "terfenadine", "astemizole", "loratadine", "acrivastine" ], "offsets": [ [ 114, 123 ], [ 148, 159 ], [ 161, 171 ], [ 173, 183 ], [ 189, 200 ] ] }, { "pmid": "2568212", "text": "Terfenadine and astemizole are chemically unrelated to histamine H1-receptor antagonists such as diphenhydramine and chlorpheniramine.", "type": "CHEMICAL", "entities": [ "Terfenadine", "astemizole", "histamine", "diphenhydramine", "chlorpheniramine" ], "offsets": [ [ 0, 11 ], [ 16, 26 ], [ 55, 64 ], [ 97, 112 ], [ 117, 133 ] ] }, { "pmid": "2568212", "text": "Loratadine is structurally related to the antihistamine azatadine, and acrivastine is a side-chain-reduced metabolite of the antihistamine triprolidine.", "type": "CHEMICAL", "entities": [ "Loratadine", "azatadine", "acrivastine", "triprolidine" ], "offsets": [ [ 0, 10 ], [ 56, 65 ], [ 71, 82 ], [ 139, 151 ] ] }, { "pmid": "2568212", "text": "Like other histamine H1-receptor antagonists, they competitively block histamine receptor sites rather than inhibiting histamine release.", "type": "CHEMICAL", "entities": [ "histamine", "histamine", "histamine" ], "offsets": [ [ 11, 20 ], [ 71, 80 ], [ 119, 128 ] ] }, { "pmid": "2568212", "text": "All four drugs have relatively long half-lives and are rapidly absorbed after oral administration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568212", "text": "Terfenadine, astemizole, and loratadine are metabolized extensively in the liver; terfenadine and astemizole are both 97% protein bound.", "type": "CHEMICAL", "entities": [ "Terfenadine", "astemizole", "loratadine", "terfenadine", "astemizole" ], "offsets": [ [ 0, 11 ], [ 13, 23 ], [ 29, 39 ], [ 82, 93 ], [ 98, 108 ] ] }, { "pmid": "2568212", "text": "Terfenadine 60 mg twice daily has been shown to be as effective as conventional antihistamines for the treatment of seasonal allergic rhinitis.", "type": "CHEMICAL", "entities": [ "Terfenadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "2568212", "text": "In clinical trials, astemizole 10 mg daily was comparable to or better than chlorpheniramine for treatment of chronic rhinitis.", "type": "CHEMICAL", "entities": [ "astemizole", "chlorpheniramine" ], "offsets": [ [ 20, 30 ], [ 76, 92 ] ] }, { "pmid": "2568212", "text": "Both terfenadine and astemizole were effective for treatment of chronic urticaria.", "type": "CHEMICAL", "entities": [ "terfenadine", "astemizole" ], "offsets": [ [ 5, 16 ], [ 21, 31 ] ] }, { "pmid": "2568212", "text": "For treatment of seasonal allergic rhinitis, loratadine combined with pseudoephedrine may be preferable to triprolidine-pseudoephedrine and acrivastine-pseudoephedrine combinations that require more frequent dosing.", "type": "CHEMICAL", "entities": [ "loratadine", "pseudoephedrine", "triprolidine", "pseudoephedrine", "acrivastine", "pseudoephedrine" ], "offsets": [ [ 45, 55 ], [ 70, 85 ], [ 107, 119 ], [ 120, 135 ], [ 140, 151 ], [ 152, 167 ] ] }, { "pmid": "2568212", "text": "Acrivastine must be administered more frequently than the other nonsedating antihistamines.", "type": "CHEMICAL", "entities": [ "Acrivastine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "2568212", "text": "None of these four agents impairs psychomotor activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568212", "text": "Infrequently reported adverse effects include dry mouth, skin reactions, and weight gain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568212", "text": "The absence of substantial sedative effects and the less-frequent dosing schedules make these agents good alternatives to the classic antihistamines for treatment of seasonal and chronic rhinitis and chronic urticaria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23597450", "text": "Anti-inflammatory effect of prunetin via the suppression of NF-κB pathway.\n", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "23597450", "text": "Prunetin is an O-methylated isoflavone, which is found in Prunus yedoensis.", "type": "CHEMICAL", "entities": [ "O-methylated isoflavone" ], "offsets": [ [ 14, 37 ] ] }, { "pmid": "23597450", "text": "To date no report has been published on anti-inflammatory activities of prunetin.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "23597450", "text": "In the present study, the anti-inflammatory effect of prunetin on LPS-stimulated RAW 264.7 macrophage and LPS-induced septic shock model were investigated.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 53, 61 ] ] }, { "pmid": "23597450", "text": "Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) expressions were determined by western blot and or realtime-PCR (RT-PCR).", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 9, 21 ] ] }, { "pmid": "23597450", "text": "To elucidate its underlying mechanism, nuclear factor-kappa B (NF-κb) activation and its downstream pathways were investigated by NF-κB transcription factor assay, reporter gene expression, and western blot.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23597450", "text": "In vivo anti-inflammatory effects of prunetin were evaluated in LPS-induced endotoxemia.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "23597450", "text": "Promoter assay revealed that prunetin inhibits LPS-induced nitric oxide and prostaglandin E2 production through the suppression of iNOS and COX-2 at the transcriptional level.", "type": "CHEMICAL", "entities": [ "prunetin", "nitric oxide", "prostaglandin E2" ], "offsets": [ [ 22, 30 ], [ 52, 64 ], [ 69, 85 ] ] }, { "pmid": "23597450", "text": "In addition, prunetin inhibits NF-κB-dependent inflammatory responses by modulating IκB kinase (IKK)-inhibitor κBα (IκBα)-NF-κB signaling.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 6, 14 ] ] }, { "pmid": "23597450", "text": "Consistent with these results, prunetin significantly reduced serum levels of inflammatory cytokines and mortality in mice challenged with lipopolysaccharide.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 17, 25 ] ] }, { "pmid": "23597450", "text": "These findings offer a potential mechanism for the anti-inflammatory activity of prunetin.", "type": "CHEMICAL", "entities": [ "prunetin" ], "offsets": [ [ 67, 75 ] ] }, { "pmid": "23274894", "text": "G6PC2: A Negative Regulator of Basal Glucose-Stimulated Insulin Secretion.\n", "type": "CHEMICAL", "entities": [ "Glucose" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "23274894", "text": "Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 23, 30 ] ] }, { "pmid": "23274894", "text": "Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 147, 154 ] ] }, { "pmid": "23274894", "text": "G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 64, 71 ] ] }, { "pmid": "23274894", "text": "A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274894", "text": "G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "23274894", "text": "G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "23274894", "text": "As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 96, 103 ] ] }, { "pmid": "23274894", "text": "Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice.", "type": "CHEMICAL", "entities": [ "Glucose", "calcium" ], "offsets": [ [ 0, 7 ], [ 70, 77 ] ] }, { "pmid": "23274894", "text": "These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.", "type": "CHEMICAL", "entities": [ "glucose-6-phosphate" ], "offsets": [ [ 108, 127 ] ] }, { "pmid": "23362262", "text": "Transforming growth factor β integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy.\n", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "23362262", "text": "In many renal diseases, transforming growth factor β (TGFβ)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 126, 135 ] ] }, { "pmid": "23362262", "text": "The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Prolonged incubation of mesangial cells with TGFβ reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Sustained TGFβ activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Using the mTOR inhibitor PP242, we found that TGFβ-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression.", "type": "CHEMICAL", "entities": [ "PP242,", "PP242" ], "offsets": [ [ 20, 26 ], [ 147, 152 ] ] }, { "pmid": "23362262", "text": "PP242-induced reversal of deptor suppression by TGFβ was associated with a significant inhibition of TGFβ-stimulated protein synthesis and hypertrophy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGFβ receptor-specific Smad 3 signaling, prevented TGFβ-induced suppression of deptor abundance and TORC1/2 activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGFβ stimulation concomitant with increased TORC1 and TORC2 activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGFβ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "These data reveal the requirement of both early and late activation of mTOR for TGFβ-induced protein synthesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23362262", "text": "Our results support that TGFβ-stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22537794", "text": "R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.\n", "type": "CHEMICAL", "entities": [ "R-modafinil", "armodafinil", "dopamine" ], "offsets": [ [ 0, 11 ], [ 13, 24 ], [ 36, 44 ] ] }, { "pmid": "22537794", "text": "BACKGROUND: (+/-)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence.", "type": "CHEMICAL", "entities": [ "(+/-)-Modafinil" ], "offsets": [ [ 12, 27 ] ] }, { "pmid": "22537794", "text": "The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated.", "type": "CHEMICAL", "entities": [ "R-enantiomer of modafinil" ], "offsets": [ [ 4, 29 ] ] }, { "pmid": "22537794", "text": "METHODS: (+/-)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria.", "type": "CHEMICAL", "entities": [ "(+/-)-Modafinil", "[(3)H] dopamine", "DA", "[(3)H]WIN 35428", "dopamine" ], "offsets": [ [ 9, 24 ], [ 108, 123 ], [ 125, 127 ], [ 140, 155 ], [ 173, 181 ] ] }, { "pmid": "22537794", "text": "Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007.", "type": "CHEMICAL", "entities": [ "cocaine", "DA", "JHW 007" ], "offsets": [ [ 24, 31 ], [ 49, 51 ], [ 70, 77 ] ] }, { "pmid": "22537794", "text": "R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure.", "type": "CHEMICAL", "entities": [ "R- and S-modafinil", "cocaine" ], "offsets": [ [ 0, 18 ], [ 110, 117 ] ] }, { "pmid": "22537794", "text": "RESULTS: (+/-)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer.", "type": "CHEMICAL", "entities": [ "(+/-)-, R-, and S-modafinil", "DA", "cocaine", "R-modafinil" ], "offsets": [ [ 9, 36 ], [ 65, 67 ], [ 94, 101 ], [ 108, 119 ] ] }, { "pmid": "22537794", "text": "Molecular docking studies revealed subtle differences in binding modes for the enantiomers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22537794", "text": "R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less.", "type": "CHEMICAL", "entities": [ "R-modafinil", "S-modafinil" ], "offsets": [ [ 0, 11 ], [ 103, 114 ] ] }, { "pmid": "22537794", "text": "Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action.", "type": "CHEMICAL", "entities": [ "cocaine", "[2-(trimethylammonium)ethyl]-methanethiosulfonate", "R- and S-modafinil", "DA", "cocaine" ], "offsets": [ [ 124, 131 ], [ 164, 213 ], [ 292, 310 ], [ 347, 349 ], [ 420, 427 ] ] }, { "pmid": "22537794", "text": "Both enantiomers fully substituted in mice trained to discriminate cocaine from saline.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "22537794", "text": "CONCLUSIONS: R-modafinil displays an in vitro profile different from cocaine.", "type": "CHEMICAL", "entities": [ "R-modafinil", "cocaine" ], "offsets": [ [ 13, 24 ], [ 69, 76 ] ] }, { "pmid": "22537794", "text": "Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.", "type": "CHEMICAL", "entities": [ "R-modafinil" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23411172", "text": "Apple polyphenols suppress antigen presentation of ovalbumin by THP-1-derived dendritic cells.\n", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 6, 17 ] ] }, { "pmid": "23411172", "text": "Apple polyphenol extract (AP) and procyanidin contained in AP were investigated for their immunomodulatory effects using THP-1-derived human dendritic cells (TDDCs).", "type": "CHEMICAL", "entities": [ "procyanidin", "polyphenol" ], "offsets": [ [ 34, 45 ], [ 6, 16 ] ] }, { "pmid": "23411172", "text": "The expression levels of HLA-DR (MHC class II) and CD86 (costimulatory molecule) were measured as an indicator of antigen presentation in TDDCs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411172", "text": "A significant decrease in HLA-DR expression was observed in the AP and fractionated procyanidin-treated cells in the presence of ovalbumin (OVA), but no effect on CD86 expression was observed.", "type": "CHEMICAL", "entities": [ "procyanidin" ], "offsets": [ [ 84, 95 ] ] }, { "pmid": "23411172", "text": "The uptake of OVA was not inhibited by AP treatment, and the gene expression of membrane-associated RING-CH ubiquitin E3 ligase, MARCH1, was up-regulated by AP treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411172", "text": "It can therefore be presumed that AP suppresses HLA-DR expression via the ubiquitin-proteasome pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411172", "text": "Furthermore, the up-regulation of IL-12 and TNF-α was found in the procyanidin trimers-treated cells in the presence of OVA.", "type": "CHEMICAL", "entities": [ "procyanidin" ], "offsets": [ [ 67, 78 ] ] }, { "pmid": "23411172", "text": "These results suggest that apple polyphenols would be an effective factor for the development of immunomodulatory agents with suppressive effects of antigen presentation.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 32, 43 ] ] }, { "pmid": "23454835", "text": "Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages.\n", "type": "CHEMICAL", "entities": [ "Alternariol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23454835", "text": "The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest.", "type": "CHEMICAL", "entities": [ "alternariol", "AOH" ], "offsets": [ [ 14, 25 ], [ 27, 30 ] ] }, { "pmid": "23454835", "text": "Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model.", "type": "CHEMICAL", "entities": [ "AOH" ], "offsets": [ [ 34, 37 ] ] }, { "pmid": "23454835", "text": "AOH resulted in an accumulation of cells in the G2/M-phase (4N).", "type": "CHEMICAL", "entities": [ "AOH" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23454835", "text": "Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454835", "text": "Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454835", "text": "Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN).", "type": "CHEMICAL", "entities": [ "AOH" ], "offsets": [ [ 30, 33 ] ] }, { "pmid": "23454835", "text": "AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis.", "type": "CHEMICAL", "entities": [ "AOH" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23454835", "text": "A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Long acting beta-agonists versus theophylline for maintenance treatment of asthma.\n", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 33, 45 ] ] }, { "pmid": "10796631", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Theophylline and long acting beta2-agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma.", "type": "CHEMICAL", "entities": [ "Theophylline" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "10796631", "text": "They represent different classes of drug with differing side-effect profiles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "To assess the comparative efficacy, safety and side-effects of long-acting beta-agonists and theophylline in the maintenance treatment of asthma.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 93, 105 ] ] }, { "pmid": "10796631", "text": "SEARCH STRATEGY: Randomised, controlled trials (RCTs) were identified using the Cochrane Airways Group register.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "The register was searched using the following terms: asthma and theophylline and long acting beta-agonist or formoterol or foradile or eformoterol or salmeterol or bambuterol or bitolterol.", "type": "CHEMICAL", "entities": [ "theophylline", "formoterol", "foradile", "eformoterol", "salmeterol", "bambuterol", "bitolterol" ], "offsets": [ [ 64, 76 ], [ 109, 119 ], [ 123, 131 ], [ 135, 146 ], [ 150, 160 ], [ 164, 174 ], [ 178, 188 ] ] }, { "pmid": "10796631", "text": "Titles and abstracts were then screened to identify potentially relevant studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "The bibliography of each RCT was searched for additional RCTs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Authors of identified RCTs were contacted for other relevant published and unpublished studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "SELECTION CRITERIA:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "All included studies were RCTs involving adults and children with clinical evidence of asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-agonist.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 77, 89 ] ] }, { "pmid": "10796631", "text": "DATA COLLECTION AND ANALYSIS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Potentially relevant trials, identified by screening titles and/or abstracts, were obtained.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Two reviewers independently assessed full text versions of these trials to decided whether the trial should be included in the review, and assessed its methodological quality.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Where there was disagreement between reviewers, this was resolved by consensus, or reference to a third party.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Data were extracted by two independent reviewers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Inter-rater reliability was assessed by simple agreement.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Study authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Relevant pharmaceutical manufacturers were also contacted.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "MAIN RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Six trials met the inclusion criteria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Five used salmeterol and one, biltoterol.", "type": "CHEMICAL", "entities": [ "salmeterol", "biltoterol" ], "offsets": [ [ 10, 20 ], [ 30, 40 ] ] }, { "pmid": "10796631", "text": "They were of varying quality.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "There was a trend for salmeterol to improve FEV1 more than theophylline in three studies and salmeterol use was associated with more symptom free nights.", "type": "CHEMICAL", "entities": [ "salmeterol", "theophylline", "salmeterol" ], "offsets": [ [ 22, 32 ], [ 59, 71 ], [ 93, 103 ] ] }, { "pmid": "10796631", "text": "Bitolterol, used in only one study, was reported to be less effective than theophylline.", "type": "CHEMICAL", "entities": [ "Bitolterol", "theophylline" ], "offsets": [ [ 0, 10 ], [ 75, 87 ] ] }, { "pmid": "10796631", "text": "Subjects taking salmeterol experienced fewer adverse events than those using theophylline (Relative Risk 0.38; 95%Confidence Intervals 0.25, 0.57).", "type": "CHEMICAL", "entities": [ "salmeterol", "theophylline" ], "offsets": [ [ 16, 26 ], [ 77, 89 ] ] }, { "pmid": "10796631", "text": "Significant reductions were reported for central nervous system adverse events (Relative Risk 0.51;", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "95%Confidence Intervals 0.30, 0.88) and gastrointestinal adverse events (Relative Risk 0.32; 95%Confidence Intervals 0.17, 0.59).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "REVIEWER'S CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10796631", "text": "Salmeterol may be more effective than theophylline in reducing asthma symptoms including night waking and improving lung function.", "type": "CHEMICAL", "entities": [ "Salmeterol", "theophylline" ], "offsets": [ [ 0, 10 ], [ 38, 50 ] ] }, { "pmid": "10796631", "text": "More adverse events occurred in subjects using theophylline when compared to salmeterol.", "type": "CHEMICAL", "entities": [ "theophylline", "salmeterol" ], "offsets": [ [ 47, 59 ], [ 77, 87 ] ] }, { "pmid": "1435788", "text": "Prohormone convertase-1 will process prorelaxin, a member of the insulin family of hormones.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "Relaxin is a polypeptide hormone involved in remodeling of the birth canal during parturition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "It is synthesized as a preprohormone precursor, which undergoes specific processing to form the mature two-chain disulfide-linked active species that is secreted by the cell.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 113, 122 ] ] }, { "pmid": "1435788", "text": "A major part of this processing requires endoproteolytic cleavage at specific pairs of basic amino acid residues, an event necessary for the maturation of a variety of important biologically active proteins, such as insulin and nerve growth factor.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 93, 103 ] ] }, { "pmid": "1435788", "text": "Human type 2 preprorelaxin was coexpressed in human kidney 293 cells with the candidate prohormone convertase-processing enzymes mPC1 or mPC2, both cloned from the mouse pituitary tumor AtT-20 cell line, or with the yeast kex2 alpha-mating factor-converting enzyme from Saccharomyces cerevisiae.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "Prorelaxin expressed alone in 293 cells was secreted into the culture medium unprocessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "Transient coexpression with mPC1 or kex2, but not with mPC2, resulted in the secretion of a low mol wt species with an electrophoretic mobility very similar, if not identical, to that of authentic mature relaxin purified from human placenta.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "This species was precipitable by monoclonal antibodies specific for relaxin and had a retention time on reverse phase HPLC comparable to that of relaxin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "Its analysis by both electrospray and fast atom bombardment mass spectrometry generated mass data that were consistent only with mature relaxin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1435788", "text": "The basic residues required for mPC1-dependent cleavage of prorelaxin are defined by site-directed mutagenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "Binding between heparin and the integrin VLA-4.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "Heparin possesses antimetastatic effects that were related to various molecular mechanisms beyond anticoagulant activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "The ability of heparin to interfere with the function of adhesion receptors in the metastatic course appears as a promising therapeutic approach.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "This refers to numerous findings that heparin attenuates metastasis in a selectin-dependent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "We recently demonstrated that heparin interferes with the integrin VLA-4 on murine melanoma cells binding to VCAM-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "To confirm this activity and to obtain further insight into molecular recognition of heparin by VLA-4, we investigated the inhibition of VLA-4 mediated binding of human melanoma MV3 cells to immobilised VCAM-1 by different heparins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "The size of heparin has an important impact on inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19888514", "text": "Unfractionated heparin (UFH) and tinzaparin, a low-molecular-weight heparin (LMWH) representing a mean of about 18-20 monomers, displayed high inhibitory activity.", "type": "CHEMICAL", "entities": [ "tinzaparin" ], "offsets": [ [ 33, 43 ] ] }, { "pmid": "19888514", "text": "Fractionating tinzaparin to 14-18 monomers reduced inhibition slightly, while the pentasaccharide fondaparinux was without effects.", "type": "CHEMICAL", "entities": [ "pentasaccharide fondaparinux", "tinzaparin" ], "offsets": [ [ 82, 110 ], [ 14, 24 ] ] }, { "pmid": "19888514", "text": "To confirm molecular recognition of tinzaparin by VLA-4, a surface acoustic wave-biosensor was applied.", "type": "CHEMICAL", "entities": [ "tinzaparin" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "19888514", "text": "A VLA-4 containing membrane preparation of MV3 cells was immobilised at the sensors to allow for detection of kinetic binding constants of tinzaparin compared to VCAM-1.", "type": "CHEMICAL", "entities": [ "tinzaparin" ], "offsets": [ [ 139, 149 ] ] }, { "pmid": "19888514", "text": "Tinzaparin binds to VLA-4 with affinity in the low micromolar range (4.61 x 10(-6) M), which clearly indicates specific molecular recognition.", "type": "CHEMICAL", "entities": [ "Tinzaparin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "19888514", "text": "Furthermore, tinzaparin displays a nearly identical k(off) compared to VCAM-1 (5.13 x 10(-3) s(-1) versus 3.44 x 10(-3) s(-1)) which is evident for interference with the ligand binding.", "type": "CHEMICAL", "entities": [ "tinzaparin" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "19888514", "text": "The data provide evidence for a direct confirmation of heparin binding to VLA-4 and thus, contribute to understand the antimetastatic activity of heparin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15635044", "text": "Extracellular loop 3 (EL3) and EL3-proximal transmembrane helix 7 of the mammalian type I and type II gonadotropin-releasing hormone (GnRH) receptors determine differential ligand selectivity to GnRH-I and GnRH-II.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15635044", "text": "Mammalian type I and II gonadotropin-releasing hormone (GnRH) receptors (GnRHRs) show differential ligand preference for GnRH-I and GnRH-II, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15635044", "text": "Using a variety of chimeric receptors based on green monkey GnRHR-2 (gmGnRHR-2), a representative type II GnRHR, and rat GnRHR, a representative type I GnRHR, this study elucidated specific domains responsible for this ligand selectivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15635044", "text": "A chimeric gmGnRHR-2 with the extracellular loop 3 (EL3) and EL3-proximal transmembrane helix 7 (TMH7) of rat GnRHR showed a great increase in ligand sensitivity to GnRH-I but not to GnRH-II.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15635044", "text": "Point-mutation studies indicate that four amino acids, Leu/Phe(7.38), Leu/Phe(7.43), Ala/Pro(7.46), and Pro/Cys(7.47) in TMH7 are critical for ligand selectivity as well as receptor conformation.", "type": "CHEMICAL", "entities": [ "amino acids", "Leu", "Phe", "Leu", "Phe", "Ala", "Pro", "Pro", "Cys" ], "offsets": [ [ 42, 53 ], [ 55, 58 ], [ 59, 62 ], [ 70, 73 ], [ 74, 77 ], [ 85, 88 ], [ 89, 92 ], [ 104, 107 ], [ 108, 111 ] ] }, { "pmid": "15635044", "text": "Furthermore, a combinatory mutation (Pro(7.31)-Pro(7.32)-Ser(7.33) motif to Ser-Glu-Pro in EL3 and Leu(7.38), Leu(7.43), Ala(7.46), and Pro(7.47) to those of rat GnRHR) in gmGnRH-2 exhibited an approximately 500-fold increased sensitivity to GnRH-I, indicating that these residues are critical for discriminating GnRH-II from GnRH-I. [Trp(7)]GnRH-I and [Trp(8)]GnRH-I but not [His(5)]GnRH-I exhibit a higher potency in activating wild-type gmGnRHR-2 than native GnRH-I, indicating that amino acids at positions 7 and 8 of GnRHs are more important than position 5 for differential recognition by type I and type II GnRHRs.", "type": "CHEMICAL", "entities": [ "amino acids", "Pro", "Pro", "Ser", "Ser-Glu-Pro", "Leu", "Leu", "Ala", "Pro" ], "offsets": [ [ 486, 497 ], [ 37, 40 ], [ 47, 50 ], [ 57, 60 ], [ 76, 87 ], [ 99, 102 ], [ 110, 113 ], [ 121, 124 ], [ 136, 139 ] ] }, { "pmid": "15635044", "text": "As a whole, these data suggest a molecular coevolution of ligands and their receptors and facilitate the understanding of the molecular interaction between GnRHs and their cognate receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10403635", "text": "Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication.\n", "type": "CHEMICAL", "entities": [ "pyridostigmine", "physostigmine", "eptastigmine", "sarin" ], "offsets": [ [ 11, 25 ], [ 27, 40 ], [ 42, 54 ], [ 98, 103 ] ] }, { "pmid": "10403635", "text": "The acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic acetylcholine levels.", "type": "CHEMICAL", "entities": [ "acetylcholine", "organophosphorus" ], "offsets": [ [ 193, 206 ], [ 22, 38 ] ] }, { "pmid": "10403635", "text": "The protective actions of intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication were studied in mice.", "type": "CHEMICAL", "entities": [ "pyridostigmine", "physostigmine", "eptastigmine", "organophosphate", "sarin" ], "offsets": [ [ 60, 74 ], [ 76, 89 ], [ 91, 103 ], [ 112, 127 ], [ 168, 173 ] ] }, { "pmid": "10403635", "text": "The acute intragastric (i.g.) toxicity (LD50) of sarin with and without the pretreatments was tested by the up-and-down method.", "type": "CHEMICAL", "entities": [ "sarin" ], "offsets": [ [ 49, 54 ] ] }, { "pmid": "10403635", "text": "The mice received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g. administration of sarin.", "type": "CHEMICAL", "entities": [ "pyridostigmine", "physostigmine", "physostigmine", "eptastigmine", "sarin" ], "offsets": [ [ 18, 32 ], [ 59, 72 ], [ 103, 116 ], [ 128, 140 ], [ 268, 273 ] ] }, { "pmid": "10403635", "text": "Physostigmine was also administered with phosphotriesterase.", "type": "CHEMICAL", "entities": [ "Physostigmine" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "10403635", "text": "Phosphotriesterase was the most effective antidote in sarin intoxication.", "type": "CHEMICAL", "entities": [ "sarin" ], "offsets": [ [ 54, 59 ] ] }, { "pmid": "10403635", "text": "The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase.", "type": "CHEMICAL", "entities": [ "sarin" ], "offsets": [ [ 19, 24 ] ] }, { "pmid": "10403635", "text": "Physostigmine was the most effective carbamate in sarin exposure.", "type": "CHEMICAL", "entities": [ "Physostigmine", "carbamate", "sarin" ], "offsets": [ [ 0, 13 ], [ 37, 46 ], [ 50, 55 ] ] }, { "pmid": "10403635", "text": "The protective ratios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respectively.", "type": "CHEMICAL", "entities": [ "physostigmine", "pyridostigmine" ], "offsets": [ [ 25, 38 ], [ 43, 57 ] ] }, { "pmid": "10403635", "text": "Eptastigmine did not give any protection against sarin toxicity.", "type": "CHEMICAL", "entities": [ "Eptastigmine", "sarin" ], "offsets": [ [ 0, 12 ], [ 49, 54 ] ] }, { "pmid": "10403635", "text": "Both the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure.", "type": "CHEMICAL", "entities": [ "physostigmine", "sarin" ], "offsets": [ [ 32, 45 ], [ 113, 118 ] ] }, { "pmid": "10403635", "text": "In phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity.", "type": "CHEMICAL", "entities": [ "physostigmine", "sarin" ], "offsets": [ [ 26, 39 ], [ 77, 82 ] ] }, { "pmid": "10403635", "text": "Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 value for sarin 4.3-fold.", "type": "CHEMICAL", "entities": [ "physostigmine", "sarin" ], "offsets": [ [ 48, 61 ], [ 91, 96 ] ] }, { "pmid": "10403635", "text": "The animals pretreated with phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls.", "type": "CHEMICAL", "entities": [ "ephysostigmine" ], "offsets": [ [ 47, 61 ] ] }, { "pmid": "10403635", "text": "In conclusion, phosphotriesterase and physostigmine were the most effective treatments against sarin intoxication.", "type": "CHEMICAL", "entities": [ "physostigmine", "sarin" ], "offsets": [ [ 38, 51 ], [ 95, 100 ] ] }, { "pmid": "10403635", "text": "However, eptastigmine did not provide any protection against sarin toxicity.", "type": "CHEMICAL", "entities": [ "eptastigmine", "sarin" ], "offsets": [ [ 9, 21 ], [ 61, 66 ] ] }, { "pmid": "23238784", "text": "Phase 1 and phase 2 drug metabolism and bile acid production of HepaRG cells in a bioartificial liver in absence of dimethyl sulfoxide.\n", "type": "CHEMICAL", "entities": [ "dimethyl sulfoxide", "bile acid" ], "offsets": [ [ 116, 134 ], [ 40, 49 ] ] }, { "pmid": "23238784", "text": "The human liver cell line HepaRG has been recognized as a promising source for in vitro testing of metabolism and toxicity of compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238784", "text": "However, currently the hepatic differentiation of these cells relies on exposure to dimethylsulfoxide (DMSO), which, as a side effect, has a cytotoxic effect and represses an all-round hepatic functionality.", "type": "CHEMICAL", "entities": [ "dimethylsulfoxide", "DMSO" ], "offsets": [ [ 84, 101 ], [ 103, 107 ] ] }, { "pmid": "23238784", "text": "The AMC-bioartificial liver (AMC-BAL) is a three-dimensional bioreactor that has previously been shown to upregulate various liver functions of cultured cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238784", "text": "We therefore cultured HepaRG cells in the AMC-BAL without DMSO and characterized the drug metabolism.", "type": "CHEMICAL", "entities": [ "DMSO" ], "offsets": [ [ 58, 62 ] ] }, { "pmid": "23238784", "text": "Within 14 days of culture, the HepaRG-AMC-BALs contained highly polarized viable liver-like tissue with heterogeneous expression of CYP3A4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238784", "text": "We found a substantial metabolism of the tested substrates, ranging from 26% (UDP-glucuronosyltransferase 1A1), 47% (CYP3A4), to 240% (CYP2C9) of primary human hepatocytes.", "type": "CHEMICAL", "entities": [ "UDP" ], "offsets": [ [ 78, 81 ] ] }, { "pmid": "23238784", "text": "The CYP3A4 activity could be induced 2-fold by rifampicin, whereas CYP2C9 activity remained equally high.", "type": "CHEMICAL", "entities": [ "rifampicin" ], "offsets": [ [ 47, 57 ] ] }, { "pmid": "23238784", "text": "The HepaRG-AMC-BAL secreted bile acids at 43% the rate of primary human hepatocytes and demonstrated hydroxylation, conjugation, and transport of bile salts.", "type": "CHEMICAL", "entities": [ "bile acids", "bile salts" ], "offsets": [ [ 28, 38 ], [ 146, 156 ] ] }, { "pmid": "23238784", "text": "Concluding, culturing HepaRG cells in the AMC-BAL yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering DMSO addition superfluous for the promotion of drug metabolism.", "type": "CHEMICAL", "entities": [ "DMSO" ], "offsets": [ [ 150, 154 ] ] }, { "pmid": "23238784", "text": "Therefore, AMC-BAL culturing makes the HepaRG cells more suitable for testing metabolism and toxicity of drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23328072", "text": "Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells.\n", "type": "CHEMICAL", "entities": [ "vitamin D" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "23328072", "text": "Fat infiltration within muscle is one of a number of features of vitamin D deficiency, which leads to a decline in muscle functionality.", "type": "CHEMICAL", "entities": [ "vitamin D" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "23328072", "text": "The origin of this fat is unclear, but one possibility is that it forms from myogenic precursor cells present in the muscle, which transdifferentiate into mature adipocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23328072", "text": "The current study examined the effect of the active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), on the capacity of the C2C12 muscle cell line to differentiate towards the myogenic and adipogenic lineages.", "type": "CHEMICAL", "entities": [ "vitamin D₃", "1,25-dihydroxyvitamin D₃", "1,25(OH)₂D₃" ], "offsets": [ [ 60, 70 ], [ 72, 96 ], [ 98, 109 ] ] }, { "pmid": "23328072", "text": "Cells were cultured in myogenic or adipogenic differentiation media containing increasing concentrations (0, 10⁻¹³, 10⁻¹¹, 10⁻⁹, 10⁻⁷ or 10⁻⁵  M) of 1,25(OH)₂D₃ for up to 6 days and markers of muscle and fat development measured.", "type": "CHEMICAL", "entities": [ "1,25(OH)₂D₃" ], "offsets": [ [ 141, 152 ] ] }, { "pmid": "23328072", "text": "Mature myofibres were formed in both adipogenic and myogenic media, but fat droplets were only observed in adipogenic media.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23328072", "text": "Relative to controls, low physiological concentrations (10⁻¹³ and 10⁻¹¹  M) of 1,25(OH)₂D3 increased fat droplet accumulation, whereas high physiological (10⁻⁹  M) and supraphysiological concentrations (≥10⁻⁷  M) inhibited fat accumulation.", "type": "CHEMICAL", "entities": [ "1,25(OH)₂D3" ], "offsets": [ [ 45, 56 ] ] }, { "pmid": "23328072", "text": "This increased accumulation of fat with low physiological concentrations (10⁻¹³ and 10⁻¹¹  M) was associated with a sequential up-regulation of PPARγ2 (PPARG) and FABP4 mRNA, indicating formation of adipocytes, whereas higher concentrations (≥10⁻⁹  M) reduced all these effects, and the highest concentration (10⁻⁵  M) appeared to have toxic effects.", "type": "CHEMICAL", "entities": [ "1,25(OH)₂D₃" ], "offsets": [ [ 356, 367 ] ] }, { "pmid": "23328072", "text": "This is the first study to demonstrate dose-dependent effects of 1,25(OH)₂D₃ on the transdifferentiation of muscle cells into adipose cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23328072", "text": "Low physiological concentrations (possibly mimicking a deficient state) induced adipogenesis, whereas higher (physiological and supraphysiological) concentrations attenuated this effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23466229", "text": "PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency.\n", "type": "CHEMICAL", "entities": [ "PF-04859989", "pyrazole" ], "offsets": [ [ 0, 11 ], [ 81, 89 ] ] }, { "pmid": "23466229", "text": "The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein.", "type": "CHEMICAL", "entities": [ "pyrazole" ], "offsets": [ [ 74, 82 ] ] }, { "pmid": "23466229", "text": "The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties.", "type": "CHEMICAL", "entities": [ "dihydroquinolinone", "tetrahydropyrazolopyridinone" ], "offsets": [ [ 61, 79 ], [ 90, 118 ] ] }, { "pmid": "23466229", "text": "Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53.", "type": "CHEMICAL", "entities": [ "pyrazole" ], "offsets": [ [ 73, 81 ] ] }, { "pmid": "23466229", "text": "The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17378584", "text": "A single residue in leucyl-tRNA synthetase affecting amino acid specificity and tRNA aminoacylation.\n", "type": "CHEMICAL", "entities": [ "leucyl", "amino acid" ], "offsets": [ [ 20, 26 ], [ 53, 63 ] ] }, { "pmid": "17378584", "text": "Human mitochondrial leucyl-tRNA synthetase (hs mt LeuRS) achieves high aminoacylation fidelity without a functional editing active site, representing a rare example of a class I aminoacyl-tRNA synthetase (aaRS) that does not proofread its products.", "type": "CHEMICAL", "entities": [ "aminoacyl", "leucyl" ], "offsets": [ [ 178, 187 ], [ 20, 26 ] ] }, { "pmid": "17378584", "text": "Previous studies demonstrated that the enzyme achieves high selectivity by using a more specific synthetic active site that is not prone to errors under physiological conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17378584", "text": "Interestingly, the synthetic active site of hs mt LeuRS displays a high degree of homology with prokaryotic, lower eukaryotic, and other mitochondrial LeuRSs that are less specific.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17378584", "text": "However, there is one residue that differs between hs mt and Escherichia coli LeuRSs located on a flexible closing loop near the signature KMSKS motif.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17378584", "text": "Here we describe studies indicating that this particular residue (K600 in hs mt LeuRS and L570 in E. coli LeuRS) strongly impacts aminoacylation in two ways: it affects both amino acid discrimination and transfer RNA (tRNA) binding.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 174, 184 ] ] }, { "pmid": "17378584", "text": "While this residue may not be in direct contact with the amino acid or tRNA substrate, substitutions of this position in both enzymes lead to altered catalytic efficiency and perturbations to the discrimination of leucine and isoleucine.", "type": "CHEMICAL", "entities": [ "amino acid", "leucine", "isoleucine" ], "offsets": [ [ 57, 67 ], [ 214, 221 ], [ 226, 236 ] ] }, { "pmid": "17378584", "text": "In addition, tRNA recognition and aminoacylation is affected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17378584", "text": "These findings indicate that the conformation of the synthetic active site, modulated by this residue, may be coupled to specificity and provide new insights into the origins of selectivity without editing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "Neurochemical control of rapid stress-induced changes in brain aromatase activity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "In the male brain, the medial preoptic nucleus (POM) is known to be a critical relay for the activation of sexual behaviour, with the aromatisation of testosterone into 17β-oestradiol (E2 ) playing a key role.", "type": "CHEMICAL", "entities": [ "testosterone", "17β-oestradiol" ], "offsets": [ [ 151, 163 ], [ 169, 183 ] ] }, { "pmid": "23253172", "text": "Acute stress has been shown to differentially modulate the aromatase enzyme in this and other brain nuclei in a sex-specific manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "In POM specifically, stress induces increases in aromatase activity (AA) that are both rapid and reversible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "How the physiological processes initiated during an acute stress response mediate sex-", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "and", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "nuclei- specific changes in AA and which stress response hormones are involved remains to be determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "By examining the relative effects of corticosterone (CORT), arginine vasotocin (AVT, the avian homologue to arginine vasopressin) and corticotrophin-releasing factor (CRF), the present study aimed to define the hormone profile regulating stress-induced increases in AA in the POM.", "type": "CHEMICAL", "entities": [ "corticosterone", "CORT", "arginine vasotocin", "AVT", "arginine vasopressin" ], "offsets": [ [ 36, 50 ], [ 52, 56 ], [ 59, 77 ], [ 79, 82 ], [ 107, 127 ] ] }, { "pmid": "23253172", "text": "We found that CORT, AVT and CRF all appear to play some role in these changes in the male brain.", "type": "CHEMICAL", "entities": [ "CORT", "AVT" ], "offsets": [ [ 13, 17 ], [ 19, 22 ] ] }, { "pmid": "23253172", "text": "In addition, these effects occur in a targeted manner, such that modulation of the enzyme by these hormones only occurs in the POM rather than in all aromatase-expressing nuclei.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "Similarly, in the female brain, the experimental effects were restricted to the POM but only CRF was capable of inducing the stress-like increases in AA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23253172", "text": "These data further demonstrate the high degree of specificity (nuclei-, sex- and hormone-specific effects) in this system, highlighting the complexity of the stress-aromatase link and suggesting modes through which the nongenomic modulation of this enzyme can result in targeted, rapid changes in local oestrogen concentrations.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 302, 311 ] ] }, { "pmid": "11330337", "text": "Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors.\n", "type": "CHEMICAL", "entities": [ "[3H]-oxotremorine-M", "[3H]-quinuclinidyl benzilate" ], "offsets": [ [ 27, 46 ], [ 51, 79 ] ] }, { "pmid": "11330337", "text": "The potential interaction of acetylcholinesterase inhibitors with cholinergic receptors may play a significant role in the therapeutic and/or side-effects associated with this class of compound.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11330337", "text": "In the present study, the capacity of acetylcholinesterase inhibitors to interact with muscarinic receptors was assessed by their ability to displace both [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding in rat brain membranes.", "type": "CHEMICAL", "entities": [ "[3H]-oxotremorine-M", "[3H]-quinuclinidyl benzilate" ], "offsets": [ [ 155, 174 ], [ 179, 207 ] ] }, { "pmid": "11330337", "text": "The [3H]-quinuclinidyl benzilate/[3H]-oxotremorine-M affinity ratios permitted predictions to be made of either the antagonist or agonist properties of the different compounds.", "type": "CHEMICAL", "entities": [ "[3H]-quinuclinidyl benzilate", "[3H]-oxotremorine-M" ], "offsets": [ [ 4, 32 ], [ 33, 52 ] ] }, { "pmid": "11330337", "text": "A series of compounds, representative of the principal classes of acetylcholinesterase inhibitors, displaced [3H]-oxotremorine-M binding with high-to-moderate potency (ambenonium>neostigmine=pyridostigmine=tacrine>physostigmine> edrophonium=galanthamine>desoxypeganine) whereas only ambenonium and tacrine displaced [3H]-quinuclinidyl benzilate binding.", "type": "CHEMICAL", "entities": [ "[3H]-oxotremorine-M", "ambenonium", "neostigmine", "pyridostigmine", "tacrine", "physostigmine", "edrophonium", "galanthamine", "desoxypeganine", "ambenonium", "tacrine", "[3H]-quinuclinidyl benzilate" ], "offsets": [ [ 109, 128 ], [ 168, 178 ], [ 179, 190 ], [ 191, 205 ], [ 206, 213 ], [ 214, 227 ], [ 229, 240 ], [ 241, 253 ], [ 254, 268 ], [ 283, 293 ], [ 298, 305 ], [ 316, 344 ] ] }, { "pmid": "11330337", "text": "Inhibitors such as desoxypeganine, parathion and gramine demonstrated negligible inhibition of the binding of both radioligands.", "type": "CHEMICAL", "entities": [ "desoxypeganine" ], "offsets": [ [ 19, 33 ] ] }, { "pmid": "11330337", "text": "Scatchard plots constructed from the inhibition of [3H]-oxotremorine-M binding in the absence and presence of different inhibitors showed an unaltered Bmax and a reduced affinity constant, indicative of potential competitive or allosteric mechanisms.", "type": "CHEMICAL", "entities": [ "[3H]-oxotremorine-M" ], "offsets": [ [ 51, 70 ] ] }, { "pmid": "11330337", "text": "The capacity of acetylcholinesterase inhibitors, with the exception of tacrine and ambenonium, to displace bound [3H]-oxotremorine-M in preference to [3H]quinuclinidyl benzilate predicts that the former compounds could act as potential agonists at muscarinic receptors.", "type": "CHEMICAL", "entities": [ "tacrine", "ambenonium", "[3H]-oxotremorine-M", "[3H]quinuclinidyl benzilate" ], "offsets": [ [ 71, 78 ], [ 83, 93 ], [ 113, 132 ], [ 150, 177 ] ] }, { "pmid": "11330337", "text": "Moreover, the rank order for potency in inhibiting acetylcholinesterase (ambenonium>neostigmine=physostigmine =tacrine>pyridostigmine=edrophonium=galanthamine >desoxypeganine>parathion>gramine) indicated that the most effective inhibitors of acetylcholinesterase also displaced [3H]-oxotremorine-M to the greatest extent.", "type": "CHEMICAL", "entities": [ "ambenonium", "neostigmine", "physostigmine", "tacrine", "pyridostigmine", "edrophonium", "galanthamine", "desoxypeganine", "parathion", "gramine", "[3H]-oxotremorine-M" ], "offsets": [ [ 73, 83 ], [ 84, 95 ], [ 96, 109 ], [ 111, 118 ], [ 119, 133 ], [ 134, 145 ], [ 146, 158 ], [ 160, 174 ], [ 175, 184 ], [ 185, 192 ], [ 278, 297 ] ] }, { "pmid": "11330337", "text": "The capacity of these inhibitors to displace [3H]-oxotremorine-M binding preclude their utilisation for the prevention of acetylcholine catabolism in rat brain membranes, the latter being required to estimate the binding of acetylcholine to [3H]-oxotremorine-M-labelled muscarinic receptors.", "type": "CHEMICAL", "entities": [ "[3H]-oxotremorine", "acetylcholine", "[3H]-oxotremorine-M" ], "offsets": [ [ 45, 62 ], [ 122, 135 ], [ 241, 260 ] ] }, { "pmid": "11330337", "text": "However, fasciculin-2, a potent peptide inhibitor of acetylcholinesterase (IC50 24 nM), did prevent catabolism of acetylcholine in rat brain membranes with an atypical inhibition isotherm of [3H]-oxotremorine-M binding, thus permitting an estimation of the \"global affinity\" of acetylcholine (Ki 85 nM) for [3H]-oxotremorine-M-labelled muscarinic receptors in rat brain.", "type": "CHEMICAL", "entities": [ "acetylcholine", "[3H]-oxotremorine-M", "acetylcholine", "[3H]-oxotremorine-M" ], "offsets": [ [ 114, 127 ], [ 191, 210 ], [ 278, 291 ], [ 307, 326 ] ] }, { "pmid": "16494569", "text": "Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements.\n", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 33, 43 ] ] }, { "pmid": "16494569", "text": "BACKGROUND: There have been many studies of the effect of high-dose supplementation of vitamin B6 on children and adults with autism, with all but one reporting benefits.", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 87, 97 ] ] }, { "pmid": "16494569", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "The aim of this study was to investigate the biochemical basis for vitamin B6 therapy by measuring the level of total vitamin B6 in the plasma of unsupplemented children with autism spectrum disorder compared to unsupplemented control subjects.", "type": "CHEMICAL", "entities": [ "vitamin B6", "vitamin B6" ], "offsets": [ [ 67, 77 ], [ 118, 128 ] ] }, { "pmid": "16494569", "text": "PARTICIPANTS: Children with autism spectrum disorders (n = 35, age 3-9 years) and unrelated typical children (n = 11, age 6-9 years), all from Arizona, were studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "(This includes the data from 24 children with autism from our previous study.)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "METHODOLOGY:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "A microbiologic assay was used to measure the level of total vitamin B6 (including phosphorylated and unphosphorylated forms), in a blinded fashion.", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 61, 71 ] ] }, { "pmid": "16494569", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "Children with autism had a 75% higher level of total vitamin B6 than the controls (medians of 56 versus 32 ng/mL, respectively, p = 0.00002).", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "16494569", "text": "Most of the autistic children (77%) had levels that were more than 2 standard deviations above the median value of the controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "The autistic girls (n = 5) also had elevated levels (mean of 54.6 ng/mL, median of 60 ng/mL).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "DISCUSSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "These results are consistent with previous studies that found that: (1) pyridoxal kinase had a very low activity in children with autism and (2) pyridoxal 5 phosphate (PLP) levels are unusually low in children with autism.", "type": "CHEMICAL", "entities": [ "pyridoxal", "pyridoxal 5 phosphate", "PLP" ], "offsets": [ [ 72, 81 ], [ 145, 166 ], [ 168, 171 ] ] }, { "pmid": "16494569", "text": "Thus, it appears that the low conversion of pyridoxal and pyridoxine to PLP results in low levels of PLP, which is the active cofactor for 113 known enzymatic reactions, including the formation of many key neurotransmitters.", "type": "CHEMICAL", "entities": [ "pyridoxal", "pyridoxine", "PLP", "PLP" ], "offsets": [ [ 44, 53 ], [ 58, 68 ], [ 72, 75 ], [ 101, 104 ] ] }, { "pmid": "16494569", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16494569", "text": "Total vitamin B6 is abnormally high in autism, consistent with previous reports of an impaired pyridoxal kinase for the conversion of pyridoxine and pyridoxal to PLP.", "type": "CHEMICAL", "entities": [ "vitamin B6", "pyridoxal", "pyridoxine", "pyridoxal", "PLP" ], "offsets": [ [ 6, 16 ], [ 95, 104 ], [ 134, 144 ], [ 149, 158 ], [ 162, 165 ] ] }, { "pmid": "16494569", "text": "This may explain the many published studies of benefits of high-dose vitamin B6 supplementation in some children and adults with autism.", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 69, 79 ] ] }, { "pmid": "23273219", "text": "Synthesis, molecular modeling and evaluation of novel N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Aβ aggregation.\n", "type": "CHEMICAL", "entities": [ "N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone" ], "offsets": [ [ 54, 107 ] ] }, { "pmid": "23273219", "text": "To develop new drugs for treatment of Alzheimer's disease, a group of N'-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones was designed, synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase and aggregation of amyloid beta peptides (1-40, 1-42 and 1-40_1-42).", "type": "CHEMICAL", "entities": [ "N'-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones" ], "offsets": [ [ 69, 123 ] ] }, { "pmid": "23273219", "text": "The enzyme inhibition assay results indicated that compounds moderately inhibit both acetylcholinesterase and butyrylcholinesterase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23273219", "text": "β-Amyloid aggregation results showed that all compounds exhibited remarkable Aβ fibril aggregation inhibition activity with a nearly similar potential as the reference compound rifampicin, which makes them promising anti-Alzheimer drug candidates.", "type": "CHEMICAL", "entities": [ "rifampicin" ], "offsets": [ [ 176, 186 ] ] }, { "pmid": "23273219", "text": "Docking experiments were carried out with the aim to understand the interactions of the most active compounds with the active site of the cholinesterase enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "Effect of anabolic-androgenic steroids and glucocorticoids on the kinetics of hAR and hGR nucleocytoplasmic translocation.\n", "type": "CHEMICAL", "entities": [ "steroids" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "20230007", "text": "Although the qualitative nucleocytoplasmic transport of nuclear hormone receptors (NHRs) has been studied, there is little documentation of the cellular kinetics of this transport.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "Here, translocation studies using the human androgen receptor (hAR) and the human glucocorticoid receptor (hGR) were performed to aid in identifying the mechanism by which anabolic-androgenic steroids (AAS) were activating hAR and potentially interacting with hGR and how glucocorticoid ligands were interacting with the hGR and hAR.", "type": "CHEMICAL", "entities": [ "androgen", "steroids" ], "offsets": [ [ 44, 52 ], [ 192, 200 ] ] }, { "pmid": "20230007", "text": "The real-time analysis of EGFP-labeled hAR and hGR ligand-induced cytoplasm-to-nucleus translocation was performed using fluorescence microscopy to better understand the action of these NHRs in a physiologically relevant cell-based model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "After transient transfection, the hAR and hGR individually translocate as expected (i.e., transport is ligand-induced and dose-dependent) in this model biological system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "Testosterone (TEST) had the fastest translocation rate for the hAR of 0.0525 min(-1).", "type": "CHEMICAL", "entities": [ "Testosterone", "TEST" ], "offsets": [ [ 0, 12 ], [ 14, 18 ] ] }, { "pmid": "20230007", "text": "The other endogenous steroids, androstenedione (ANE) and dihydrotestosterone (DHT), had considerably lower hAR transport rates.", "type": "CHEMICAL", "entities": [ "steroids", "androstenedione", "ANE", "dihydrotestosterone", "DHT" ], "offsets": [ [ 21, 29 ], [ 31, 46 ], [ 48, 51 ], [ 57, 76 ], [ 78, 81 ] ] }, { "pmid": "20230007", "text": "The rates of hAR transport for the exogenous steroids methyltrienelone (MET), nandrolone (NAN), and oxandrolone (OXA) are lower than that of testosterone and similar to those of the endogenous steroids ANE and DHT.", "type": "CHEMICAL", "entities": [ "steroids", "methyltrienelone", "MET", "nandrolone", "NAN", "oxandrolone", "OXA", "testosterone", "steroids", "ANE", "DHT" ], "offsets": [ [ 45, 53 ], [ 54, 70 ], [ 72, 75 ], [ 78, 88 ], [ 90, 93 ], [ 100, 111 ], [ 113, 116 ], [ 141, 153 ], [ 193, 201 ], [ 202, 205 ], [ 210, 213 ] ] }, { "pmid": "20230007", "text": "The hGR transport rates for cortisol (COR) and dexamethasone (DEX) are also presented.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "The synthetic GC, DEX, had a more rapid translocation rate (0.1599 min(-1)) at the highest dose of 100 nM compared to the endogenous GC COR (0.0431 min(-1)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "The data obtained agrees with the existing qualitative data and adds an important ligand-dependent kinetic component to hAR and hGR transport.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20230007", "text": "These kinetic data can aid our understanding of NHR action and interaction with other regulatory proteins, and can be useful in the development of new therapies.", "type": "CHEMICAL", "entities": [ "NHR" ], "offsets": [ [ 48, 51 ] ] }, { "pmid": "17015640", "text": "Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis.\n", "type": "CHEMICAL", "entities": [ "Licofelone" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17015640", "text": "Licofelone, a dual anti-inflammatory drug that inhibits 5-lipoxygenase (LOX) and cyclooxygenase (COX) enzymes, may have a better cardiovascular profile that cycloxygenase-2 inhibitors due to cycloxygenase-1 blockade-mediated antithrombotic effect and a better gastrointestinal tolerability.", "type": "CHEMICAL", "entities": [ "Licofelone" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17015640", "text": "We examined the anti-inflammatory effect of licofelone on atherosclerotic lesions as well as in isolated neutrophils from whole blood of rabbits compared with a selective inhibitor of COX-2, rofecoxib.", "type": "CHEMICAL", "entities": [ "licofelone", "rofecoxib" ], "offsets": [ [ 44, 54 ], [ 191, 200 ] ] }, { "pmid": "17015640", "text": "We also assessed the antithrombotic effect of licofelone in rabbit platelet-rich plasma.", "type": "CHEMICAL", "entities": [ "licofelone" ], "offsets": [ [ 46, 56 ] ] }, { "pmid": "17015640", "text": "For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases.", "type": "CHEMICAL", "entities": [ "licofelone", "rofecoxib" ], "offsets": [ [ 116, 126 ], [ 142, 151 ] ] }, { "pmid": "17015640", "text": "Ten healthy rabbits were used as controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17015640", "text": "Neutrophils and platelets were isolated from peripheral blood of rabbits for ex vivo studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17015640", "text": "Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-kappaB in rabbit atheroma.", "type": "CHEMICAL", "entities": [ "Licofelone" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17015640", "text": "Moreover, licofelone inhibited COX-2 and 5-LOX protein expression in vascular lesions.", "type": "CHEMICAL", "entities": [ "licofelone" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "17015640", "text": "Rofecoxib only diminished COX-2 protein expression and MCP-1 gene expression in vascular atheroma.", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17015640", "text": "Prostaglandin E(2) in rabbit plasma was attenuated by both drugs.", "type": "CHEMICAL", "entities": [ "Prostaglandin E(2)" ], "offsets": [ [ 0, 18 ] ] }, { "pmid": "17015640", "text": "Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B2 production from whole blood.", "type": "CHEMICAL", "entities": [ "Licofelone", "leukotriene B4", "thromboxane B2" ], "offsets": [ [ 0, 10 ], [ 57, 71 ], [ 128, 142 ] ] }, { "pmid": "17015640", "text": "Licofelone reduces neointimal formation and inflammation in an atherosclerotic rabbit model more markedly than rofecoxib.", "type": "CHEMICAL", "entities": [ "Licofelone", "rofecoxib" ], "offsets": [ [ 0, 10 ], [ 111, 120 ] ] }, { "pmid": "17015640", "text": "This effect, together with the antiplatelet activity of licofelone, suggests that this drug may have a favorable cardiovascular profile.", "type": "CHEMICAL", "entities": [ "licofelone" ], "offsets": [ [ 56, 66 ] ] }, { "pmid": "15177307", "text": "No influence of moderate hepatic impairment on the pharmacokinetics of lumiracoxib, an oral COX-2 selective inhibitor.\n", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 71, 82 ] ] }, { "pmid": "15177307", "text": "The aim of this study was to evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of the novel cyclooxygenase-2 (COX-2) selective inhibitor lumiracoxib (Prexige), so that dose recommendations for clinical use can be provided.", "type": "CHEMICAL", "entities": [ "lumiracoxib", "Prexige" ], "offsets": [ [ 161, 172 ], [ 174, 181 ] ] }, { "pmid": "15177307", "text": "This was an open-label, single dose, case-controlled study in which eight subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score: 7-9) and eight demographically-matched healthy subjects received a single oral 400 mg dose of lumiracoxib.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 256, 267 ] ] }, { "pmid": "15177307", "text": "Routine safety assessments were made and blood samples were taken for determination of lumiracoxib concentrations for 96 h post dose.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 87, 98 ] ] }, { "pmid": "15177307", "text": "The ex vivo binding of lumiracoxib to plasma proteins was determined pre dose and at 2 and 12 h post dose.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "15177307", "text": "An analysis of variance was used to detect differences in PK parameters (AUC, Cmax and Tmax) between the treatment groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15177307", "text": "There were no significant differences between subjects with moderate hepatic insufficiency and healthy subjects in the area under the lumiracoxib plasma concentration-time curves (AUC(0-infinity)): 29.2 +/- 6.7 microg h ml(-1) versus 28.7 +/- 6.3 mircrog h ml(-1).", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 134, 145 ] ] }, { "pmid": "15177307", "text": "The rate of absorption of lumiracoxib was not significantly altered by hepatic impairment based on Cmax and Tmax.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "15177307", "text": "The protein-bound fraction of lumiracoxib exceeded 98% both in healthy control subjects and in those with moderate hepatic insufficiency.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 30, 41 ] ] }, { "pmid": "15177307", "text": "A single dose of 400 mg lumiracoxib was well tolerated.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "15177307", "text": "In conclusion, no dose adjustments appear to be required when lumiracoxib is administered to patients with either mild or moderate hepatic impairment.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 62, 73 ] ] }, { "pmid": "23395981", "text": "Alcohol modulates expression of DNA methyltranferases and methyl CpG-/CpG domain-binding proteins in murine embryonic fibroblasts.\n", "type": "CHEMICAL", "entities": [ "Alcohol", "methyl CpG", "CpG" ], "offsets": [ [ 0, 7 ], [ 58, 68 ], [ 70, 73 ] ] }, { "pmid": "23395981", "text": "Fetal alcohol syndrome (FAS), presenting with a constellation of neuro-/psychological, craniofacial and cardiac abnormalities, occurs frequently in offspring of women who consume alcohol during pregnancy, with a prevalence of 1-3 per 1000 livebirths.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 179, 186 ], [ 6, 13 ] ] }, { "pmid": "23395981", "text": "The present study was designed to test the hypothesis that alcohol alters global DNA methylation, and modulates expression of the DNA methyltransferases (DNMTs) and various methyl CpG-binding proteins.", "type": "CHEMICAL", "entities": [ "alcohol", "methyl CpG" ], "offsets": [ [ 59, 66 ], [ 173, 183 ] ] }, { "pmid": "23395981", "text": "Murine embryonic fibroblasts (MEFs), utilized as an in vitro embryonic model system, demonstrated ∼5% reduction in global DNA methylation following exposure to 200mM ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 166, 173 ] ] }, { "pmid": "23395981", "text": "In addition, ethanol induced degradation of DNA methyltransferases (DNMT-1, DNMT-3a, and DNMT-3b), as well as the methyl CpG-binding proteins (MeCP-2, MBD-2 and MBD-3), in MEF cells by the proteasomal pathway.", "type": "CHEMICAL", "entities": [ "ethanol", "methyl CpG" ], "offsets": [ [ 11, 18 ], [ 112, 122 ] ] }, { "pmid": "23395981", "text": "Such degradation could be completely rescued by pretreatment of MEF cells with the proteasomal inhibitor, MG-132.", "type": "CHEMICAL", "entities": [ "MG-132" ], "offsets": [ [ 104, 110 ] ] }, { "pmid": "23395981", "text": "These data support a potential epigenetic molecular mechanism underlying the pathogenesis of FAS during mammalian development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "Clock Gene Expression in the Liver of Streptozotocin-induced and Spontaneous Type 1 Diabetic Rats.\n", "type": "CHEMICAL", "entities": [ "Streptozotocin" ], "offsets": [ [ 38, 52 ] ] }, { "pmid": "23632905", "text": "Several investigations have shown a relation between diabetes and alterations of the liver circadian clock.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "We investigated the diurnal expression of clock genes and clock-controlled genes (CCGs) in 3-hour intervals for a 24-h period in the livers of male streptozotocin (STZ)-treated rats, male spontaneous type 1 diabetic LEW.1AR1-iddm (Iddm) rats, and Iddm rats treated for 10 days with insulin.", "type": "CHEMICAL", "entities": [ "streptozotocin", "STZ" ], "offsets": [ [ 148, 162 ], [ 164, 167 ] ] }, { "pmid": "23632905", "text": "Hepatic mRNA was extracted, and the relative expression of clock genes (Per1, Per2, Bmal1, Clock, Cry1), as well as CCGs (Dbp, E4bp4, RevErbα, Rorα, Pparγ), was analyzed by reverse transcription followed by real-time polymerase chain reaction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "Diabetic STZ and Iddm rats, as well as insulin-substituted Iddm rats, exhibited a significant diurnal expression pattern of clock genes as determined by Cosinor analysis; however, the MESOR (midline estimating statistic of rhythm) of Bmal1, Per2, and Clock transcript expression was altered in Iddm and insulin-substituted Iddm rats.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 6, 9 ] ] }, { "pmid": "23632905", "text": "The hepatic expression of the CCGs Dbp and RevErbα revealed a diurnal rhythm in all investigated groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "Insulin administration to Iddm rats normalized the enhanced MESOR in the expression of Dbp, RevErbα, and E4bp4 to the levels of normoglycemic controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "Cosinor analysis indicated no diurnal rhythm of Pparγ expression in the livers of diabetic STZ or Iddm rats or in those of insulin-substituted Iddm rats.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 86, 89 ] ] }, { "pmid": "23632905", "text": "Also, insulin substitution could not reverse the decreased MESOR of Pparγ expression in Iddm rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632905", "text": "In consequence of the diabetic disease, changes in the expression of clock genes and CCGs suggest alterations in the hepatic peripheral clock mechanism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.\n", "type": "CHEMICAL", "entities": [ "moclobemide", "toloxatone", "monoamine", "monoamine" ], "offsets": [ [ 121, 132 ], [ 137, 147 ], [ 18, 27 ], [ 90, 99 ] ] }, { "pmid": "1705137", "text": "1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "The effects of two reversible, predominantly monoamine oxidase-A (MAO-A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400-200-400 mg day-1) on monoamine metabolites and psychometric performance were compared in a double-blind placebo controlled crossover study in 12 healthy subjects.", "type": "CHEMICAL", "entities": [ "toloxatone", "monoamine", "monoamine", "moclobemide" ], "offsets": [ [ 128, 138 ], [ 165, 174 ], [ 45, 54 ], [ 85, 96 ] ] }, { "pmid": "1705137", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8.", "type": "CHEMICAL", "entities": [ "moclobemide", "toloxatone" ], "offsets": [ [ 16, 27 ], [ 28, 38 ] ] }, { "pmid": "1705137", "text": "Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA).", "type": "CHEMICAL", "entities": [ "noradrenaline", "NA", "3,4-dihydroxyphenylglycol", "DHPG", "homovanillic acid", "HVA", "5-hydroxyindolacetic acid", "5-HIAA" ], "offsets": [ [ 63, 76 ], [ 78, 80 ], [ 83, 108 ], [ 110, 114 ], [ 117, 134 ], [ 136, 139 ], [ 145, 170 ], [ 172, 178 ] ] }, { "pmid": "1705137", "text": "Urine was collected for measurements of normetanephrine and 3-methoxytyramine excretion.", "type": "CHEMICAL", "entities": [ "normetanephrine", "3-methoxytyramine" ], "offsets": [ [ 40, 55 ], [ 60, 77 ] ] }, { "pmid": "1705137", "text": "Psychometric performance (short- and long-term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "3. Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA.", "type": "CHEMICAL", "entities": [ "DHPG", "HVA", "monoamine" ], "offsets": [ [ 109, 113 ], [ 118, 121 ], [ 42, 51 ] ] }, { "pmid": "1705137", "text": "The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P less than 0.001) and the overall decrease in HVA was 38% and 20% (P less than 0.005) on moclobemide and toloxatone, respectively.", "type": "CHEMICAL", "entities": [ "DHPG", "moclobemide", "toloxatone", "HVA", "moclobemide", "toloxatone" ], "offsets": [ [ 20, 24 ], [ 61, 72 ], [ 88, 98 ], [ 147, 150 ], [ 190, 201 ], [ 206, 216 ] ] }, { "pmid": "1705137", "text": "4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "Before the next drug intake, MAO-A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone.", "type": "CHEMICAL", "entities": [ "DHPG", "moclobemide", "toloxatone" ], "offsets": [ [ 83, 87 ], [ 149, 160 ], [ 174, 184 ] ] }, { "pmid": "1705137", "text": "5. Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5-hydroxytryptamine (5-HT) as judged by the fall in plasma 5-HIAA concentration.", "type": "CHEMICAL", "entities": [ "Moclobemide", "toloxatone", "5-hydroxytryptamine", "5-HT", "5-HIAA" ], "offsets": [ [ 3, 14 ], [ 24, 34 ], [ 105, 124 ], [ 126, 130 ], [ 164, 170 ] ] }, { "pmid": "1705137", "text": "Neither drug influenced plasma NA concentration.", "type": "CHEMICAL", "entities": [ "NA" ], "offsets": [ [ 31, 33 ] ] }, { "pmid": "1705137", "text": "6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone.", "type": "CHEMICAL", "entities": [ "normetanephrine", "moclobemide", "toloxatone" ], "offsets": [ [ 43, 58 ], [ 75, 86 ], [ 113, 123 ] ] }, { "pmid": "1705137", "text": "The urinary excretion of 3-methoxytyramine was significantly raised by moclobemide but not by toloxatone.", "type": "CHEMICAL", "entities": [ "3-methoxytyramine", "moclobemide", "toloxatone" ], "offsets": [ [ 25, 42 ], [ 71, 82 ], [ 94, 104 ] ] }, { "pmid": "1705137", "text": "7.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705137", "text": "Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.", "type": "CHEMICAL", "entities": [ "moclobemide", "toloxatone" ], "offsets": [ [ 8, 19 ], [ 24, 34 ] ] }, { "pmid": "23453071", "text": "Synthesis and evaluation of nicotinamide derivative as anti-angiogenic agents.\n", "type": "CHEMICAL", "entities": [ "nicotinamide" ], "offsets": [ [ 28, 40 ] ] }, { "pmid": "23453071", "text": "Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells.", "type": "CHEMICAL", "entities": [ "BRN-103", "nicotinamide" ], "offsets": [ [ 31, 38 ], [ 42, 54 ] ] }, { "pmid": "23453071", "text": "During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects.", "type": "CHEMICAL", "entities": [ "nicotinamide" ], "offsets": [ [ 101, 113 ] ] }, { "pmid": "23453071", "text": "We found that 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM. Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway.", "type": "CHEMICAL", "entities": [ "2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide", "BRN-250", "BRN-250", "tyrosine" ], "offsets": [ [ 14, 123 ], [ 125, 132 ], [ 327, 334 ], [ 396, 404 ] ] }, { "pmid": "23453071", "text": "Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy.", "type": "CHEMICAL", "entities": [ "BRN-250" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "10328230", "text": "Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma.\n", "type": "CHEMICAL", "entities": [ "batimastat", "captopril" ], "offsets": [ [ 38, 48 ], [ 53, 62 ] ] }, { "pmid": "10328230", "text": "We have examined the effects of the synthetic matrix metalloproteinase inhibitor, batimastat (BB-94) and the angiotensin-converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis-lung-carcinoma cells (3LL) in vitro, and on local growth and lung metastasis of the same tumor implanted intramuscularly in syngeneic C57BL/6 mice.", "type": "CHEMICAL", "entities": [ "angiotensin", "captopril", "batimastat", "BB-94" ], "offsets": [ [ 109, 120 ], [ 150, 159 ], [ 82, 92 ], [ 94, 99 ] ] }, { "pmid": "10328230", "text": "The effect of BB-94 and captopril on the survival of the 3LL-tumor-bearing mice was also examined.", "type": "CHEMICAL", "entities": [ "BB-94", "captopril" ], "offsets": [ [ 14, 19 ], [ 24, 33 ] ] }, { "pmid": "10328230", "text": "Here we report that captopril treatment resulted in decreased transcription and protein levels of gelatinase A by 3LL cells.", "type": "CHEMICAL", "entities": [ "captopril" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "10328230", "text": "Both BB-94 and captopril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells.", "type": "CHEMICAL", "entities": [ "BB-94" ], "offsets": [ [ 5, 10 ] ] }, { "pmid": "10328230", "text": "Treatment of tumor-bearing animals with BB-94 (i.p.) or captopril (in drinking water) resulted in significant inhibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively).", "type": "CHEMICAL", "entities": [ "BB-94", "captopril" ], "offsets": [ [ 40, 45 ], [ 56, 65 ] ] }, { "pmid": "10328230", "text": "When both agents were given, they acted in synergy, resulting in 51 and 80% inhibition of tumor growth and metastasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10328230", "text": "The survival time of the mice treated with both BB-94 and captopril was also significantly longer compared with the groups treated with each agent alone or with the vehicle.", "type": "CHEMICAL", "entities": [ "BB-94", "captopril" ], "offsets": [ [ 48, 53 ], [ 58, 67 ] ] }, { "pmid": "10328230", "text": "Our data support the hypothesis of an essential role of metalloproteinase(s) in the metastatic process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10328230", "text": "Moreover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti-tumor and anti-metastatic effect of BB-94 and captopril and their combination.", "type": "CHEMICAL", "entities": [ "BB-94", "captopril" ], "offsets": [ [ 154, 159 ], [ 164, 173 ] ] }, { "pmid": "10328230", "text": "It is conceivable that this combination could be tested in selected clinical conditions as an adjuvant modality to cytotoxic therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17079868", "text": "Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women.\n", "type": "CHEMICAL", "entities": [ "Methionine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17079868", "text": "Homocysteine (Hcy) is thought to play an important role in the development of osteoporosis and fracture.", "type": "CHEMICAL", "entities": [ "Homocysteine", "Hcy" ], "offsets": [ [ 0, 12 ], [ 14, 17 ] ] }, { "pmid": "17079868", "text": "Methionine synthase reductase (MTRR) is an enzyme involved in the conversion of Hcy to methionine.", "type": "CHEMICAL", "entities": [ "Methionine", "Hcy", "methionine" ], "offsets": [ [ 0, 10 ], [ 80, 83 ], [ 87, 97 ] ] }, { "pmid": "17079868", "text": "We hypothesized that certain genetic polymorphisms of MTRR leading to reduced enzyme activity may cause hyperhomocysteinemia and affect bone metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17079868", "text": "We therefore examined the associations of the A66G and C524T polymorphisms of the MTRR gene with bone mineral density (BMD) and serum osteocalcin levels in postmenopausal women.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17079868", "text": "Although we did not detect any significant associations between MTRR polymorphisms and BMD or serum osteocalcin levels, we found that the 66G/524C haplotype, which has reduced enzyme activity, was significantly associated with serum osteocalcin levels in a gene-dose dependent manner (P = 0.002).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17079868", "text": "That is, the highest osteocalcin levels (34.5 +/- 16.8 ng/ml) were observed in subjects bearing two copies, intermediate osteocalcin levels (32.6 +/- 14.4 ng/ml) were observed in subjects bearing one copy, and the lowest levels of osteocalcin (28.8 +/- 10.9 ng/ml) were observed in subjects bearing no copies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17079868", "text": "These results suggest that the 66G/524C haplotype of the MTRR gene affect bone turn over rate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "Glutathione peroxidases and redox-regulated transcription factors.\n", "type": "CHEMICAL", "entities": [ "Glutathione" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17081103", "text": "Analysis of the selenoproteome identified five glutathione peroxidases (GPxs) in mammals: cytosolic GPx (cGPx, GPx1), phospholipid hydroperoxide GPx (PHGPX, GPx4), plasma GPx (pGPX, GPx3), gastrointestinal GPx (GI-GPx, GPx2) and, in humans, GPx6, which is restricted to the olfactory system.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 47, 58 ] ] }, { "pmid": "17081103", "text": "GPxs reduce hydroperoxides to the corresponding alcohols by means of glutathione (GSH).", "type": "CHEMICAL", "entities": [ "alcohols", "glutathione", "GSH" ], "offsets": [ [ 48, 56 ], [ 69, 80 ], [ 82, 85 ] ] }, { "pmid": "17081103", "text": "They have long been considered to only act as antioxidant enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "Increasing evidence, however, suggests that nature has not created redundant GPxs just to detoxify hydroperoxides.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "cGPx clearly acts as an antioxidant, as convincingly demonstrated in GPx1-knockout mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "PHGPx specifically interferes with NF-kappaB activation by interleukin-1, reduces leukotriene and prostanoid biosynthesis, prevents COX-2 expression, and is indispensable for sperm maturation and embryogenesis.", "type": "CHEMICAL", "entities": [ "leukotriene", "prostanoid" ], "offsets": [ [ 82, 93 ], [ 98, 108 ] ] }, { "pmid": "17081103", "text": "GI-GPx, which is not exclusively expressed in the gastrointestinal system, is upregulated in colon and skin cancers and in certain cultured cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "GI-GPx is a target for Nrf2, and thus is part of the adaptive response by itself, while PHGPx might prevent cancer by interfering with inflammatory pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "In conclusion, cGPx, PHGPx and GI-GPx have distinct roles, particularly in cellular defence mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17081103", "text": "Redox sensing and redox regulation of metabolic events have become attractive paradigms to unravel the specific and in part still enigmatic roles of GPxs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPL(S447X)) gene therapy for lipoprotein lipase deficiency: an open-label trial.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a 40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline.", "type": "CHEMICAL", "entities": [ "triglyceride" ], "offsets": [ [ 133, 145 ] ] }, { "pmid": "22717743", "text": "Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "Half of the patients demonstrated a 40% reduction in fasting TG between 3 and 12 weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22717743", "text": "TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23152189", "text": "2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.\n", "type": "CHEMICAL", "entities": [ "2,3,7,8-Tetrachlorodibenzo-p-dioxin", "oxygen" ], "offsets": [ [ 0, 35 ], [ 68, 74 ] ] }, { "pmid": "23152189", "text": "Chloracne is commonly observed in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood.", "type": "CHEMICAL", "entities": [ "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD" ], "offsets": [ [ 52, 87 ], [ 89, 93 ] ] }, { "pmid": "23152189", "text": "Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 77, 81 ] ] }, { "pmid": "23152189", "text": "TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis.", "type": "CHEMICAL", "entities": [ "TCDD", "ceramide" ], "offsets": [ [ 0, 4 ], [ 158, 166 ] ] }, { "pmid": "23152189", "text": "Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids.", "type": "CHEMICAL", "entities": [ "ceramides", "TCDD", "ceramides", "fatty acids" ], "offsets": [ [ 62, 71 ], [ 90, 94 ], [ 118, 127 ], [ 136, 147 ] ] }, { "pmid": "23152189", "text": "TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate.", "type": "CHEMICAL", "entities": [ "TCDD", "glucose", "pyruvate" ], "offsets": [ [ 0, 4 ], [ 37, 44 ], [ 167, 175 ] ] }, { "pmid": "23152189", "text": "NADH and Krebs cycle intermediates were decreased, whereas NAD(+) was increased.", "type": "CHEMICAL", "entities": [ "NADH", "NAD(+)" ], "offsets": [ [ 0, 4 ], [ 59, 65 ] ] }, { "pmid": "23152189", "text": "Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide.", "type": "CHEMICAL", "entities": [ "GSH", "glutathione disulfide", "TCDD", "ATP", "oxygen", "hydrogen peroxide", "glutathione", "GSH" ], "offsets": [ [ 59, 62 ], [ 63, 84 ], [ 109, 113 ], [ 234, 237 ], [ 291, 297 ], [ 313, 330 ], [ 14, 25 ], [ 27, 30 ] ] }, { "pmid": "23152189", "text": "Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR.", "type": "CHEMICAL", "entities": [ "Aryl hydrocarbon", "TCDD", "ATP" ], "offsets": [ [ 0, 16 ], [ 88, 92 ], [ 125, 128 ] ] }, { "pmid": "23152189", "text": "Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 83, 87 ] ] }, { "pmid": "23152189", "text": "Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 6, 10 ] ] }, { "pmid": "19427182", "text": "ATP-binding cassette transporter A1 is involved in hepatic alpha-tocopherol secretion.\n", "type": "CHEMICAL", "entities": [ "ATP", "alpha-tocopherol" ], "offsets": [ [ 0, 3 ], [ 59, 75 ] ] }, { "pmid": "19427182", "text": "Vitamin E (alpha-tocopherol) is an essential fat-soluble nutrient with antioxidant properties.", "type": "CHEMICAL", "entities": [ "Vitamin E", "alpha-tocopherol" ], "offsets": [ [ 0, 9 ], [ 11, 27 ] ] }, { "pmid": "19427182", "text": "alpha-Tocopherol transfer protein (alpha-TTP), the product of the gene responsible for familial isolated vitamin E deficiency, plays an important role in maintaining the plasma alpha-tocopherol level by mediating the secretion of alpha-tocopherol by the liver.", "type": "CHEMICAL", "entities": [ "vitamin E", "alpha-tocopherol", "alpha-tocopherol", "alpha-Tocopherol" ], "offsets": [ [ 105, 114 ], [ 177, 193 ], [ 230, 246 ], [ 0, 16 ] ] }, { "pmid": "19427182", "text": "However, the mechanisms underlying hepatic alpha-tocopherol secretion are not fully understood.", "type": "CHEMICAL", "entities": [ "alpha-tocopherol" ], "offsets": [ [ 43, 59 ] ] }, { "pmid": "19427182", "text": "This study was undertaken to elucidate the mechanism of alpha-tocopherol re-efflux from hepatocytes, the cells that have the most important role in regulating plasma-alpha-tocopherol concentrations.", "type": "CHEMICAL", "entities": [ "alpha-tocopherol", "alpha-tocopherol" ], "offsets": [ [ 56, 72 ], [ 166, 182 ] ] }, { "pmid": "19427182", "text": "From in vitro experiments using [(3)H]alpha-tocopheryl acetate and McARH7777 cells that stably express alpha-tocopherol transfer protein (alpha-TTP), the following results were obtained.", "type": "CHEMICAL", "entities": [ "[(3)H]alpha-tocopheryl acetate", "alpha-tocopherol" ], "offsets": [ [ 32, 62 ], [ 103, 119 ] ] }, { "pmid": "19427182", "text": "First, addition of apolipoprotein A-I (apoA-I), a direct acceptor of the ATP-binding cassette transporter A1 (ABCA1)-secreted lipids, increased alpha-tocopherol secretion in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "ATP", "alpha-tocopherol" ], "offsets": [ [ 73, 76 ], [ 144, 160 ] ] }, { "pmid": "19427182", "text": "Second, probucol, an antiatherogenic compound reported to be an inactivator of ABCA1 reduced hepatic alpha-tocopherol secretion.", "type": "CHEMICAL", "entities": [ "probucol", "alpha-tocopherol" ], "offsets": [ [ 8, 16 ], [ 101, 117 ] ] }, { "pmid": "19427182", "text": "Third, ABCA1-RNAi suppressed hepatic alpha-tocopherol secretion.", "type": "CHEMICAL", "entities": [ "alpha-tocopherol" ], "offsets": [ [ 37, 53 ] ] }, { "pmid": "19427182", "text": "In a mouse in vivo experiment, addition of 1% probucol to the diet decreased plasma alpha-tocopherol concentrations.", "type": "CHEMICAL", "entities": [ "probucol", "alpha-tocopherol" ], "offsets": [ [ 46, 54 ], [ 84, 100 ] ] }, { "pmid": "19427182", "text": "These results strongly suggest that ABCA1 is substantially involved in hepatic alpha-tocopherol secretion.", "type": "CHEMICAL", "entities": [ "alpha-tocopherol" ], "offsets": [ [ 79, 95 ] ] }, { "pmid": "16343532", "text": "Crystal structures of protein phosphatase-1 bound to motuporin and dihydromicrocystin-LA: elucidation of the mechanism of enzyme inhibition by cyanobacterial toxins.\n", "type": "CHEMICAL", "entities": [ "motuporin", "dihydromicrocystin-LA" ], "offsets": [ [ 53, 62 ], [ 67, 88 ] ] }, { "pmid": "16343532", "text": "The microcystins and nodularins are tumour promoting hepatotoxins that are responsible for global adverse human health effects and wildlife fatalities in countries where drinking water supplies contain cyanobacteria.", "type": "CHEMICAL", "entities": [ "nodularins", "microcystins" ], "offsets": [ [ 21, 31 ], [ 4, 16 ] ] }, { "pmid": "16343532", "text": "The toxins function by inhibiting broad specificity Ser/Thr protein phosphatases in the host cells, thereby disrupting signal transduction pathways.", "type": "CHEMICAL", "entities": [ "Ser", "Thr" ], "offsets": [ [ 52, 55 ], [ 56, 59 ] ] }, { "pmid": "16343532", "text": "A previous crystal structure of a microcystin bound to the catalytic subunit of protein phosphatase-1 (PP-1c) showed distinct changes in the active site region when compared with protein phosphatase-1 structures bound to other toxins.", "type": "CHEMICAL", "entities": [ "microcystin" ], "offsets": [ [ 34, 45 ] ] }, { "pmid": "16343532", "text": "We have elucidated the crystal structures of the cyanotoxins, motuporin (nodularin-V) and dihydromicrocystin-LA bound to human protein phosphatase-1c (gamma isoform).", "type": "CHEMICAL", "entities": [ "motuporin", "nodularin-V", "dihydromicrocystin-LA" ], "offsets": [ [ 62, 71 ], [ 73, 84 ], [ 90, 111 ] ] }, { "pmid": "16343532", "text": "The atomic structures of these complexes reveal the structural basis for inhibition of protein phosphatases by these toxins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16343532", "text": "Comparisons of the structures of the cyanobacterial toxin:phosphatase complexes explain the biochemical mechanism by which microcystins but not nodularins permanently modify their protein phosphatase targets by covalent addition to an active site cysteine residue.", "type": "CHEMICAL", "entities": [ "microcystins", "nodularins", "cysteine" ], "offsets": [ [ 123, 135 ], [ 144, 154 ], [ 247, 255 ] ] }, { "pmid": "8302852", "text": "A cocaine-sensitive Drosophila serotonin transporter: cloning, expression, and electrophysiological characterization.\n", "type": "CHEMICAL", "entities": [ "cocaine", "serotonin" ], "offsets": [ [ 2, 9 ], [ 31, 40 ] ] }, { "pmid": "8302852", "text": "A cocaine-sensitive, high-affinity Drosophila serotonin (5-hydroxytryptamine; 5HT) transporter cDNA, denoted dSERT1, was isolated and characterized in oocytes.", "type": "CHEMICAL", "entities": [ "cocaine", "serotonin", "5-hydroxytryptamine", "5HT" ], "offsets": [ [ 2, 9 ], [ 46, 55 ], [ 57, 76 ], [ 78, 81 ] ] }, { "pmid": "8302852", "text": "dSERT1 shows little transport of other monoamines and is Na+ and Cl- dependent.", "type": "CHEMICAL", "entities": [ "monoamines", "Na+", "Cl-" ], "offsets": [ [ 39, 49 ], [ 57, 60 ], [ 65, 68 ] ] }, { "pmid": "8302852", "text": "Sequence analysis indicates 12 putative transmembrane domains and strong homologies (approximately 50%) among dSERT1 and mammalian 5HT, norepinephrine, and dopamine transporters.", "type": "CHEMICAL", "entities": [ "5HT", "norepinephrine", "dopamine" ], "offsets": [ [ 131, 134 ], [ 136, 150 ], [ 156, 164 ] ] }, { "pmid": "8302852", "text": "Interestingly, the pharmacological properties of dSERT1, including sensitivity to antidepressants, are more similar to those of mammalian catecholamine transporters than to mammalian 5HT transporters.", "type": "CHEMICAL", "entities": [ "catecholamine", "5HT" ], "offsets": [ [ 138, 151 ], [ 183, 186 ] ] }, { "pmid": "8302852", "text": "Two-electrode voltage-clamp analysis demonstrated 5HT-induced, voltage-dependent currents.", "type": "CHEMICAL", "entities": [ "5HT" ], "offsets": [ [ 50, 53 ] ] }, { "pmid": "8302852", "text": "Cloning and characterization of dSERT1 adds significantly to our knowledge of the diversity of 5HT transporters with regard to primary sequence, pharmacological profile, and permeation properties.", "type": "CHEMICAL", "entities": [ "5HT" ], "offsets": [ [ 95, 98 ] ] }, { "pmid": "23357567", "text": "Formation of mainstream cigarette smoke constituents prioritized by the World Health Organization--yield patterns observed in market surveys, clustering and inverse correlations.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "The WHO TobReg proposed mandating ceilings on selected smoke constituents determined from the market-specific median of nicotine-normalized yield distributions.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 120, 128 ] ] }, { "pmid": "23357567", "text": "Data validating this regulatory concept were obtained from essentially single-blend surveys.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "This process is strongly impacted by inverse correlations among yields.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "In the present study, 18 priority WHO smoke constituent yields (nicotine-normalized) were determined (using two smoking regimens) from 262 commercial brands including American, Virginia and local blends from 13 countries.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 64, 72 ] ] }, { "pmid": "23357567", "text": "Principal Component Analysis was used to identify yields patterns, clustering of blend types and the inverse correlations causing these clusters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "Three principal components explain about 75% of total data variability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "PC1 was sensitive to the relative levels of gas- and particle-phase compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "PC2 and PC3 cluster American- and Virginia-blends, revealing inverse correlations: Nitrogen oxides and amino- or nitroso-aromatic compounds inversely correlate to either formaldehyde and acrolein, or benzo(a)pyrene and di-hydroxybenzenes.", "type": "CHEMICAL", "entities": [ "formaldehyde", "acrolein", "benzo(a)pyrene", "di-hydroxybenzenes", "Nitrogen oxides", "amino", "nitroso" ], "offsets": [ [ 170, 182 ], [ 187, 195 ], [ 200, 214 ], [ 219, 237 ], [ 83, 98 ], [ 103, 108 ], [ 113, 120 ] ] }, { "pmid": "23357567", "text": "These results can be explained by reviewing the processes determining each components smoke delivery.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "Regulatory initiatives simultaneously targeting selected smoke constituents in markets with mixed blend styles will be strongly impacted by the inverse correlations described.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357567", "text": "It is difficult to predict the ultimate impact of such regulations on public health, considering the complex chemistry of cigarette smoke formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 44, 52 ] ] }, { "pmid": "9015795", "text": "This review examines the possible receptor basis of the atypical action of those atypical antipsychotic drugs that elicit low levels of Parkinsonism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "Such an examination requires consistent and accurate dissociation constants for the antipsychotic drugs at the relevant dopamine and serotonin receptors.", "type": "CHEMICAL", "entities": [ "dopamine", "serotonin" ], "offsets": [ [ 120, 128 ], [ 133, 142 ] ] }, { "pmid": "9015795", "text": "It has long been known, however, that the dissociation constant of a given antipsychotic drug at the dopamine D2 receptor varies between laboratories.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 101, 109 ] ] }, { "pmid": "9015795", "text": "Although such variation depends on several factors, it has recently been recognized that the radioligand used to measure the competition between the antipsychotic drug and the radioligand is an important variable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "The present review summarizes information on this radioligand dependence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "In general, a radioligand of low solubility in the membrane (i.e., low tissue:buffer partition) results in a low value for the antipsychotic dissociation constant when the drug competes with the radioligand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "Hence, by first obtaining the antipsychotic dissociation constants using different radioligands of different solubility in the membrane, one can then extrapolate the data to low or \"zero\" ligand solubility.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "The extrapolated value represents the radioligand-independent dissociation constant of the antipsychotic.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "These values are here given for dopamine D2 and D4 receptors, as well as for serotonin 5-HT2A receptors.", "type": "CHEMICAL", "entities": [ "dopamine", "serotonin" ], "offsets": [ [ 32, 40 ], [ 77, 86 ] ] }, { "pmid": "9015795", "text": "These values, moreover, agree with the dissociation constant directly obtained with the radioactive antipsychotic itself.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "For example, clozapine revealed a radioligand-independent value of 1.6 nM at the dopamine D4 receptor, agreeing with the value directly measured with [3H]-clozapine at D4.", "type": "CHEMICAL", "entities": [ "clozapine", "dopamine", "[3H]-clozapine" ], "offsets": [ [ 13, 22 ], [ 81, 89 ], [ 150, 164 ] ] }, { "pmid": "9015795", "text": "However, because clozapine competes with endogenous dopamine, the in vivo concentration of clozapine (to occupy dopamine D4 receptors) can be derived to be about 13 nM, agreeing with the value of 12 to 20 nM in the plasma water or spinal fluid observed in treated patients.", "type": "CHEMICAL", "entities": [ "clozapine", "dopamine", "clozapine", "dopamine" ], "offsets": [ [ 17, 26 ], [ 52, 60 ], [ 91, 100 ], [ 112, 120 ] ] }, { "pmid": "9015795", "text": "The atypical neuroleptics remoxipride, clozapine, perlapine, seroquel, and melperone had low affinity for the dopamine D2 receptor (radioligand-independent dissociation constants of 30 to 90 nM).", "type": "CHEMICAL", "entities": [ "remoxipride", "clozapine", "perlapine", "seroquel", "melperone", "dopamine" ], "offsets": [ [ 26, 37 ], [ 39, 48 ], [ 50, 59 ], [ 61, 69 ], [ 75, 84 ], [ 110, 118 ] ] }, { "pmid": "9015795", "text": "Such low affinity makes these latter five drugs readily displaceable by high levels of endogenous dopamine in the caudate or putamen.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 98, 106 ] ] }, { "pmid": "9015795", "text": "Most typical neuroleptics have radioligand-independent values of 0.3 to 5 nM at dopamine D2 receptors, making them more resistant to displacement by endogenous dopamine.", "type": "CHEMICAL", "entities": [ "dopamine", "dopamine" ], "offsets": [ [ 80, 88 ], [ 160, 168 ] ] }, { "pmid": "9015795", "text": "Finally, a relation was found between the neuroleptic doses for rat catalepsy and the D2:D4 ratio of the radioligand-independent K values for these two receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9015795", "text": "Thus, the atypical neuroleptics appear to fall into two groups, those that have a low affinity for dopamine D2 receptors and those that are selective for dopamine D4 receptors.", "type": "CHEMICAL", "entities": [ "dopamine", "dopamine" ], "offsets": [ [ 99, 107 ], [ 154, 162 ] ] }, { "pmid": "17360707", "text": "alpha7 nicotinic receptor gene promoter polymorphisms in inbred mice affect expression in a cell type-specific fashion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "Inbred mouse strains display significant differences in their levels of brain alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) expression, as measured by binding of the alpha7-selective antagonist alpha-bungarotoxin.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 95, 108 ] ] }, { "pmid": "17360707", "text": "Variations in alpha-bungarotoxin binding have been shown to correlate with an animal's sensitivity to nicotine-induced seizures and sensory gating.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 102, 110 ] ] }, { "pmid": "17360707", "text": "In two inbred mouse strains, C3H/2Ibg (C3H) and DBA/2Ibg (DBA/2), the inter-strain binding differences are linked to a restriction length polymorphism in the alpha7 nAChR gene, Chrna7.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "Despite this finding, the molecular mechanism(s) through which genetic variability in Chrna7 may contribute to alpha7 nAChR expression differences remains unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "However, studies of the human alpha7 nAChR gene (CHRNA7) previously have demonstrated that CHRNA7 promoter polymorphisms are associated with differences in promoter activity as well as differences in sensory processing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "In the present study, a 947-base pair region of the Chrna7 promoter was cloned from both the C3H and DBA/2 inbred mouse strains in an attempt to identify polymorphisms that may underlie alpha7 nAChR differential expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "Sequence analysis of these fragments identified 14 single nucleotide polymorphisms (SNPs).", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 58, 68 ] ] }, { "pmid": "17360707", "text": "A combination of two of these SNPs affects promoter activity in an in vitro luciferase reporter assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17360707", "text": "These results suggest a mechanism through which the Chrna7 promoter genotype may influence interstrain variations in alpha7 nAChR expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "13129570", "text": "Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate receptors of 4-heteroarylmethylidene glutamate analogues.\n", "type": "CHEMICAL", "entities": [ "AMPA", "kainate", "glutamate", "4-heteroarylmethylidene glutamate" ], "offsets": [ [ 39, 43 ], [ 48, 55 ], [ 67, 76 ], [ 90, 123 ] ] }, { "pmid": "13129570", "text": "2-Amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (1) is a potent AMPA receptor agonist with moderate affinity for native kainic acid (KA) receptors, whereas (S)-E-4-(2,2-dimethylpropylidene)glutamic acid (3) show high affinity for the GluR5 subtype of KA receptors and much lower affinity for the GluR2 subtype of AMPA receptors.", "type": "CHEMICAL", "entities": [ "2-Amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid", "kainic acid", "KA", "(S)-E-4-(2,2-dimethylpropylidene)glutamic acid", "KA", "AMPA", "AMPA" ], "offsets": [ [ 0, 64 ], [ 137, 148 ], [ 150, 152 ], [ 173, 219 ], [ 268, 270 ], [ 330, 334 ], [ 81, 85 ] ] }, { "pmid": "13129570", "text": "As an attempt to develop new pharmacological tools for studies of GluR5 receptors, (S)-E-4-(2-thiazolylmethylene)glutamic acid (4a) was designed as a structural hybrid between 1 and 3. 4a was shown to be a potent GluR5 agonist and a high affinity ligand and to indiscriminately bind to the AMPA receptor subtypes GluR1-4 with lower affinities.", "type": "CHEMICAL", "entities": [ "(S)-E-4-(2-thiazolylmethylene)glutamic acid", "AMPA" ], "offsets": [ [ 83, 126 ], [ 290, 294 ] ] }, { "pmid": "13129570", "text": "Compounds 4b-h, in which the 2-thiazolyl substituent of 4a was replaced by other heterocyclic rings, which have previously been incorporated as 5-substituents in AMPA analogues, as exemplified by 1 were also synthesized.", "type": "CHEMICAL", "entities": [ "2-thiazolyl", "heterocyclic", "AMPA" ], "offsets": [ [ 29, 40 ], [ 81, 93 ], [ 162, 166 ] ] }, { "pmid": "13129570", "text": "Compounds 4b-h were either inactive (4e,f) or weaker than 4a as affinity ligands for GluR1-4 and GluR5 with relative potencies comparable with those of the corresponding AMPA analogues as AMPA receptor agonists.", "type": "CHEMICAL", "entities": [ "AMPA", "AMPA" ], "offsets": [ [ 170, 174 ], [ 188, 192 ] ] }, { "pmid": "13129570", "text": "Compounds 4a-h may be useful tools for the progressing pharmacophore mapping of the GluR5 agonist binding site.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "Pranlukast, a leukotriene receptor antagonist, inhibits interleukin-5 production via a mechanism distinct from leukotriene receptor antagonism.\n", "type": "CHEMICAL", "entities": [ "Pranlukast", "leukotriene", "leukotriene" ], "offsets": [ [ 0, 10 ], [ 111, 122 ], [ 14, 25 ] ] }, { "pmid": "15650315", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "Pranlukast, a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist, inhibits not only airway smooth muscle contraction, but also allergic inflammation.", "type": "CHEMICAL", "entities": [ "Pranlukast", "cysteinyl leukotriene" ], "offsets": [ [ 0, 10 ], [ 14, 35 ] ] }, { "pmid": "15650315", "text": "The aim of this study was to determine the mechanism of pranlukast-induced interleukin-5 (IL-5) inhibition in allergic inflammation.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 56, 66 ] ] }, { "pmid": "15650315", "text": "METHODS: Surgically resected human lung tissue was passively sensitized in vitro with mite-allergen-sensitized sera, followed by stimulation with mite allergen after pretreatment of the tissue with pranlukast, dexamethasone, or both.", "type": "CHEMICAL", "entities": [ "pranlukast", "dexamethasone" ], "offsets": [ [ 198, 208 ], [ 210, 223 ] ] }, { "pmid": "15650315", "text": "The IL-5 protein level in the culture medium was measured, and in situ hybridization of IL-5 and CysLTR1 mRNA was performed using lung tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "Pretreatment of lung tissues with pranlukast alone significantly decreased the amount of IL-5 protein in the culture medium by 40%.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "15650315", "text": "The combination of pranlukast and dexamethasone synergistically enhanced this effect.", "type": "CHEMICAL", "entities": [ "pranlukast", "dexamethasone" ], "offsets": [ [ 19, 29 ], [ 34, 47 ] ] }, { "pmid": "15650315", "text": "Quantitative in situ hybridization with image analysis revealed abundant expression of IL-5 mRNA in eosinophils, lymphocytes, and mast cells in sensitized and allergen-stimulated lung tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "CysLTR1 mRNA was detected in macrophages, smooth muscle cells, eosinophils, and mast cells, but was less expressed in lymphocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "Pranlukast-induced inhibition of IL-5 mRNA expression was noted in various cells, irrespective of their CysLTR1 mRNA expression status.", "type": "CHEMICAL", "entities": [ "Pranlukast" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15650315", "text": "In addition, cysteinyl leukotrienes per se failed to upregulate the IL-5 production.", "type": "CHEMICAL", "entities": [ "cysteinyl leukotrienes" ], "offsets": [ [ 13, 35 ] ] }, { "pmid": "15650315", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15650315", "text": "Our results indicate that pranlukast inhibits IL-5 synthesis via a mechanism distinct from CysLTR1 antagonism.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "15955565", "text": "The platelet P2 receptors as molecular targets for old and new antiplatelet drugs.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15955565", "text": "Platelet activation by ADP and ATP plays a crucial role in haemostasis and thrombosis, and their so-called P2 receptors are potential targets for antithrombotic drugs.", "type": "CHEMICAL", "entities": [ "ADP", "ATP" ], "offsets": [ [ 23, 26 ], [ 31, 34 ] ] }, { "pmid": "15955565", "text": "The ATP-gated channel P2X1 and the 2 G protein-coupled P2Y1 and", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "15955565", "text": "P2Y12", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15955565", "text": "ADP receptors selectively contribute to platelet aggregation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15955565", "text": "The P2Y1 receptor is responsible for ADP-induced shape change and weak and transient aggregation, while the P2Y12 receptor is responsible for the completion and amplification of the response to ADP and to all platelet agonists, including thromboxane A2 (TXA2), thrombin, and collagen.", "type": "CHEMICAL", "entities": [ "ADP", "ADP", "thromboxane A2", "TXA2" ], "offsets": [ [ 37, 40 ], [ 194, 197 ], [ 238, 252 ], [ 254, 258 ] ] }, { "pmid": "15955565", "text": "The P2X1 receptor is involved in platelet shape change and in activation by collagen under shear conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15955565", "text": "Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well-established target of antithrombotic drugs like ticlopidine or clopidogrel, which have proved efficacy in many clinical trials and experimental models of thrombosis.", "type": "CHEMICAL", "entities": [ "ticlopidine", "clopidogrel" ], "offsets": [ [ 151, 162 ], [ 166, 177 ] ] }, { "pmid": "15955565", "text": "Competitive P2Y12 antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15955565", "text": "Studies in P2Y1 and P2X1 knockout mice and experimental thrombosis models using selective P2Y1 and P2X1 antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963471", "text": "Effect of thiazolidinediones on equilibrative nucleoside transporter-1 in human aortic smooth muscle cells.\n", "type": "CHEMICAL", "entities": [ "thiazolidinediones" ], "offsets": [ [ 10, 28 ] ] }, { "pmid": "15963471", "text": "Thiazolidinediones are a new class of anti-diabetic agents which increase insulin sensitivity by binding to the peroxisome proliferator-activated receptor gamma (PPAR(gamma)) and stimulating the expression of insulin-responsive genes involved in glucose and lipid metabolism.", "type": "CHEMICAL", "entities": [ "Thiazolidinediones", "glucose" ], "offsets": [ [ 0, 18 ], [ 246, 253 ] ] }, { "pmid": "15963471", "text": "These drugs also have vasodilatory and anti-proliferative effects on vascular smooth muscle cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963471", "text": "However the mechanisms for these actions are not fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963471", "text": "Adenosine is a vasodilator and a substrate of equilibrative nucleoside transporters (ENT).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15963471", "text": "The present study studied the effects of three thiazolidinediones, troglitazone, pioglitazone and ciglitazone, on ENT1 in the human aortic smooth muscle cells (HASMCs).", "type": "CHEMICAL", "entities": [ "thiazolidinediones", "troglitazone", "pioglitazone", "ciglitazone" ], "offsets": [ [ 47, 65 ], [ 67, 79 ], [ 81, 93 ], [ 98, 109 ] ] }, { "pmid": "15963471", "text": "Although incubating HASMCs for 48h with thiazolidinediones had no effect on ENT1 mRNA and protein levels, troglitazone acutely inhibited [3H]adenosine uptake and [3H]NBMPR binding of HASMCs with IC50 values of 2.35+/-0.35 and 3.99+/-0.57microM, respectively.", "type": "CHEMICAL", "entities": [ "thiazolidinediones", "troglitazone", "[3H]adenosine", "[3H]NBMPR" ], "offsets": [ [ 40, 58 ], [ 106, 118 ], [ 137, 150 ], [ 162, 171 ] ] }, { "pmid": "15963471", "text": "The effect of troglitazone on ENT1 was PPAR(gamma)-independent and kinetic studies revealed that troglitazone was a competitive inhibitor of ENT1.", "type": "CHEMICAL", "entities": [ "troglitazone", "troglitazone" ], "offsets": [ [ 97, 109 ], [ 14, 26 ] ] }, { "pmid": "15963471", "text": "In contrast, pioglitazone and ciglitazone had minimal effects on [3H]adenosine uptake by HASMCs.", "type": "CHEMICAL", "entities": [ "pioglitazone", "ciglitazone", "[3H]adenosine" ], "offsets": [ [ 13, 25 ], [ 30, 41 ], [ 65, 78 ] ] }, { "pmid": "15963471", "text": "Troglitazone differs from pioglitazone and ciglitazone in that its side-chain contains a Vitamin E moiety.", "type": "CHEMICAL", "entities": [ "Troglitazone", "pioglitazone", "ciglitazone", "Vitamin E" ], "offsets": [ [ 0, 12 ], [ 26, 38 ], [ 43, 54 ], [ 89, 98 ] ] }, { "pmid": "15963471", "text": "The difference in structure of troglitazone did not account for its inhibitory effect on ENT1 because Vitamin E did not inhibit [3H]adenosine uptake by HASMCs.", "type": "CHEMICAL", "entities": [ "troglitazone", "Vitamin E", "[3H]adenosine" ], "offsets": [ [ 31, 43 ], [ 102, 111 ], [ 128, 141 ] ] }, { "pmid": "15963471", "text": "Using the nucleoside transporter deficient PK15NTD cells stably expressing ENT1 and ENT2, it was found that troglitazone inhibited ENT1 but had no effect on ENT2.", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 108, 120 ] ] }, { "pmid": "15963471", "text": "From these results, it is suggested that troglitazone may enhance the vasodilatory effect of adenosine by inhibiting ENT1.", "type": "CHEMICAL", "entities": [ "troglitazone", "adenosine" ], "offsets": [ [ 41, 53 ], [ 93, 102 ] ] }, { "pmid": "15963471", "text": "Pharmacologically, troglitazone is a novel inhibitor of ENT1.", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 19, 31 ] ] }, { "pmid": "15805193", "text": "Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.\n", "type": "CHEMICAL", "entities": [ "carbamazepine", "phenytoin" ], "offsets": [ [ 105, 118 ], [ 123, 132 ] ] }, { "pmid": "15805193", "text": "Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs).", "type": "CHEMICAL", "entities": [ "Phenytoin", "carbamazepine" ], "offsets": [ [ 0, 9 ], [ 14, 27 ] ] }, { "pmid": "15805193", "text": "As with many AEDs, a broad range of doses is used, with the final \"maintenance\" dose normally determined by trial and error.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15805193", "text": "Although many genes could influence response to these medicines, there are obvious candidates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15805193", "text": "Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 43, 49 ] ] }, { "pmid": "15805193", "text": "Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein.", "type": "CHEMICAL", "entities": [ "Phenytoin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15805193", "text": "We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively.", "type": "CHEMICAL", "entities": [ "carbamazepine", "phenytoin" ], "offsets": [ [ 91, 104 ], [ 109, 118 ] ] }, { "pmid": "15805193", "text": "We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066).", "type": "CHEMICAL", "entities": [ "phenytoin" ], "offsets": [ [ 103, 112 ] ] }, { "pmid": "15805193", "text": "We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively).", "type": "CHEMICAL", "entities": [ "carbamazepine", "phenytoin" ], "offsets": [ [ 135, 148 ], [ 153, 162 ] ] }, { "pmid": "15805193", "text": "This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15805193", "text": "These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine.", "type": "CHEMICAL", "entities": [ "phenytoin", "carbamazepine" ], "offsets": [ [ 238, 247 ], [ 252, 265 ] ] }, { "pmid": "15805193", "text": "Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23517912", "text": "Fisetin regulates obesity by targeting mTORC1 signaling.\n", "type": "CHEMICAL", "entities": [ "Fisetin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23517912", "text": "Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties.", "type": "CHEMICAL", "entities": [ "Fisetin", "flavonol" ], "offsets": [ [ 0, 7 ], [ 11, 19 ] ] }, { "pmid": "23517912", "text": "In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis.", "type": "CHEMICAL", "entities": [ "fisetin", "rapamycin" ], "offsets": [ [ 41, 48 ], [ 138, 147 ] ] }, { "pmid": "23517912", "text": "To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 20, 27 ] ] }, { "pmid": "23517912", "text": "Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "Fisetin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23517912", "text": "To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells.", "type": "CHEMICAL", "entities": [ "fisetin", "fisetin" ], "offsets": [ [ 36, 43 ], [ 140, 147 ] ] }, { "pmid": "23517912", "text": "The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 27, 34 ] ] }, { "pmid": "23517912", "text": "Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23517912", "text": "Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR.", "type": "CHEMICAL", "entities": [ "Fisetin", "fisetin" ], "offsets": [ [ 0, 7 ], [ 94, 101 ] ] }, { "pmid": "23517912", "text": "The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling.", "type": "CHEMICAL", "entities": [ "fisetin", "fisetin", "triglycerides" ], "offsets": [ [ 25, 32 ], [ 96, 103 ], [ 164, 177 ] ] }, { "pmid": "23517912", "text": "Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue.", "type": "CHEMICAL", "entities": [ "Fisetin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23517912", "text": "We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "23517912", "text": "Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "23517912", "text": "Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 11, 18 ] ] }, { "pmid": "10047461", "text": "Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex.\n", "type": "CHEMICAL", "entities": [ "thymidylate", "Tomudex" ], "offsets": [ [ 111, 122 ], [ 142, 149 ] ] }, { "pmid": "10047461", "text": "Tomudex (ZD1694) is a specific antifolate-based thymidylate synthase inhibitor active in a variety of solid tumor malignancies.", "type": "CHEMICAL", "entities": [ "Tomudex", "thymidylate", "ZD1694" ], "offsets": [ [ 0, 7 ], [ 48, 59 ], [ 9, 15 ] ] }, { "pmid": "10047461", "text": "Studies were carried out in vitro to evaluate downstream molecular alterations induced as a consequence of the potent and sustained inhibition of thymidylate synthase by Tomudex.", "type": "CHEMICAL", "entities": [ "thymidylate", "Tomudex" ], "offsets": [ [ 146, 157 ], [ 170, 177 ] ] }, { "pmid": "10047461", "text": "Twenty-four hours following the initial 2-h treatment with Tomudex, human A253 head and neck squamous carcinoma cells, not expressing p53 and p21(WAF1), were accumulated with DNA content characteristic of early S phase of the cell cycle with a concomitant reduction of cells in G1 and G2/M phases.", "type": "CHEMICAL", "entities": [ "Tomudex" ], "offsets": [ [ 59, 66 ] ] }, { "pmid": "10047461", "text": "The changes in cyclin and cdk protein expression and their kinase activities were examined in control and drug-treated A253 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "Tomudex treatment resulted in the decrease in p27(kip1) expression, with an increase in cyclin E and cdk2 protein expression and kinase activities 24 h after a 2-h exposure.", "type": "CHEMICAL", "entities": [ "Tomudex" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10047461", "text": "Although cyclin A protein expression was markedly increased, cyclin A kinase activity was only slightly increased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "Cyclin D1, cyclin B, cdk4, and cdc2 protein expression and kinase activities remain constant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "Lack of activation of cyclin A- and B-cdc2 was associated with a reduced proportion of cells in G2/M phases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "Increased cyclin E-cdk2 protein expression was accompanied by the inhibition of DNA synthesis, with a decrease in E2F-1 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "These results propose that cyclin E-cdk2 kinase can negatively regulate DNA replication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "The studies with dThyd rescue from cyclin E-cdk2 protein overexpression and growth inhibition by Tomudex indicate that increased cyclin E-cdk2 protein expression is associated with effective inhibition of thymidylate synthase and resultant dNTP pool imbalance.", "type": "CHEMICAL", "entities": [ "Tomudex", "thymidylate" ], "offsets": [ [ 97, 104 ], [ 205, 216 ] ] }, { "pmid": "10047461", "text": "Provision of dThyd more than 24 h after exposure to Tomudex allowed cells to replicate DNA for a single cycle back to G1, but did not prevent the profound growth-inhibitory effect manifested in the following 5 days.", "type": "CHEMICAL", "entities": [ "Tomudex" ], "offsets": [ [ 52, 59 ] ] }, { "pmid": "10047461", "text": "Tomudex treatment resulted in a time-dependent induction of the megabase DNA fragments, followed by secondary 50- to 300-kb DNA fragmentation.", "type": "CHEMICAL", "entities": [ "Tomudex" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10047461", "text": "The 50- to 300-kb DNA fragmentation may be derived from the inhibition of DNA synthesis associated with cyclin E-cdk2 activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "These results suggest that the megabase DNA fragmentation is induced as a consequence of inhibition of thymidylate synthase by Tomudex and kilobase DNA fragmentation may correlate with the reduction of p27(kip1) expression and the increase in cyclin E and cdk2 kinase activities.", "type": "CHEMICAL", "entities": [ "thymidylate", "Tomudex" ], "offsets": [ [ 103, 114 ], [ 127, 134 ] ] }, { "pmid": "10047461", "text": "Activation of cyclin E and cdk2 kinases allows cells to transit from G1 to S phase accompanied by the inhibition of DNA synthesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10047461", "text": "The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent.", "type": "CHEMICAL", "entities": [ "Tomudex" ], "offsets": [ [ 98, 105 ] ] }, { "pmid": "23481236", "text": "Modulation of cellular insulin signaling and PTP1B effects by lipid metabolites in skeletal muscle cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481236", "text": "Normal glucose regulation is achieved by having adequate insulin secretion and effective glucose uptake/disposal.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 7, 14 ], [ 89, 96 ] ] }, { "pmid": "23481236", "text": "Excess lipids in peripheral tissues - skeletal muscle, liver and adipose tissue - may attenuate insulin signaling through the protein kinase B (AKt) pathway and up-regulate protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 181, 189 ] ] }, { "pmid": "23481236", "text": "We studied accumulation of lipid metabolites [triglycerides (TAGs), diglycerides (DAGs)] and ceramides in relation to insulin signaling and expression and phosphorylation of PTP1B by preincubating rat skeletal muscle cells (L6 myotubes) with three saturated and three unsaturated free fatty acids (FFAs) (200 μM).", "type": "CHEMICAL", "entities": [ "triglycerides", "TAGs", "diglycerides", "DAGs", "ceramides", "fatty acids" ], "offsets": [ [ 46, 59 ], [ 61, 65 ], [ 68, 80 ], [ 82, 86 ], [ 93, 102 ], [ 285, 296 ] ] }, { "pmid": "23481236", "text": "Cells were also evaluated in the presence of wortmannin, an inhibitor of phosphatidylinositol 3-kinases and thus AKt (0-100 nM).", "type": "CHEMICAL", "entities": [ "wortmannin", "phosphatidylinositol" ], "offsets": [ [ 44, 54 ], [ 72, 92 ] ] }, { "pmid": "23481236", "text": "Unsaturated FFAs increased DAGs, TAGs and PTP1B expression significantly, but cells remained insulin sensitive as assessed by robust AKt and PTP1B phosphorylation at serine (Ser) 50, Ser 398 and tyrosine 152.", "type": "CHEMICAL", "entities": [ "tyrosine", "DAGs", "TAGs", "serine", "Ser", "Ser" ], "offsets": [ [ 194, 202 ], [ 26, 30 ], [ 32, 36 ], [ 165, 171 ], [ 173, 176 ], [ 182, 185 ] ] }, { "pmid": "23481236", "text": "Saturated palmitic and stearic acids increased ceramides, up-regulated PTP1B, and had AKt and PTP1B phosphorylation at Ser 50 impaired.", "type": "CHEMICAL", "entities": [ "palmitic and stearic acids", "ceramides", "Ser" ], "offsets": [ [ 9, 35 ], [ 46, 55 ], [ 118, 121 ] ] }, { "pmid": "23481236", "text": "We show a significant correlation between phosphorylation levels of AKt and of PTP1B at Ser 50 (R(2)=0.84, P<.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481236", "text": "The same was observed with increasing wortmannin dose (R(2)=0.73, P<.05).", "type": "CHEMICAL", "entities": [ "wortmannin" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "23481236", "text": "Only FFAs that increased ceramides caused impairment of AKt and PTP1B phosphorylation at Ser 50.", "type": "CHEMICAL", "entities": [ "ceramides", "Ser" ], "offsets": [ [ 24, 33 ], [ 88, 91 ] ] }, { "pmid": "23481236", "text": "PTP1B overexpression in the presence of excess lipids may not directly cause insulin resistance unless it is accompanied by decreased PTP1B phosphorylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481236", "text": "A clear relationship between PTP1B phosphorylation levels at Ser 50 and its negative effect on insulin signaling is shown.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 60, 63 ] ] }, { "pmid": "17035524", "text": "Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons.\n", "type": "CHEMICAL", "entities": [ "glycyl" ], "offsets": [ [ 23, 29 ] ] }, { "pmid": "17035524", "text": "Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal neuropathies characterized by a phenotype that is more severe in the upper extremities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035524", "text": "We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. GARS is a member of the family of aminoacyl-tRNA synthetases responsible for charging tRNA with cognate amino acids; GARS ligates glycine to tRNA(Gly).", "type": "CHEMICAL", "entities": [ "glycyl", "aminoacyl", "amino acids", "glycine" ], "offsets": [ [ 56, 62 ], [ 154, 163 ], [ 224, 235 ], [ 250, 257 ] ] }, { "pmid": "17035524", "text": "Here, we present functional analyses of disease-associated GARS mutations and show that there are not any significant mutation-associated changes in GARS expression levels; that the majority of identified GARS mutations modeled in yeast severely impair viability; and that, in most cases, mutant GARS protein mislocalizes in neuronal cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035524", "text": "Indeed, four of the five mutations studied show loss-of-function features in at least one assay, suggesting that tRNA-charging deficits play a role in disease pathogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035524", "text": "Finally, we detected endogenous GARS-associated granules in the neurite projections of cultured neurons and in the peripheral nerve axons of normal human tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035524", "text": "These data are particularly important in light of the recent identification of CMT-associated mutations in another tRNA synthetase gene [YARS (tyrosyl-tRNA synthetase gene)].", "type": "CHEMICAL", "entities": [ "tyrosyl" ], "offsets": [ [ 143, 150 ] ] }, { "pmid": "17035524", "text": "Together, these findings suggest that tRNA-charging enzymes play a key role in maintaining peripheral axons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4.\nIndoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders.", "type": "CHEMICAL", "entities": [ "Indoleamine", "tryptophan" ], "offsets": [ [ 91, 102 ], [ 128, 138 ] ] }, { "pmid": "17661345", "text": "IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid.", "type": "CHEMICAL", "entities": [ "quinolinic acid" ], "offsets": [ [ 80, 95 ] ] }, { "pmid": "17661345", "text": "Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites.", "type": "CHEMICAL", "entities": [ "tryptophan", "tryptophan" ], "offsets": [ [ 59, 69 ], [ 101, 111 ] ] }, { "pmid": "17661345", "text": "IL-4", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "Here, we investigated the effects of these cytokines on IDO expression in microglia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13.", "type": "CHEMICAL", "entities": [ "tryptophanyl" ], "offsets": [ [ 9, 21 ] ] }, { "pmid": "17661345", "text": "The effect of IL-4 and IL-13 was independent of STAT-6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17661345", "text": "The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 4, 24 ] ] }, { "pmid": "17661345", "text": "These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.", "type": "CHEMICAL", "entities": [ "tryptophan" ], "offsets": [ [ 100, 110 ] ] }, { "pmid": "23422569", "text": "SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: Implications for vascular aging.\n", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 15, 20 ] ] }, { "pmid": "23422569", "text": "Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 52, 57 ] ] }, { "pmid": "23422569", "text": "Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects.", "type": "CHEMICAL", "entities": [ "NAD(+)" ], "offsets": [ [ 79, 85 ] ] }, { "pmid": "23422569", "text": "To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats.", "type": "CHEMICAL", "entities": [ "NADPH", "oxygen", "nicotinamide", "sirtinol", "EX527" ], "offsets": [ [ 53, 58 ], [ 100, 106 ], [ 231, 243 ], [ 245, 253 ], [ 255, 260 ] ] }, { "pmid": "23422569", "text": "Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187.", "type": "CHEMICAL", "entities": [ "acetylcholine", "calcium", "A23187" ], "offsets": [ [ 144, 157 ], [ 166, 173 ], [ 184, 190 ] ] }, { "pmid": "23422569", "text": "Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase.", "type": "CHEMICAL", "entities": [ "NADPH", "apocynin", "superoxide" ], "offsets": [ [ 103, 108 ], [ 127, 135 ], [ 139, 149 ] ] }, { "pmid": "23422569", "text": "Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol.", "type": "CHEMICAL", "entities": [ "superoxide", "NADPH", "resveratrol" ], "offsets": [ [ 53, 63 ], [ 85, 90 ], [ 189, 200 ] ] }, { "pmid": "23422569", "text": "Peroxisome proliferator-activated receptor-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator.", "type": "CHEMICAL", "entities": [ "resveratrol" ], "offsets": [ [ 88, 99 ] ] }, { "pmid": "23422569", "text": "SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, which was suppressed by resveratrol.", "type": "CHEMICAL", "entities": [ "nicotinamide", "resveratrol" ], "offsets": [ [ 34, 46 ], [ 130, 141 ] ] }, { "pmid": "23422569", "text": "In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 85, 90 ] ] }, { "pmid": "23422569", "text": "Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation.", "type": "CHEMICAL", "entities": [ "NADPH", "NO" ], "offsets": [ [ 185, 190 ], [ 225, 227 ] ] }, { "pmid": "23500776", "text": "EROD activity induction in peripheral blood lymphocytes, liver and brain tissues of rats orally exposed to polycyclic aromatic hydrocarbons.\n", "type": "CHEMICAL", "entities": [ "polycyclic aromatic hydrocarbons" ], "offsets": [ [ 107, 139 ] ] }, { "pmid": "23500776", "text": "Little is known in terms of multi-matrix cytochrome P450 activity induction under repeated oral exposure to planar halogenated and polycyclic aromatic hydrocarbons (PHH, PAH).", "type": "CHEMICAL", "entities": [ "halogenated and polycyclic aromatic hydrocarbons", "PAH" ], "offsets": [ [ 115, 163 ], [ 170, 173 ] ] }, { "pmid": "23500776", "text": "In the present study, 60 rats were daily exposed, during 28days, to oral ingestion of a mixture consisting of phenanthrene, pyrene and benzo(a)pyrene at 0, 6 or 600μg/day.", "type": "CHEMICAL", "entities": [ "phenanthrene", "pyrene", "benzo(a)pyrene" ], "offsets": [ [ 110, 122 ], [ 124, 130 ], [ 135, 149 ] ] }, { "pmid": "23500776", "text": "EROD activity, reflecting almost exclusively CYP1A1 and CYP1B1 activities, was measured in brain and liver microsomes as well as in peripheral blood lymphocytes (PBLs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500776", "text": "All induction kinetics could be appropriately fitted using logistic-like models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500776", "text": "After 28days of exposure to a 6μg/day dose, EROD activity was found to be 91, 152 and 94-fold increased in lymphocytes, liver and brain, respectively, compared to day 0.", "type": "CHEMICAL", "entities": [ "EROD" ], "offsets": [ [ 43, 47 ] ] }, { "pmid": "23500776", "text": "Plateau activities could be appropriately fitted versus ingested doses using Hill or Michaelis-Menten models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500776", "text": "Correlations between matrices made it possible to conclude that EROD activity in PBL should be considered as a sensitive, convenient and non-destructive approach for (i) evaluating EROD activity in liver, which was found to represent 98% of the observed EROD activities in the three tested matrices and (ii) evaluating oral exposure of homogeneous groups of farm animals (race, diet) to CYP inducing PAH and PHH.", "type": "CHEMICAL", "entities": [ "EROD", "EROD", "PHH", "EROD" ], "offsets": [ [ 179, 183 ], [ 252, 256 ], [ 406, 409 ], [ 62, 66 ] ] }, { "pmid": "23322769", "text": "Genome-wide screen for modulation of hepatic apolipoprotein A-I (ApoA-I) secretion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "Control of plasma cholesterol levels is a major therapeutic strategy for management of coronary artery disease (CAD).", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "23322769", "text": "Although reducing LDL cholesterol (LDL-c) levels decreases morbidity and mortality, this therapeutic intervention only translates into a 25-40% reduction in cardiovascular events.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "23322769", "text": "Epidemiological studies have shown that a high LDL-c level is not the only risk factor for CAD; low HDL cholesterol (HDL-c) is an independent risk factor for CAD.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 104, 115 ] ] }, { "pmid": "23322769", "text": "Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-c that mediates reverse cholesterol transport from tissues to the liver for excretion.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 90, 101 ] ] }, { "pmid": "23322769", "text": "Therefore, increasing ApoA-I levels is an attractive strategy for HDL-c elevation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "Using genome-wide siRNA screening, targets that regulate hepatocyte ApoA-I secretion were identified through transfection of 21,789 siRNAs into hepatocytes whereby cell supernatants were assayed for ApoA-I. Approximately 800 genes were identified and triaged using a convergence of information, including genetic associations with HDL-c levels, tissue-specific gene expression, druggability assessments, and pathway analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "Fifty-nine genes were selected for reconfirmation; 40 genes were confirmed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "Here we describe the siRNA screening strategy, assay implementation and validation, data triaging, and example genes of interest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "The genes of interest include known and novel genes encoding secreted enzymes, proteases, G-protein-coupled receptors, metabolic enzymes, ion transporters, and proteins of unknown function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23322769", "text": "Repression of farnesyltransferase (FNTA) by siRNA and the enzyme inhibitor manumycin A caused elevation of ApoA-I secretion from hepatocytes and from transgenic mice expressing hApoA-I and cholesterol ester transfer protein transgenes.", "type": "CHEMICAL", "entities": [ "manumycin A", "cholesterol ester" ], "offsets": [ [ 75, 86 ], [ 189, 206 ] ] }, { "pmid": "23322769", "text": "In total, this work underscores the power of functional genetic assessment to identify new therapeutic targets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17020418", "text": "Update on the use of aromatase inhibitors in breast cancer.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17020418", "text": "Estrogens are biosynthesised from androgens by the CYP450 enzyme complex called aromatase.", "type": "CHEMICAL", "entities": [ "Estrogens", "androgens" ], "offsets": [ [ 0, 9 ], [ 34, 43 ] ] }, { "pmid": "17020418", "text": "Aromatase is expressed in the ovary, placenta, brain, bone, adipose tissue and breast tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17020418", "text": "In breast cancer, intratumoural aromatase is the source for local estrogen production in the tissue.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "17020418", "text": "Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer.", "type": "CHEMICAL", "entities": [ "estrogens", "estrogen" ], "offsets": [ [ 92, 101 ], [ 105, 113 ] ] }, { "pmid": "17020418", "text": "The potent and selective third-generation aromatase inhibitors anastrozole, letrozole and exemestane were introduced to the market as endocrine therapy in postmenopausal patients failing anti-estrogen therapy alone, or multiple hormonal therapies.", "type": "CHEMICAL", "entities": [ "anastrozole", "letrozole", "estrogen" ], "offsets": [ [ 63, 74 ], [ 76, 85 ], [ 192, 200 ] ] }, { "pmid": "17020418", "text": "Anastrozole and letrozole are both non-steroidal aromatase inhibitors that compete with the substrate for binding to the enzyme active site.", "type": "CHEMICAL", "entities": [ "Anastrozole", "letrozole", "steroidal" ], "offsets": [ [ 0, 11 ], [ 16, 25 ], [ 39, 48 ] ] }, { "pmid": "17020418", "text": "Exemestane is a mechanism-based steroidal inhibitor that mimics the substrate, is converted by the enzyme to a reactive intermediate, and results in inactivation of aromatase.", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "17020418", "text": "These third-generation aromatase inhibitors are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 147, 155 ] ] }, { "pmid": "17020418", "text": "The use of an aromatase inhibitor as initial therapy, or after treatment with tamoxifen, is now recommended as adjuvant hormonal therapy for postmenopausal women with hormone-dependent breast cancer.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 78, 87 ] ] }, { "pmid": "17020418", "text": "Several clinical studies of aromatase inhibitors focus on the use of these agents in the adjuvant setting, for the treatment of early breast cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17020418", "text": "Recently published results show improved responses with these agents compared with tamoxifen.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 83, 92 ] ] }, { "pmid": "23511897", "text": "High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C.\nFew studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans.", "type": "CHEMICAL", "entities": [ "cholesterol", "steroid", "cholesterol" ], "offsets": [ [ 190, 201 ], [ 222, 229 ], [ 40, 51 ] ] }, { "pmid": "23511897", "text": "While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23511897", "text": "To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations.", "type": "CHEMICAL", "entities": [ "steroid hormone", "ATP", "cholesterol", "cholesterol" ], "offsets": [ [ 15, 30 ], [ 119, 122 ], [ 182, 193 ], [ 266, 277 ] ] }, { "pmid": "23511897", "text": "HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23511897", "text": "In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04).", "type": "CHEMICAL", "entities": [ "17-ketogenic steroids" ], "offsets": [ [ 58, 79 ] ] }, { "pmid": "23511897", "text": "In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23511897", "text": "In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23511897", "text": "These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 51, 62 ] ] }, { "pmid": "17035141", "text": "Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.\n", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 24, 30 ] ] }, { "pmid": "17035141", "text": "BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect.", "type": "CHEMICAL", "entities": [ "folic acid", "Folate" ], "offsets": [ [ 119, 129 ], [ 12, 18 ] ] }, { "pmid": "17035141", "text": "Most studies addressed these genes individually, often with different populations providing conflicting results.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.", "type": "CHEMICAL", "entities": [ "folate", "folate" ], "offsets": [ [ 28, 34 ], [ 132, 138 ] ] }, { "pmid": "17035141", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.", "type": "CHEMICAL", "entities": [ "cystathionine", "folate", "folate", "methylenetetrahydrofolate", "serine hydroxymethyl", "1, 5,10-methylenetetrahydrofolate", "5-methyltetrahydrofolate-homo-cysteine", "5-methyltetrahydrofolate", "homocysteine", "betaine", "homocysteine" ], "offsets": [ [ 516, 529 ], [ 119, 125 ], [ 138, 144 ], [ 211, 236 ], [ 254, 274 ], [ 287, 320 ], [ 340, 378 ], [ 398, 422 ], [ 423, 435 ], [ 465, 472 ], [ 473, 485 ] ] }, { "pmid": "17035141", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception.", "type": "CHEMICAL", "entities": [ "nucleotide", "folate" ], "offsets": [ [ 12, 22 ], [ 157, 163 ] ] }, { "pmid": "17035141", "text": "The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 14, 20 ] ] }, { "pmid": "17035141", "text": "CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17035141", "text": "Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.", "type": "CHEMICAL", "entities": [ "folate", "methionine" ], "offsets": [ [ 25, 31 ], [ 36, 46 ] ] }, { "pmid": "23489628", "text": "Identification and synthesis of N-(thiophen-2-yl) benzamide derivatives as BRAF(V600E) inhibitors.\n", "type": "CHEMICAL", "entities": [ "N-(thiophen-2-yl) benzamide" ], "offsets": [ [ 32, 59 ] ] }, { "pmid": "23489628", "text": "The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly occurs in about 8% of all human malignancies and about 50% of all melanomas.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489628", "text": "In this study, we employed virtual screening and chemical synthesis to identify a series of N-(thiophen-2-yl) benzamide derivatives as potent BRAF(V600E) inhibitors.", "type": "CHEMICAL", "entities": [ "N-(thiophen-2-yl) benzamide" ], "offsets": [ [ 92, 119 ] ] }, { "pmid": "23489628", "text": "Structure-activity relationship studies of these derivatives revealed that compounds b40 and b47 are the two most potent BRAF(V600E) inhibitors in this series.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "Robust array-based coregulator binding assay predicting ERα-agonist potency and generating binding profiles reflecting ligand structure.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "Testing chemicals for their endocrine-disrupting potential, including interference with estrogen receptor (ER) signaling, is an important aspect of chemical safety testing.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 87, 95 ] ] }, { "pmid": "23383871", "text": "Because of the practical drawbacks of animal testing, the development of in vitro alternatives for the uterotrophic assay and other in vivo (anti)estrogenicity tests has high priority.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "It was previously demonstrated that an in vitro assay that profiles ligand-induced binding of ERα to a microarray of coregulator-derived peptides might be a valuable candidate for a panel of in vitro assays aiming at an ultimate replacement of the uterotrophic assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "In the present study, the reproducibility and robustness of this coregulator binding assay was determined by measuring the binding profiles of 14 model compounds that are recommended by the Office of Prevention, Pesticides and Toxic Substances for testing laboratory proficiency in estrogen receptor transactivation assays.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 280, 288 ] ] }, { "pmid": "23383871", "text": "With a median coefficient of variation of 5.0% and excellent correlation (R(2) = 0.993) between duplicate measurements, the reproducibility of the ERα-coregulator binding assay was better than the reproducibility of other commonly used in vitro ER functional assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "In addition, the coregulator binding assay is correctly predicting the estrogenicity for 13 out of 14 compounds tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "When the potency of the ER-agonists to induce ERα-coregulator binding was compared to their ER binding affinity, their ranking was similar, and the correlation between the EC50 values was excellent (R(2) = 0.96), as was the correlation with their potency in a transactivation assay (R(2) = 0.94).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383871", "text": "Moreover, when the ERα-coregulator binding profiles were hierarchically clustered using Euclidian cluster distance, the structurally related compounds were found to cluster together, whereas the steroid test compounds having an aromatic A-ring were separated from those with a cyclohexene A-ring.", "type": "CHEMICAL", "entities": [ "steroid", "cyclohexene" ], "offsets": [ [ 191, 198 ], [ 273, 284 ] ] }, { "pmid": "23383871", "text": "We concluded that this assay is capable of distinguishing ERα agonists and antagonists and that it even reflects the structural similarity of ERα agonists, indicating a potential to achieve identification and classification of ERα endocrine disruptors with high fidelity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "Rapid and specific purification of Argonaute-small RNA complexes from crude cell lysates.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "Small interfering RNAs (siRNAs) direct Argonaute proteins, the core components of the RNA-induced silencing complex (RISC), to cleave complementary target RNAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "Here, we describe a method to purify active RISC containing a single, unique small RNA guide sequence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "We begin by capturing RISC using a complementary 2'-O-methyl oligonucleotide tethered to beads.", "type": "CHEMICAL", "entities": [ "2'-O-methyl" ], "offsets": [ [ 49, 60 ] ] }, { "pmid": "23249751", "text": "Unlike other methods that capture RISC but do not allow its recovery, our strategy purifies active, soluble RISC in good yield.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "The method takes advantage of the finding that RISC partially paired to a target through its siRNA guide dissociates more than 300 times faster than a fully paired siRNA in RISC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "We use this strategy to purify fly Ago1- and Ago2-RISC, as well as mouse AGO2-RISC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "The method can discriminate among RISCs programmed with different guide strands, making it possible to deplete and recover specific RISC populations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "Endogenous microRNA:Argonaute complexes can also be purified from cell lysates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249751", "text": "Our method scales readily and takes less than a day to complete.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578390", "text": "Sodium fluoride induces apoptosis in odontoblasts via a JNK-dependent mechanism.\n", "type": "CHEMICAL", "entities": [ "Sodium fluoride" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "23578390", "text": "Sodium fluoride (NaF) is widely used for the treatment of dental caries and dentin hypersensitivity.", "type": "CHEMICAL", "entities": [ "Sodium fluoride", "NaF" ], "offsets": [ [ 0, 15 ], [ 17, 20 ] ] }, { "pmid": "23578390", "text": "However, its pro-apoptotic effect on odontoblasts may lead to harmful side-effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578390", "text": "The purpose of this study was to evaluate the pro-apoptotic effects of NaF in odontoblasts and elucidate the possible underlying molecular mechanisms.", "type": "CHEMICAL", "entities": [ "NaF" ], "offsets": [ [ 71, 74 ] ] }, { "pmid": "23578390", "text": "NaF generated cytotoxic effects in odontoblast-lineage cell (OLC) in a dose- and time-dependent manner.", "type": "CHEMICAL", "entities": [ "NaF" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23578390", "text": "Exposure of cells to 4mM NaF for 24h induced caspase-3 activation, ultrastructural alterations, and resulted in the translocation of Bax to the mitochondria and the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol, indicating that fluoride-mediated apoptosis is mitochondria-dependent.", "type": "CHEMICAL", "entities": [ "NaF", "fluoride" ], "offsets": [ [ 25, 28 ], [ 267, 275 ] ] }, { "pmid": "23578390", "text": "Fluoride treatment also increased phosphorylation of JNK and ERK, but not p38, and apoptosis induced by fluoride was notably or partly suppressed by treatment with JNK or ERK inhibitors, respectively.", "type": "CHEMICAL", "entities": [ "Fluoride", "fluoride" ], "offsets": [ [ 0, 8 ], [ 104, 112 ] ] }, { "pmid": "23578390", "text": "Taken together, these findings suggest that NaF induces apoptosis in OLC odontoblasts through a JNK-dependent mitochondrial pathway.", "type": "CHEMICAL", "entities": [ "NaF" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "19780818", "text": "The potassium channel subunit Kvbeta3 interacts with pannexin 1 and attenuates its sensitivity to changes in redox potentials.\n", "type": "CHEMICAL", "entities": [ "potassium" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "19780818", "text": "Pannexin 1 (Panx1), a member of the second gap junction protein family identified in vertebrates, appears to preferentially form non-junctional membrane channels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19780818", "text": "A candidate regulatory protein of Panx1 is the potassium channel subunit Kvbeta3, previously identified by bacterial two-hybrid strategies.", "type": "CHEMICAL", "entities": [ "potassium" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "19780818", "text": "Here, we report on the physical association of Panx1 with Kvbeta3 by immunoprecipitation when co-expressed in a neuroblastoma cell line (Neuro2A).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19780818", "text": "Furthermore, in vivo co-expression of Panx1 and Kvbeta3 was shown to occur in murine hippocampus and cerebellum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19780818", "text": "Kvbeta3 is known to accelerate inactivation of otherwise slowly inactivating potassium channels under reducing conditions.", "type": "CHEMICAL", "entities": [ "potassium" ], "offsets": [ [ 77, 86 ] ] }, { "pmid": "19780818", "text": "We subsequently found that Panx1 channel currents exhibit a significant reduction when exposed to reducing agents, and that this effect is attenuated in the presence of Kvbeta3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19780818", "text": "Apparently, Kvbeta3 is involved in regulating the susceptibility of Panx1 channels to redox potential.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19780818", "text": "Furthermore, the Panx1 channel blockers carbenoxolone and Probenecid were less effective in inhibiting Panx1 currents when Kvbeta3 was co-expressed.", "type": "CHEMICAL", "entities": [ "carbenoxolone", "Probenecid" ], "offsets": [ [ 40, 53 ], [ 58, 68 ] ] }, { "pmid": "19780818", "text": "The influence of Kvbeta3 on Panx1 is the first example of modulation of Panx1 channel function(s) by interacting proteins, and suggests the physiological importance of sensing changes in redox potentials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580394", "text": "Optoelectronic Processes in Squaraine Dye-Doped OLEDs for Emission in the Near-Infrared.\n", "type": "CHEMICAL", "entities": [ "Squaraine Dye" ], "offsets": [ [ 28, 41 ] ] }, { "pmid": "23580394", "text": "A novel all-organic host-guest system for emission in the NIR is introduced and investigated with respect to its opto-electronic processes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580394", "text": "The good agreement between theoretical and experimental results highlights the model character of this system and its potential for electroluminescent application.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580394", "text": "Comparative measurements provide access to the recombination mechanisms on molecular length scale and show that the emission behavior of the device under operation is controlled by charge carrier dynamics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23200255", "text": "Phosphodiesterase inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23200255", "text": "Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23200255", "text": "(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent.", "type": "CHEMICAL", "entities": [ "(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one", "KCA-1490" ], "offsets": [ [ 0, 104 ], [ 106, 114 ] ] }, { "pmid": "23200255", "text": "N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition.", "type": "CHEMICAL", "entities": [ "N", "pyridazinone" ], "offsets": [ [ 0, 1 ], [ 20, 32 ] ] }, { "pmid": "23200255", "text": "Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition.", "type": "CHEMICAL", "entities": [ "6-aryl-4,5-dihydropyridazin-3(2H)-one", "N" ], "offsets": [ [ 14, 51 ], [ 69, 70 ] ] }, { "pmid": "23200255", "text": "Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics.", "type": "CHEMICAL", "entities": [ "dihydropyridazinone", "4,4-dimethylpyrazolone", "pyrazolopyridine" ], "offsets": [ [ 5, 24 ], [ 86, 108 ], [ 131, 147 ] ] }, { "pmid": "23200255", "text": "In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 87, 96 ] ] }, { "pmid": "23344974", "text": "Using a fragment-based approach to target protein-protein interactions.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "The ability to identify inhibitors of protein-protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "In recent years, fragment-based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "Herein, we describe the fragment-based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344974", "text": "The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X-ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2.", "type": "CHEMICAL", "entities": [ "phenylalanine" ], "offsets": [ [ 263, 276 ] ] }, { "pmid": "23344974", "text": "This represents the first report of fragments or any small molecule binding at this protein-protein interaction site.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "Fumarate reductase is essential for Helicobacter pylori colonization of the mouse stomach.\n", "type": "CHEMICAL", "entities": [ "Fumarate" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "11031122", "text": "Fumarate reductase (FRD) is the key enzyme in fumarate respiration induced by anaerobic growth of bacteria.", "type": "CHEMICAL", "entities": [ "Fumarate", "fumarate" ], "offsets": [ [ 0, 8 ], [ 46, 54 ] ] }, { "pmid": "11031122", "text": "In Helicobacter pylori, this enzyme appears to be constitutively expressed under microaerobic conditions and is not essential for its survival in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "In this study, the role of FRD in the colonization of H. pylori was investigated using a mouse model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "The frdA gene coding for subunit A of FRD, and two control genes, copA and copP associated with the export of copper out of H. pylori, were inactivated by insertion of the chloramphenicol acetyltransferase cassette into these individual genes.", "type": "CHEMICAL", "entities": [ "copper", "chloramphenicol" ], "offsets": [ [ 110, 116 ], [ 172, 187 ] ] }, { "pmid": "11031122", "text": "The isogenic mutants of H. pylori strain AH244 were obtained by natural transformation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "Seventy-five ICR mice (15 mice/group) were orogastrically dosed with either the wild type H. pylori strain AH244, its isogenic mutants, or Brucella broth (negative control).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "Five mice from each group were killed at 2, 4 and 8 weeks post-inoculation (WPI), respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "H. pylori colonization was not detected in mouse gastric mucosa infected with the frdA mutant at any time point in the study by both quantitative culture and PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "In contrast, the mice inoculated with either wild type AH244, copA or copPH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "pylori mutants became readily infected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "These data indicate that FRD plays a crucial role in H. pylori survival in the gastric mucosa of mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11031122", "text": "Given that FRD, present in all H. pylori strains, is immunogenic in H. pylori -infected patients and H. pylori growth in vitro can be inhibited by three anthelmintics (morantel, oxantel and thiabendazole), this enzyme could potentially be used both as a novel drug target as well as in the development of vaccines for H. pylori prevention and eradication.", "type": "CHEMICAL", "entities": [ "morantel", "oxantel", "thiabendazole" ], "offsets": [ [ 168, 176 ], [ 178, 185 ], [ 190, 203 ] ] }, { "pmid": "10381000", "text": "Tryptophan hydroxylase mRNA levels are elevated by repeated immobilization stress in rat raphe nuclei but not in pineal gland.\n", "type": "CHEMICAL", "entities": [ "Tryptophan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10381000", "text": "Repeated stress triggers a wide range of adaptive changes in the central nervous system including the elevation of serotonin (5-HT) metabolism and an increased susceptibility to affective disorders.", "type": "CHEMICAL", "entities": [ "serotonin", "5-HT" ], "offsets": [ [ 115, 124 ], [ 126, 130 ] ] }, { "pmid": "10381000", "text": "To begin to examine whether these changes are mediated by alterations in gene expression for tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis, we quantitated its mRNA levels by competitive reverse transcription-polymerase chain reaction (RT-PCR).", "type": "CHEMICAL", "entities": [ "tryptophan", "5-HT" ], "offsets": [ [ 93, 103 ], [ 151, 155 ] ] }, { "pmid": "10381000", "text": "Repeated immobilization stress (2 h, 7 days) elicited a six- or ten-fold rise in TPH mRNA in median raphe nucleus (MRN) and dorsal raphe nucleus (DRN), respectively, without significantly altering TPH mRNA levels in the pineal gland.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10381000", "text": "In contrast, there was little change in mRNA levels for GTP cyclohydrolase I (GTPCH), the rate limiting enzyme in synthesis of the tetrahydrobiopterin (BH4), the obligate cofactor for TPH.", "type": "CHEMICAL", "entities": [ "tetrahydrobiopterin", "BH4" ], "offsets": [ [ 131, 150 ], [ 152, 155 ] ] }, { "pmid": "10381000", "text": "This is the first study to reveal stress-elicited activation of TPH gene expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411246", "text": "Iron and zinc bioavailability in Caco-2 cells: influence of caseinophosphopeptides.\n", "type": "CHEMICAL", "entities": [ "Iron", "zinc" ], "offsets": [ [ 0, 4 ], [ 9, 13 ] ] }, { "pmid": "23411246", "text": "A study has been made of the influence of two pools of caseinophosphopeptides (CPPs) obtained from α(s)- and β-casein (CN) fractions, and of three specific CPPs (β-CN(1-25)4P, α(s1)-CN(64-74)4P and α(s2)-CN(1-19)4P), on iron bioavailability (ferritin synthesis) and zinc bioavailability (retention, transport and uptake of zinc) in Caco-2 cells.", "type": "CHEMICAL", "entities": [ "iron", "zinc", "zinc" ], "offsets": [ [ 220, 224 ], [ 266, 270 ], [ 323, 327 ] ] }, { "pmid": "23411246", "text": "α-CPP and β-CPP pools did not improve ferritin synthesis, but the three specific CPPs showed an increase in ferritin synthesis in Caco-2 cells versus iron sulphate, β-CN(1-25)4P being the most effective.", "type": "CHEMICAL", "entities": [ "iron sulphate" ], "offsets": [ [ 145, 158 ] ] }, { "pmid": "23411246", "text": "In relation to zinc bioavailability, α-CPPs, β-CPPs, α(s1)-CN(64-74)4P and β-CN(1-25)4P increased zinc uptake.", "type": "CHEMICAL", "entities": [ "zinc", "zinc" ], "offsets": [ [ 7, 11 ], [ 90, 94 ] ] }, { "pmid": "23411246", "text": "However, this increase was of the same order as the increase due to the presence of zinc sulphate.", "type": "CHEMICAL", "entities": [ "zinc sulphate" ], "offsets": [ [ 72, 85 ] ] }, { "pmid": "23535394", "text": "An overview on the marine neurotoxin, saxitoxin: genetics, molecular targets, methods of detection and ecological functions.\n", "type": "CHEMICAL", "entities": [ "saxitoxin" ], "offsets": [ [ 38, 47 ] ] }, { "pmid": "23535394", "text": "Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535394", "text": "These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types.", "type": "CHEMICAL", "entities": [ "sodium", "potassium", "calcium" ], "offsets": [ [ 44, 50 ], [ 52, 61 ], [ 66, 73 ] ] }, { "pmid": "23535394", "text": "This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535394", "text": "Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life.", "type": "CHEMICAL", "entities": [ "Saxitoxin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23535394", "text": "Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535394", "text": "Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning.", "type": "CHEMICAL", "entities": [ "saxitoxin" ], "offsets": [ [ 181, 190 ] ] }, { "pmid": "23535394", "text": "These illnesses are a result of saxitoxin's ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis.", "type": "CHEMICAL", "entities": [ "saxitoxin", "sodium" ], "offsets": [ [ 32, 41 ], [ 81, 87 ] ] }, { "pmid": "23535394", "text": "Recent advances in saxitoxin research are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection.", "type": "CHEMICAL", "entities": [ "saxitoxin" ], "offsets": [ [ 19, 28 ] ] }, { "pmid": "23535394", "text": "The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23178380", "text": "Pulmonary delivery of an aerosolized recombinant human butyrylcholinesterase pretreatment protects against aerosolized paraoxon in macaques.\n", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 119, 127 ] ] }, { "pmid": "23178380", "text": "Butyrylcholinesterase (BChE) is the leading pretreatment candidate against exposure to organophosphates (OPs), which pose an ever increasing public and military health.", "type": "CHEMICAL", "entities": [ "organophosphates" ], "offsets": [ [ 87, 103 ] ] }, { "pmid": "23178380", "text": "Since respiratory failure is the primary cause of death following acute OP poisoning, an inhaled BChE therapeutic could prove highly efficacious in preventing acute toxicity as well as the associated delayed neuropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23178380", "text": "To address this, studies have been performed in mice and macaques using Chinese Hamster Ovary cells (CHO)-derived recombinant (r) BChE delivered by the pulmonary route, to examine whether the deposition of both macaque (Ma) and human (Hu) rBChE administered as aerosols (aer) favored the creation and retention of an efficient protective \"pulmonary bioshield\" that could scavenge incoming (inhaled) OPs in situ thereby preventing entry into the circulation and inhibition of plasma BChE and AChE on red blood cells (RBC-AChE) and in cholinergic synapses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23178380", "text": "In contrast to parenteral delivery of rBChE, which currently requires posttranslational modification for good plasma stability, an unmodified aer-rBChE pretreatment given 1-40h prior to >1 LD50 of aer-paraoxon (Px) was able to prevent inhibition of circulating cholinesterase in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 201, 209 ] ] }, { "pmid": "23178380", "text": "These studies are the first to show protection by rBChE against a pesticide such as paraoxon when delivered directly into the lung and bode well for the use of a non-invasive and consumer friendly method of rHuBChE delivery as a human treatment to counteract OP toxicity.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 84, 92 ] ] }, { "pmid": "23290487", "text": "Anti-diabetic property of Tinospora cordifolia and its active compound is mediated through the expression of Glut-4 in L6 myotubes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290487", "text": "Tinospora cordifolia is a well reported plant possessing numerous medicinal values including anti-diabetic property.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290487", "text": "Aim of the present study is to study the mechanism of action of Tinospora cordifolia and its active compound in differentiated myocytes, L6 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290487", "text": "Key marker of diabetes in cells is the insulin dependent glucose transporter-4 (Glut-4) which also responds to exogenous chemicals, and is over expressed up to 5- and 4-fold, by Tinospora cordifolia and palmatine, respectively.", "type": "CHEMICAL", "entities": [ "glucose", "palmatine" ], "offsets": [ [ 57, 64 ], [ 203, 212 ] ] }, { "pmid": "23290487", "text": "Next to Glut-4, the predominant protein influencing glucose metabolism is PPARα and γ whose expressions were also positively modulated.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 52, 59 ] ] }, { "pmid": "23290487", "text": "Further, the inhibitors of insulin pathway prevented glucose uptake mediated by Tinospora cordifolia and palmatine which shows that the activity is majorly mediated through insulin pathway.", "type": "CHEMICAL", "entities": [ "glucose", "palmatine" ], "offsets": [ [ 51, 58 ], [ 103, 112 ] ] }, { "pmid": "2571203", "text": "Differential IL-2 receptor expression in renal allograft recipients treated with an anti-IL-2-receptor antibody.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2571203", "text": "Patients were entered into a randomized trial of prophylaxis for renal allograft rejection by the administration of an anti-human IL-2 receptor antibody, anti-Tac, during the first ten days posttransplant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2571203", "text": "Interleukin-2 receptor (IL-2 R) expression was measured using two anti-IL-2 R monoclonal antibodies (moAbs), anti-Tac and 1HT4-4H3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2571203", "text": "These two antibodies recognize closely spaced epitopes on the 55 kD chain of the IL-2 R. IL-2 R expression was examined on peripheral blood small lymphocytes in three groups of patients who received: (A) cyclosporine CsA and prednisone for baseline immunosuppression (n = 9); (B) anti-Tac with CsA and prednisone as baseline immunosuppression (n = 12); and (C) anti-Tac with azathioprine and prednisone as baseline immunosuppression (n = 5).", "type": "CHEMICAL", "entities": [ "(A) cyclosporine", "CsA", "prednisone", "CsA", "prednisone", "azathioprine", "prednisone" ], "offsets": [ [ 200, 216 ], [ 217, 220 ], [ 225, 235 ], [ 294, 297 ], [ 302, 312 ], [ 375, 387 ], [ 392, 402 ] ] }, { "pmid": "2571203", "text": "We found that large numbers of T cells express IL-2 receptors despite the presence of anti-Tac (average of IL-2 R-positive cells at day of peak IL-2 R expression 56.0 +/- 20.8% in group A, 65.2 +/- 26.6% in group B, 21.0 +/- 7.4% in group C).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2571203", "text": "IL-2 R expression did not correlate with clinical activity, and the presence or accessibility of epitopes on the same 55 kD chain varied dramatically from patient to patient.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "Medical therapy and quality of life.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "The risk of mortality and long-term morbidity, including loss of sexual function, associated with surgical procedures for symptomatic benign prostatic hyperplasia (BPH) has prompted research into alternative medical therapies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "Phytotherapy involves the use of herbal formulations, where the mechanisms of action are usually obscure and although studies have confirmed their effectiveness in symptom relief and improving quality of life (QOL), few placebo-controlled trials exist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "Both the 5 alpha-reductase inhibitor finasteride and alpha 1-adrenoceptor antagonists (e.g. alfuzosin, doxazosin, prazosin, tamsulosin and terazosin) have been recommended as appropriate treatment options for patients with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO), and their efficacy has been proven in several placebo-controlled trials.", "type": "CHEMICAL", "entities": [ "finasteride", "alfuzosin", "doxazosin", "prazosin", "tamsulosin", "terazosin" ], "offsets": [ [ 37, 48 ], [ 92, 101 ], [ 103, 112 ], [ 114, 122 ], [ 124, 134 ], [ 139, 148 ] ] }, { "pmid": "9732824", "text": "Finasteride reduces the static component of BPO--by reducing the size of the prostate--and, as a result, symptom relief is slow (6-12 months) and is predominantly restricted to patients with large prostates (> 40 g).", "type": "CHEMICAL", "entities": [ "Finasteride" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "9732824", "text": "The alpha 1-adrenoceptor antagonists, on the other hand, reduce the dynamic component of obstruction--relaxation of smooth muscle in the prostate, urethra and bladder neck--and provide rapid symptom relief after only a few doses, relieving LUTS more effectively than finasteride and irrespective of prostate size.", "type": "CHEMICAL", "entities": [ "finasteride" ], "offsets": [ [ 267, 278 ] ] }, { "pmid": "9732824", "text": "All of the various alpha 1-adrenoceptor antagonists provide effective and comparable relief of LUTS, and an improvement in bothersomeness and symptom-related QOL.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "However, it is also important that the therapy is fast acting and acceptable to the patient, in that it does not interfere with other medication or produce unpleasant side effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9732824", "text": "These documented properties of the alpha 1A-adrenoceptor antagonists make them an ideal choice for the medical treatment of symptomatic BPH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "Bioinspired Water-Enhanced Mechanical Gradient Nanocomposite Films That Mimic the Architecture and Properties of the Squid Beak.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "Inspired by the water-enhanced mechanical gradient character of the squid beak, we herein report a nanocomposite that mimics both the architecture and properties of this interesting natural material.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "Similar to the squid beak, we have developed nanocomposites where the degree of cross-linking is controlled along the length of the film.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "In this study, we utilized tunicate cellulose nanocrystals as the nanofiller that are functionalized with allyl moieties.", "type": "CHEMICAL", "entities": [ "allyl" ], "offsets": [ [ 106, 111 ] ] }, { "pmid": "23530595", "text": "Using photoinduced thiol-ene chemistry, we have been able to cross-link the CNC nanofiller.", "type": "CHEMICAL", "entities": [ "thiol" ], "offsets": [ [ 19, 24 ] ] }, { "pmid": "23530595", "text": "In the dry state where strong CNC interactions can occur, only a small mechanical contrast is observed between the cross-linked and uncross-linked samples.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "However, when the films are exposed to water, which \"switches off\" the noncovalent CNC interactions, a significant mechanical contrast is observed between the same films.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "For example, at 20 wt % CNC (in the dry film), an increase in wet modulus from 60 to 300 MPa (∼500% increase) is observed after photoirradiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530595", "text": "Furthermore, we show that the wet modulus can be controlled by altering the UV exposure time which allows access to mechanical gradient films.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23589476", "text": "Wired Enzyme Electrodes-A Retroperspective Story about an Exciting Time at University of Texas at Austin and Its Impact on My Scientific Career.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23589476", "text": "The present paper features an exciting time in the late 1980s when I, as a visiting scientist, had the privilege to participate in the early and very exciting development of the in vivo redox-polymer-wired glucose sensor in Professor Adam Heller's laboratory at the Department of Chemical Engineering at University of Texas at Austin.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 206, 213 ] ] }, { "pmid": "23589476", "text": "This story is followed by an overview of the research my visit initiated at Uppsala University.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23589476", "text": "In collaboration with Swedish colleagues, we explored a few of the many possibilities to form new biosensors by utilizing Prof. Heller's concept of cross-linked redox-polymer/redox-enzyme electrodes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "Antithrombotic activity of a newly synthesized coumarin derivative 3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide.\n", "type": "CHEMICAL", "entities": [ "coumarin", "3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide" ], "offsets": [ [ 47, 55 ], [ 67, 188 ] ] }, { "pmid": "23534412", "text": "Anti-platelet therapy is a useful strategy to prevent acute thromboembolic artery occlusions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "This study was designed to assess the efficacy of seselin derivatives against murine pulmonary thromboembolism, bleeding time, platelet activation and thrombosis.", "type": "CHEMICAL", "entities": [ "seselin" ], "offsets": [ [ 50, 57 ] ] }, { "pmid": "23534412", "text": "Administration of C3 (16 mg/kg) offered 70% protection against collagen- and epinephrine-induced pulmonary thromboembolism and 30% protection against arachidonic acid-induced death in mice, without adversely affecting bleeding time.", "type": "CHEMICAL", "entities": [ "epinephrine", "arachidonic acid" ], "offsets": [ [ 77, 88 ], [ 150, 166 ] ] }, { "pmid": "23534412", "text": "No significant difference was observed by C3 in ferric chloride-induced arterial thrombosis in rats.", "type": "CHEMICAL", "entities": [ "ferric chloride" ], "offsets": [ [ 48, 63 ] ] }, { "pmid": "23534412", "text": "Significant reduction in thrombus weight was observed in arteriovenous shunt model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "In rat PRP, C3 reduced ADP and collagen-induced platelet aggregation.", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 23, 26 ] ] }, { "pmid": "23534412", "text": "In chronic hamster model of dyslipidemia, administration of C3 (16 mg/kg p.o. for 90 days) had no effect on plasma lipids, vasoreactivity and platelet adhesion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "C3 fed hamsters showed reduced whole-blood aggregation response to ADP and collagen compared to HC-fed hamsters.", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 67, 70 ] ] }, { "pmid": "23534412", "text": "In addition, C3 augmented thrombin time; however, time to occlusion was not increased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "These results convincingly demonstrated that C3 is a novel molecule that reduces the risk of thrombosis and alleviates prothrombotic state associated with hyperlipidemia without any adverse effect on bleeding time.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534412", "text": "The high benefit/risk ratio of this compound makes it a suitable candidate for future valid studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972287", "text": "Central 5-HT3 receptor stimulation by m-CPBG increases blood glucose in rats.\n", "type": "CHEMICAL", "entities": [ "m-CPBG", "glucose" ], "offsets": [ [ 38, 44 ], [ 61, 68 ] ] }, { "pmid": "11972287", "text": "The aim of the present study was to investigate the role of central 5-HT3 receptors on the control of blood glucose in stressed and non-stressed rats in both fasted and fed states.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 108, 115 ] ] }, { "pmid": "11972287", "text": "Adult Wistar male rats had each their third ventricle cannulated 7 days before the experiments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972287", "text": "Injections of m-CPBG, a selective 5-HT3 receptor agonist, induced a significant increase in blood glucose in non-stressed rats in both fasted and in fed states.", "type": "CHEMICAL", "entities": [ "m-CPBG", "glucose" ], "offsets": [ [ 14, 20 ], [ 98, 105 ] ] }, { "pmid": "11972287", "text": "The same procedure was unable to modify stress-induced hyperglycemia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972287", "text": "The hyperglycemic effect of m-CPBG central administration was blocked by pretreatment with ondansetron, a specific 5-HT3 receptor antagonist, indicating that the effects here obtained with m-CPBG were a result of its interaction with 5-HT3 receptors.", "type": "CHEMICAL", "entities": [ "m-CPBG", "m-CPBG" ], "offsets": [ [ 28, 34 ], [ 189, 195 ] ] }, { "pmid": "11972287", "text": "Third ventricle injections of ondansetron alone were not able to modify blood glucose in non-stressed animals and did not change the hyperglycemic responses observed after immobilization stress.", "type": "CHEMICAL", "entities": [ "ondansetron", "glucose" ], "offsets": [ [ 30, 41 ], [ 78, 85 ] ] }, { "pmid": "11972287", "text": "We conclude that pharmacological activation of the central 5-HT3 receptor induces a hyperglycemic effect in non-stressed animals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375813", "text": "3'-R/S-Hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata.\n", "type": "CHEMICAL", "entities": [ "3'-R/S-Hydroxyvoacamine" ], "offsets": [ [ 0, 23 ] ] }, { "pmid": "23375813", "text": "Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory.", "type": "CHEMICAL", "entities": [ "bisindole alkaloid", "3'-R/S-hydroxyvoacamine" ], "offsets": [ [ 60, 78 ], [ 79, 102 ] ] }, { "pmid": "23375813", "text": "The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1)H and (13)C NMR spectra is reported.", "type": "CHEMICAL", "entities": [ "(1)H", "(13)C" ], "offsets": [ [ 117, 121 ], [ 126, 131 ] ] }, { "pmid": "23375813", "text": "The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7.00±1.99μM. An HPLC method was developed for the quantitative analysis of the AChE inhibitor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375813", "text": "It suggested that there was 12.4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem.", "type": "CHEMICAL", "entities": [ "3'-R/S-hydroxyvoacamine" ], "offsets": [ [ 41, 64 ] ] }, { "pmid": "23434931", "text": "TCF7L2 Variation and Proliferative Diabetic Retinopathy.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434931", "text": "Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434931", "text": "To investigated genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM-no DR) were genotyped with rs7903146 in TCF7L2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434931", "text": "We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2.52E-04).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434931", "text": "In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than that in rs7903146-CC cells (P = 0.02 for TCF7L2; P = 0.004 for VEGFA), suggesting ER stress plays a role in PDR pathogenesis.", "type": "CHEMICAL", "entities": [ "tunicamycin" ], "offsets": [ [ 93, 104 ] ] }, { "pmid": "23434931", "text": "Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434931", "text": "Retinas of oxygen-induced retinopathy (OIR) mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than controls (P = 2.9E-04 for TCF7L2; P = 1.9E-07 for VEGFA).", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "23434931", "text": "Together, our study showed that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggested TCF7L2 promoted pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22931530", "text": "α-Amino-α´-Halomethylketones: Synthetic Methodologies and Pharmaceutical Applications as Serine and Cysteine Protease Inhibitors.\n", "type": "CHEMICAL", "entities": [ "α-Amino-α´-Halomethylketones", "Cysteine", "Serine" ], "offsets": [ [ 0, 28 ], [ 100, 108 ], [ 89, 95 ] ] }, { "pmid": "22931530", "text": "α-Amino-α´-halomethylketones are interesting scaffolds bearing (at least) two sequential electrophilic carbons that by interacting with the nucleophilic moieties of several enzymes, represent the ideal candidates for in vivo and in vitro inhibition studies.", "type": "CHEMICAL", "entities": [ "carbons" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "22931530", "text": "In this work a summary of their use as optimal inhibitors of physiologically relevant serine and cysteine proteases is given with a particular emphasis on recently established SAR studies.", "type": "CHEMICAL", "entities": [ "serine", "cysteine" ], "offsets": [ [ 80, 86 ], [ 91, 99 ] ] }, { "pmid": "22931530", "text": "A brief survey of the most relevant synthetic processes for their obtainment and the importance they possess in synthetic medicinal chemistry is reported.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "5-Lipoxygenase inhibitors: a review of recent patents (2010 - 2012).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Introduction: 5-Lipoxygenase (5-LO) is a crucial enzyme of the arachidonic acid (AA) cascade and catalyzes the formation of bioactive leukotrienes (LTs) with the help of FLAP, the 5-LO-activating protein.", "type": "CHEMICAL", "entities": [ "arachidonic acid" ], "offsets": [ [ 63, 79 ] ] }, { "pmid": "23600432", "text": "LTs are inflammatory mediators playing a pathophysiological role in different diseases like asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes increasingly important.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Areas covered: Here, both recent findings regarding the pathophysiological role of 5-LO and the patents claimed for 5-LO inhibitors are discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Focusing on direct inhibitors, several patents disclosing FLAP antagonists are also subject of this review.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Novel compounds include 1,5-diarylpyrazoles, indolizines and indoles and several natural product extracts.", "type": "CHEMICAL", "entities": [ "1,5-diarylpyrazoles", "indolizines", "indoles" ], "offsets": [ [ 24, 43 ], [ 45, 56 ], [ 61, 68 ] ] }, { "pmid": "23600432", "text": "Expert opinion: Evaluation of the patent activities revealed only quite moderate action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Nevertheless, several auspicious drug-like molecules were disclosed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "It seems that in the near future, FLAP inhibitors can be expected to enter the market for the treatment of asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "With the resolved structure of 5-LO, structure-based drug design is now applicable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600432", "text": "Together with the identification of downstream enzyme inhibitors and dual-targeting drugs within the AA cascade, several tools are at hand to cope with 5-LOs increasing pathophysiological roles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23258671", "text": "Super-stable ultrafine beta-tungsten nanocrystals with metastable phase and related magnetism.\n", "type": "CHEMICAL", "entities": [ "beta-tungsten" ], "offsets": [ [ 23, 36 ] ] }, { "pmid": "23258671", "text": "Ultrafine tungsten nanocrystals (average size of 3 nm) with a metastable phase (beta-tungsten with A15 structure, β-W) have been prepared by laser ablation of tungsten in liquid nitrogen.", "type": "CHEMICAL", "entities": [ "tungsten", "W", "tungsten", "nitrogen", "beta-tungsten" ], "offsets": [ [ 10, 18 ], [ 116, 117 ], [ 159, 167 ], [ 178, 186 ], [ 80, 93 ] ] }, { "pmid": "23258671", "text": "The as-prepared metastable nanocrystals exhibited super-stablity, and can keep the same metastable structure over a period of 6 months at room temperature.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23258671", "text": "This super-stability is attributed to the nanosized confinement effect of ultrafine nanocrystals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23258671", "text": "The magnetism measurements showed that the β-W nanocrystals have weak ferromagnetic properties at 2 K, which may arise from surface defects and unpaired electrons on the surface of the ultrafine nanocrystals.", "type": "CHEMICAL", "entities": [ "W" ], "offsets": [ [ 44, 45 ] ] }, { "pmid": "23258671", "text": "These findings provided useful information for the application of ultrafine β-W nanocrystals in microelectronics and spintronics.", "type": "CHEMICAL", "entities": [ "W" ], "offsets": [ [ 76, 77 ] ] }, { "pmid": "23531488", "text": "Transport Function and Transcriptional Regulation of a Liver-Enriched Human Organic Anion Transporting Polypeptide 2B1 Transcriptional Start Site Variant.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "Human Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is a membrane transporter that facilitates the cellular uptake of a number of endogenous compounds and drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "OATP2B1 is widely expressed in tissues including the small intestine, liver, kidney, placenta, heart, skeletal muscle and platelets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "Recently, it has been shown that differential promoter usage in tissues results in expression of five OATP2B1 transcriptional start site variants which utilize distinct first exons but share common subsequent exons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "These variants are expected to encode either a full length (OATP2B1-FL) or shortened protein lacking 22 N-terminus amino acids (OATP2B-Short).", "type": "CHEMICAL", "entities": [ "N", "amino acids" ], "offsets": [ [ 104, 105 ], [ 115, 126 ] ] }, { "pmid": "23531488", "text": "Little is known regarding the transport activity and regulation of OATP2B1 variants with N-terminus truncation.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 89, 90 ] ] }, { "pmid": "23531488", "text": "Here, using absolute quantitative polymerase chain reaction we find the full length variant is the major form expressed in duodenum but the short variant predominates in liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "Using a transient heterologous cell expression system, we find that the transport activities of the short OATP2B1 variant towards substrates estrone sulfate and rosuvastatin are similar to the well-characterized full length variant.", "type": "CHEMICAL", "entities": [ "estrone sulfate", "rosuvastatin" ], "offsets": [ [ 141, 156 ], [ 161, 173 ] ] }, { "pmid": "23531488", "text": "Transcriptional activity screening of the liver enriched OATP2B1 variant promoter identified hepatocyte nuclear factor 4 alpha (HNF4α) as a novel transacting factor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "With a combination of in silico screening, promoter mutation in cell-based reporter assays, siRNA knockdown and chromatin immunoprecipitation studies, we identified a functional HNF4α binding site close to the transcription start site (-17 to -4 bp).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531488", "text": "We conclude that the major OATP2B1 protein form in liver is transport competent and its hepatic expression is regulated by HNF4α.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe(-/-))", "type": "CHEMICAL", "entities": [ "streptozotocin" ], "offsets": [ [ 178, 192 ] ] }, { "pmid": "23060524", "text": "mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe(-/-) mice for 10 weeks significantly reduced atherosclerotic lesions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "Although atherosclerotic lesions in nondiabetic Apoe(-/-) mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice.", "type": "CHEMICAL", "entities": [ "cholesterol", "triglycerides" ], "offsets": [ [ 73, 84 ], [ 89, 102 ] ] }, { "pmid": "23060524", "text": "Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23060524", "text": "Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe(-/-) mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe(-/-) mice.", "type": "CHEMICAL", "entities": [ "cholesterol", "triglyceride" ], "offsets": [ [ 175, 186 ], [ 191, 203 ] ] }, { "pmid": "14530799", "text": "The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [ "memantine" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "14530799", "text": "Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD).", "type": "CHEMICAL", "entities": [ "Memantine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "14530799", "text": "While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies.", "type": "CHEMICAL", "entities": [ "memantine" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "14530799", "text": "Memantine can interact with a variety of ligand-gated ion channels.", "type": "CHEMICAL", "entities": [ "Memantine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "14530799", "text": "However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations.", "type": "CHEMICAL", "entities": [ "NMDA", "memantine" ], "offsets": [ [ 9, 13 ], [ 53, 62 ] ] }, { "pmid": "14530799", "text": "Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist.", "type": "CHEMICAL", "entities": [ "Memantine", "NMDA" ], "offsets": [ [ 0, 9 ], [ 49, 53 ] ] }, { "pmid": "14530799", "text": "Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory.", "type": "CHEMICAL", "entities": [ "NMDA", "memantine" ], "offsets": [ [ 11, 15 ], [ 38, 47 ] ] }, { "pmid": "14530799", "text": "However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD.", "type": "CHEMICAL", "entities": [ "memantine" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "14530799", "text": "In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons.", "type": "CHEMICAL", "entities": [ "memantine" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "14530799", "text": "Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the \"weak\" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia.", "type": "CHEMICAL", "entities": [ "NMDA", "memantine", "NMDA" ], "offsets": [ [ 12, 16 ], [ 30, 39 ], [ 125, 129 ] ] }, { "pmid": "14530799", "text": "Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production.", "type": "CHEMICAL", "entities": [ "memantine" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "14530799", "text": "Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801).", "type": "CHEMICAL", "entities": [ "memantine", "NMDA", "phencyclidine", "ketamine", "MK-801" ], "offsets": [ [ 106, 115 ], [ 127, 131 ], [ 267, 280 ], [ 282, 290 ], [ 292, 298 ] ] }, { "pmid": "14530799", "text": "A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14530799", "text": "These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.", "type": "CHEMICAL", "entities": [ "memantine", "glutamate" ], "offsets": [ [ 24, 33 ], [ 92, 101 ] ] }, { "pmid": "23564921", "text": "Expansion of the Homeostasis Model Assessment of β-Cell Function and Insulin Resistance to Enable Clinical Trial Outcome Modeling Through the Interactive Adjustment of Physiology and Treatment Effects--iHOMA2.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23564921", "text": "OBJECTIVETo describe and make available an interactive, 24-variable homeostasis model assessment (iHOMA2) that extends the HOMA2 model, enabling the modeling of physiology and treatment effects, to present equations of the HOMA2 and iHOMA2 models, and to exemplify iHOMA2 in two widely differing scenarios: changes in insulin sensitivity with thiazolidinediones and changes in renal threshold with sodium glucose transporter (SGLT2) inhibition.", "type": "CHEMICAL", "entities": [ "thiazolidinediones", "sodium", "glucose" ], "offsets": [ [ 342, 360 ], [ 397, 403 ], [ 404, 411 ] ] }, { "pmid": "23564921", "text": "RESEARCH DESIGN AND METHODSiHOMA2 enables a user of the available software to examine and modify the mathematical functions describing the organs and tissues involved in the glucose and hormonal compartments.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 173, 180 ] ] }, { "pmid": "23564921", "text": "We exemplify this with SGLT2 inhibition modeling (by changing the renal threshold parameters) using published data of renal effect, showing that the modeled effect is concordant with the effects on fasting glucose from independent data.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 205, 212 ] ] }, { "pmid": "23564921", "text": "RESULTSiHOMA2 modeling of thiazolidinediones effect suggested that changes in insulin sensitivity in the fasting state are predominantly hepatic.", "type": "CHEMICAL", "entities": [ "thiazolidinediones" ], "offsets": [ [ 25, 43 ] ] }, { "pmid": "23564921", "text": "SGLT2 inhibition modeled by iHOMA2 resulted in a decrease in mean glucose of 1.1 mmol/L. Observed data showed a decrease in glucose of 0.9 mmol/L.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 65, 72 ], [ 123, 130 ] ] }, { "pmid": "23564921", "text": "There was no significant difference between the model and the independent data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23564921", "text": "Manipulation of iHOMA2s renal excretion threshold variable suggested that a decrease of 17% was required to obtain a 0.9 mmol/L decrease in mean glucose.CONCLUSIONSiHOMA2 is an extended mathematical model for the assessment of insulin resistance and β-cell function.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 144, 151 ] ] }, { "pmid": "23564921", "text": "The model can be used to evaluate therapeutic agents and predict effects on fasting glucose and insulin and on β-cell function and insulin sensitivity.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "16480505", "text": "Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor.\n", "type": "CHEMICAL", "entities": [ "pregnane", "rifampicin" ], "offsets": [ [ 101, 109 ], [ 9, 19 ] ] }, { "pmid": "16480505", "text": "Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems.", "type": "CHEMICAL", "entities": [ "Rifampicin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16480505", "text": "The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16480505", "text": "The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver.", "type": "CHEMICAL", "entities": [ "rifampicin" ], "offsets": [ [ 42, 52 ] ] }, { "pmid": "16480505", "text": "This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16480505", "text": "In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities.", "type": "CHEMICAL", "entities": [ "rifampicin", "rifampicin", "pregnane" ], "offsets": [ [ 12, 22 ], [ 45, 55 ], [ 78, 86 ] ] }, { "pmid": "16480505", "text": "This pattern of action may explain many of the rifampicin inducing drug-drug interactions.", "type": "CHEMICAL", "entities": [ "rifampicin" ], "offsets": [ [ 47, 57 ] ] }, { "pmid": "16480505", "text": "However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "Screening for (anti)androgenic properties using a standard operation protocol based on the human stably transfected androgen sensitive PALM cell line.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 116, 124 ] ] }, { "pmid": "19836445", "text": "First steps towards validation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "Despite more than a decade of research in the field of endocrine active compounds targeting the androgen receptor (AR), and although suitable cell lines can be obtained, no validated human stably transfected androgen sensitive transactivation assay is available.", "type": "CHEMICAL", "entities": [ "androgen", "androgen" ], "offsets": [ [ 208, 216 ], [ 96, 104 ] ] }, { "pmid": "19836445", "text": "Bayer Schering Pharma (BSP) and the Flemish Institute for Technological Research (VITO), partners within the EU-sponsored 6th framework project ReProTect, made first steps towards such a validation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "A standard operation protocol (SOP) developed at BSP based on the androgen sensitive PALM cell line was transferred to VITO and its performance and transferability were thoroughly studied.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "19836445", "text": "The investigation followed a generic protocol prepared for all reporter gene assays evaluated within ReProTect, and in both laboratories at least three independent experiments were performed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "The highest concentration to be tested was limited to 10 microM, if needed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "A few compounds, 17alpha-methyltestosterone (17alpha-MT), vinclozolin and linuron, were studied using a real world scenario, i.e., assuming that their interaction with the AR was not known: A prescreening for agonism and true, competitive antagonism was used to select conditions such as the appropriate mode of action, and the working range excluding cytotoxicity for the final screening.", "type": "CHEMICAL", "entities": [ "17alpha-methyltestosterone", "17alpha-MT", "vinclozolin", "linuron" ], "offsets": [ [ 17, 43 ], [ 45, 55 ], [ 58, 69 ], [ 74, 81 ] ] }, { "pmid": "19836445", "text": "All other compounds were tested according to the generic protocol: Compounds screened for agonism were the reference androgen 17alpha-methyldihydrotestosterone (MDHT), levonorgestrel, norethynodrel, progesterone, o,p'-DDT, and dibutylphthalate (DBP), while compounds screened for antagonism were the reference anti-androgen flutamide, prochloraz, o,p'-DDT, progesterone, norethynodrel, and DBP.", "type": "CHEMICAL", "entities": [ "androgen", "17alpha-methyldihydrotestosterone", "MDHT", "levonorgestrel", "norethynodrel", "progesterone", "o,p'-DDT", "dibutylphthalate", "DBP", "anti-androgen", "flutamide", "prochloraz", "o,p'-DDT", "progesterone", "norethynodrel", "DBP" ], "offsets": [ [ 117, 125 ], [ 126, 159 ], [ 161, 165 ], [ 168, 182 ], [ 184, 197 ], [ 199, 211 ], [ 213, 221 ], [ 227, 243 ], [ 245, 248 ], [ 310, 323 ], [ 324, 333 ], [ 335, 345 ], [ 347, 355 ], [ 357, 369 ], [ 371, 384 ], [ 390, 393 ] ] }, { "pmid": "19836445", "text": "Cytotoxicity was assessed in parallel as lactate dehydrogenase release.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 41, 48 ] ] }, { "pmid": "19836445", "text": "The prescreen classified 17alpha-MT as androgenic, vinclozolin and linuron as anti-androgenic and compounds were tested accordingly.", "type": "CHEMICAL", "entities": [ "17alpha-MT", "vinclozolin" ], "offsets": [ [ 25, 35 ], [ 51, 62 ] ] }, { "pmid": "19836445", "text": "In the absence of cytotoxicity, appropriate androgenic properties of reference and test compounds were detected by both laboratories, o,p'-DDT and DBP had no androgenic activity.", "type": "CHEMICAL", "entities": [ "o,p'-DDT", "DBP" ], "offsets": [ [ 134, 142 ], [ 147, 150 ] ] }, { "pmid": "19836445", "text": "Across the two laboratories EC(50)-values for MDHT, 17alpha-MT, and levonorgestrel varied by not more than a factor of 3.4, for norethynodrel by a factor of 9.7.", "type": "CHEMICAL", "entities": [ "MDHT", "17alpha-MT", "levonorgestrel", "norethynodrel" ], "offsets": [ [ 46, 50 ], [ 52, 62 ], [ 68, 82 ], [ 128, 141 ] ] }, { "pmid": "19836445", "text": "Progesterone effects could not fully be evaluated, as frequently concentration response curves were incomplete.", "type": "CHEMICAL", "entities": [ "Progesterone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19836445", "text": "In the absence of cytotoxicity anti-androgenic properties of reference and test compounds were also detected in both laboratories.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "DBP, the putative negative reference compound, was inactive, norethynodrel rather showed agonistic properties.", "type": "CHEMICAL", "entities": [ "DBP", "norethynodrel" ], "offsets": [ [ 0, 3 ], [ 61, 74 ] ] }, { "pmid": "19836445", "text": "Progesterone was an antagonist at low concentrations, but agonistic properties were observed in one laboratory at high concentrations.", "type": "CHEMICAL", "entities": [ "Progesterone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19836445", "text": "Since the highest test concentration was limited to 10 microM, for some compounds no complete concentration response curves were obtained and estimation of EC(50)-values was less robust.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "Our data demonstrated that the SOP was transferable, and that the assay was able to rank compounds with strong, weak, and without affinity for the AR and to discriminate agonists and antagonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "The sensitivity of the assay could be improved further, if the limit of solubility or beginning cytotoxicity was chosen as the highest test concentration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "The assay avoids the use of tissues from laboratory animals, and thus contributes to the 3R concept.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "Furthermore, it could be adjusted to an intermediate/high throughput format.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19836445", "text": "On the whole, this PALM assay is a promising candidate for further validation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354070", "text": "Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin.\n", "type": "CHEMICAL", "entities": [ "palinurin" ], "offsets": [ [ 87, 96 ] ] }, { "pmid": "23354070", "text": "Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354070", "text": "Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354070", "text": "We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor.", "type": "CHEMICAL", "entities": [ "sesquiterpene", "palinurin" ], "offsets": [ [ 84, 97 ], [ 98, 107 ] ] }, { "pmid": "23354070", "text": "Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate.", "type": "CHEMICAL", "entities": [ "palinurin", "ATP" ], "offsets": [ [ 107, 116 ], [ 143, 146 ] ] }, { "pmid": "23354070", "text": "Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354070", "text": "Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition.", "type": "CHEMICAL", "entities": [ "palinurin" ], "offsets": [ [ 96, 105 ] ] }, { "pmid": "23354070", "text": "The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site.", "type": "CHEMICAL", "entities": [ "palinurin" ], "offsets": [ [ 115, 124 ] ] }, { "pmid": "23354070", "text": "The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Pharmacological Inhibition of Platelet-tumor Cell Cross-talk Prevents Platelet-induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Cyclooxygenase(COX)-2-derived prostanoids can influence several processes that are linked to carcinogenesis.", "type": "CHEMICAL", "entities": [ "prostanoids" ], "offsets": [ [ 30, 41 ] ] }, { "pmid": "23580446", "text": "We aimed to address the hypothesis that platelets contribute to aberrant COX-2 expression in HT29 colon carcinoma cells and to reveal the role of platelet-induced COX-2 on the expression of proteins involved in malignancy and marker genes of epithelial-mesenchymal transition(EMT).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Human platelets co-cultured with HT29 cells rapidly adhered to cancer cells and induced COX-2 mRNA expression, but not protein synthesis which required the late release of platelet PDGF and COX-2 mRNA stabilization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Platelet-induced COX-2-dependent PGE2 synthesis in HT29 cells was involved in downregulation of p21(WAF1/CIP1) and upregulation of cyclinB1, since these effects were prevented by rofecoxib(a selective COX-2 inhibitor) and rescued by exogenous PGE2.", "type": "CHEMICAL", "entities": [ "PGE2", "rofecoxib", "PGE2" ], "offsets": [ [ 33, 37 ], [ 179, 188 ], [ 243, 247 ] ] }, { "pmid": "23580446", "text": "Galectin-3, highly expressed in HT29 cells, is unique among galectins because it contains a collagen-like domain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Thus, we studied the role of galectin-3 and platelet collagen receptors in platelet-induced COX-2 overexpression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580446", "text": "Inhibitors of galectin-3 function(β-lactose, a dominant-negative form of galectin-3,Gal-3C, and anti-galectin-3 antibody M3/38) or collagen receptor-mediated platelet adhesion(revacept, a dimeric collagen receptor GPVI-Fc) prevented aberrant COX-2 expression.", "type": "CHEMICAL", "entities": [ "β-lactose" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "23580446", "text": "Inhibition of platelet-cancer cell interaction by revacept was more effective than rofecoxib in preventing platelet-induced mRNA changes of EMT markers suggesting that direct cell-cell contact and aberrant COX-2 expression synergistically induced gene expression modifications associated with EMT.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "23580446", "text": "In conclusion, our findings provide the rationale for testing blockers of collagen binding sites, such as revacept, and galectin-3 inhibitors in the prevention of colon cancer metastasis in animal models followed by studies in patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23495691", "text": "Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease.\n", "type": "CHEMICAL", "entities": [ "cyclic AMP" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "23495691", "text": "The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein-protein interactions, which act to bring together signaling intermediates at defined locations within cells.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 4, 8 ] ] }, { "pmid": "23495691", "text": "In the heart, cAMP participates in the fine control of excitation-contraction coupling, hence, any disregulation of this signaling cascade can lead to cardiac disease.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 14, 18 ] ] }, { "pmid": "23495691", "text": "Due to the ubiquitous nature of the cAMP pathway, general inhibitors of cAMP signaling proteins such as PKA, EPAC and PDEs would act non-specifically and universally, increasing the likelihood of serious 'off target' effects.", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP" ], "offsets": [ [ 36, 40 ], [ 72, 76 ] ] }, { "pmid": "23495691", "text": "Recent advances in the discovery of peptides and small molecules that disrupt the protein-protein interactions that underpin cellular targeting of cAMP signaling proteins are described and discussed.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 147, 151 ] ] }, { "pmid": "22634361", "text": "Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor.\n", "type": "CHEMICAL", "entities": [ "Lu AF21934" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "22634361", "text": "Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration.", "type": "CHEMICAL", "entities": [ "LSP1-2111" ], "offsets": [ [ 92, 101 ] ] }, { "pmid": "22634361", "text": "Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests.", "type": "CHEMICAL", "entities": [ "Lu AF21934" ], "offsets": [ [ 47, 57 ] ] }, { "pmid": "22634361", "text": "In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22634361", "text": "The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin.", "type": "CHEMICAL", "entities": [ "Lu AF21934", "benzodiazepine", "flumazenil", "serotonin", "serotonin", "5-HT", "WAY100635", "5-HT", "ritanserin" ], "offsets": [ [ 30, 40 ], [ 88, 102 ], [ 123, 133 ], [ 157, 166 ], [ 197, 206 ], [ 250, 254 ], [ 272, 281 ], [ 286, 290 ], [ 311, 321 ] ] }, { "pmid": "22634361", "text": "These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents.", "type": "CHEMICAL", "entities": [ "Lu AF21934" ], "offsets": [ [ 145, 155 ] ] }, { "pmid": "22634361", "text": "Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22634361", "text": "This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.", "type": "CHEMICAL", "entities": [ "Glutamate" ], "offsets": [ [ 61, 70 ] ] }, { "pmid": "22921426", "text": "Lead-induced ER calcium release and inhibitory effects of methionine choline in cultured rat hippocampal neurons.\n", "type": "CHEMICAL", "entities": [ "calcium", "methionine choline" ], "offsets": [ [ 16, 23 ], [ 58, 76 ] ] }, { "pmid": "22921426", "text": "Lead, a ubiquitous neurotoxicant, can result in learning and memory dysfunction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22921426", "text": "Long term potentiation in the hippocampus, a potential neural substrate for learning and memory, is thought to be linked to calcium-triggered intracellular events.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 124, 131 ] ] }, { "pmid": "22921426", "text": "In this study, laser scanning confocal microscopy was used to examine the effects of Pb(2+) on intracellular and endoplasmic reticulum free calcium concentration ([Ca(2+)](i) and [Ca(2+)](ER)) in cultured neonatal rat hippocampal neurons and their possible antagonism by methionine choline; understanding these effects would help explain the lead-induced cognitive and learning dysfunction and explore efficient safety and relief strategies.", "type": "CHEMICAL", "entities": [ "Pb(2+)", "calcium", "Ca(2+)", "Ca(2+)", "methionine choline" ], "offsets": [ [ 85, 91 ], [ 140, 147 ], [ 164, 170 ], [ 180, 186 ], [ 271, 289 ] ] }, { "pmid": "22921426", "text": "The results showed that Pb(2+) increased [Ca(2+)](i) and decreased [Ca(2+)](ER) linearly in a time- and concentration-dependant manner, and Pb(2+) addition after the applying of a ryanodine receptor (RyR) antagonist and an inositol-1,4,5-triphosphate receptor (IP(3)R) antagonist did not increase [Ca(2+)](i).", "type": "CHEMICAL", "entities": [ "Pb(2+)", "Ca(2+)", "Ca(2+)", "Pb(2+)", "ryanodine", "inositol-1,4,5-triphosphate", "Ca(2+)" ], "offsets": [ [ 24, 30 ], [ 42, 48 ], [ 68, 74 ], [ 140, 146 ], [ 180, 189 ], [ 223, 250 ], [ 298, 304 ] ] }, { "pmid": "22921426", "text": "The addition of 10, 20, or 40 mmol/L methionine choline simultaneously with addition of 10 μmol/L Pb(2+) decreased [Ca(2+)](i) in Ca(2+)-free culture medium by 39.0%, 66.0%, and 61.6%, respectively, in a concentration-dependant manner in a certain dose range.", "type": "CHEMICAL", "entities": [ "methionine choline", "Pb(2+)", "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 37, 55 ], [ 98, 104 ], [ 116, 122 ], [ 130, 136 ] ] }, { "pmid": "22921426", "text": "Our results suggest that Pb(2+) induces ER calcium release to increase the resting [Ca(2+)](i); and methionine choline inhibit this increase in [Ca(2+)](i).", "type": "CHEMICAL", "entities": [ "Pb(2+)", "calcium", "Ca(2+)", "methionine choline", "Ca(2+)" ], "offsets": [ [ 24, 30 ], [ 42, 49 ], [ 83, 89 ], [ 99, 117 ], [ 144, 150 ] ] }, { "pmid": "17979301", "text": "Critical amino acids in phosphodiesterase-5 catalytic site that provide for high-affinity interaction with cyclic guanosine monophosphate and inhibitors.\n", "type": "CHEMICAL", "entities": [ "cyclic guanosine monophosphate", "amino acids" ], "offsets": [ [ 107, 137 ], [ 9, 20 ] ] }, { "pmid": "17979301", "text": "The molecular bases for phosphodiesterase 5 (PDE5) catalytic-site affinity for cyclic guanosine monophosphate (cGMP) and potency of inhibitors are poorly understood.", "type": "CHEMICAL", "entities": [ "cGMP", "cyclic guanosine monophosphate" ], "offsets": [ [ 111, 115 ], [ 79, 109 ] ] }, { "pmid": "17979301", "text": "Cocrystal structures of PDE5 catalytic (C) domain with inhibitors reveal a hydrogen bond and hydrophobic interactions with Tyr-612, hydrogen bonds with Gln-817, a hydrophobic clamp formed by Phe-820 and Val-782, and contacts with His-613, Leu-765, and Phe-786", "type": "CHEMICAL", "entities": [ "hydrogen", "Tyr", "hydrogen", "Gln", "Phe", "Val", "His", "Leu", "Phe" ], "offsets": [ [ 75, 83 ], [ 123, 126 ], [ 132, 140 ], [ 152, 155 ], [ 191, 194 ], [ 203, 206 ], [ 230, 233 ], [ 239, 242 ], [ 252, 255 ] ] }, { "pmid": "17979301", "text": "[Sung et al.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "(2003)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "Nature 425, 98-102; Huai et al.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "(2004) J. Biol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "Chem.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "279, 13095-13101].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17979301", "text": "Present results of point mutations of full-length PDE5 showed that maximum catalysis was decreased 2650-fold in H613A and 55-fold in F820A. Catalytic-site affinities for cGMP, vardenafil, sildenafil, tadalafil, or 3-isobutyl-1-methylxanthine (IBMX) were respectively weakened 14-, 123-, 30-, 51-, and 43-fold for Y612A; 63-, 511-, 43-, 95- and 61-fold for Q817A; and 59-, 448-, 71-, 137-, and 93-fold for F820A. The data indicate that these three amino acids are major determinants of affinity for cGMP and potency of selective and nonselective inhibitors, and that higher vardenafil potency over sildenafil and tadalafil results from stronger contacts with Tyr-612, Gln-817, and Phe-820.", "type": "CHEMICAL", "entities": [ "cGMP", "vardenafil", "sildenafil", "tadalafil", "Tyr", "Gln", "Phe", "cGMP", "vardenafil", "sildenafil", "tadalafil", "3-isobutyl-1-methylxanthine", "IBMX", "amino acids" ], "offsets": [ [ 498, 502 ], [ 573, 583 ], [ 597, 607 ], [ 612, 621 ], [ 658, 661 ], [ 667, 670 ], [ 680, 683 ], [ 170, 174 ], [ 176, 186 ], [ 188, 198 ], [ 200, 209 ], [ 214, 241 ], [ 243, 247 ], [ 447, 458 ] ] }, { "pmid": "17979301", "text": "Affinity of V782A for cGMP, vardenafil, sildenafil, tadalafil, or IBMX was reduced 5.5-, 23-, 10-, 3-, and 12-fold, respectively.", "type": "CHEMICAL", "entities": [ "cGMP", "vardenafil", "sildenafil", "tadalafil", "IBMX" ], "offsets": [ [ 22, 26 ], [ 28, 38 ], [ 40, 50 ], [ 52, 61 ], [ 66, 70 ] ] }, { "pmid": "17979301", "text": "Change in affinity for cGMP, vardenafil, sildenafil, or IBMX in Y612F, H613A, L765A, or F786A was less, but affinity of H613A or F786A for tadalafil was weakened 37- and 17-fold, respectively.", "type": "CHEMICAL", "entities": [ "cGMP", "vardenafil", "sildenafil", "IBMX", "tadalafil" ], "offsets": [ [ 23, 27 ], [ 29, 39 ], [ 41, 51 ], [ 56, 60 ], [ 139, 148 ] ] }, { "pmid": "17979301", "text": "The results quantify the role of PDE5 catalytic-site residues for cGMP and inhibitors, indicate that Tyr-612, Gln-817, and Phe-820 are the most important cGMP or inhibitor contacts studied, and identify residues that contribute to selectivity among different classes of inhibitors.", "type": "CHEMICAL", "entities": [ "cGMP", "Tyr", "Gln", "Phe", "cGMP" ], "offsets": [ [ 66, 70 ], [ 101, 104 ], [ 110, 113 ], [ 123, 126 ], [ 154, 158 ] ] }, { "pmid": "23411208", "text": "Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development.\n", "type": "CHEMICAL", "entities": [ "α-tocopherol" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "23411208", "text": "Breast cancer is the most common malignancy among women and has an age-specific incidence profile.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411208", "text": "Over the last decade, many studies have demonstrated the anticancer activity of α-tocopherol, the main and most active form of natural vitamin E. α-Tocopherol-associated protein (TAP) was found to be one of the major α-tocopherol binding proteins in human serum and in liver, brain, and prostate tissues.", "type": "CHEMICAL", "entities": [ "α-tocopherol", "vitamin E", "α-Tocopherol", "α-tocopherol" ], "offsets": [ [ 79, 91 ], [ 134, 143 ], [ 145, 157 ], [ 216, 228 ] ] }, { "pmid": "23411208", "text": "In this study, we found that reduced TAP expression was significantly correlated with Her2/neu receptor expression, breast cancer stage and nodal stage in paired normal and cancerous breast tissue samples from 93 patients using real-time PCR analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411208", "text": "A cell viability assay showed that α-tocopheryl succinate (α-TOS), a synthetic derivative of α-tocopherol, enhanced the cells' sensitivity to doxorubicin and resulted in a reduction in cell viability in breast cancers.", "type": "CHEMICAL", "entities": [ "α-tocopheryl succinate", "α-TOS", "α-tocopherol", "doxorubicin" ], "offsets": [ [ 31, 53 ], [ 55, 60 ], [ 89, 101 ], [ 138, 149 ] ] }, { "pmid": "23411208", "text": "Taken together, these data suggest that the use of vitamin E or its analogue as a dietary supplement may be beneficial for the treatment of cancer.", "type": "CHEMICAL", "entities": [ "vitamin E" ], "offsets": [ [ 44, 53 ] ] }, { "pmid": "23383423", "text": "International Union of Pharmacology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "LXXXVII.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "Complement peptide C5a, C4a, and C3a receptors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "The activation of the complement cascade, a cornerstone of the innate immune response, produces a number of small (74-77 amino acid) fragments, originally termed anaphylatoxins, that are potent chemoattractants and secretagogues that act on a wide variety of cell types.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 121, 131 ] ] }, { "pmid": "23383423", "text": "These fragments, C5a, C4a, and C3a, participate at all levels of the immune response and are also involved in other processes such as neural development and organ regeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "Their primary function, however, is in inflammation, so they are important targets for the development of antiinflammatory therapies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "Only three receptors for complement peptides have been found, but there are no satisfactory antagonists as yet, despite intensive investigation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "In humans, there is a single receptor for C3a (C3a receptor), no known receptor for C4a, and two receptors for C5a (C5a₁ receptor and C5a₂ receptor).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "The most recently characterized receptor, the C5a₂ receptor (previously known as C5L2 or GPR77), has been regarded as a passive binding protein, but signaling activities are now ascribed to it, so we propose that it be formally identified as a receptor and be given a name to reflect this.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23383423", "text": "Here, we describe the complex biology of the complement peptides, introduce a new suggested nomenclature, and review our current knowledge of receptor pharmacology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages.\n", "type": "CHEMICAL", "entities": [ "NO", "allicin" ], "offsets": [ [ 119, 121 ], [ 171, 178 ] ] }, { "pmid": "23583806", "text": "Garlic has a variety of biologic activities, including anti-inflammatory properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "Although garlic has several biologic activities, some people dislike eating fresh raw garlic because of its strong taste and smell.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "Therefore, garlic formulations involving heating procedures have been developed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "In this study, we investigated whether short-term heating affects the anti-inflammatory properties of garlic.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "Fresh and heated raw garlic extracts (FRGE and HRGE) were prepared with incubation at 25°C and 95°C, respectively, for 2h.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "Treatment with FRGE and HRGE significantly reduced the LPS-induced increase in the pro-inflammatory cytokine concentration (TNF-α, IL-1β, and IL-6) and NO through HO-1 upregulation in RAW 264.7 macrophages.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 150, 152 ] ] }, { "pmid": "23583806", "text": "The anti-inflammatory effect was greater in FRGE than in HRGE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583806", "text": "The allicin concentration was higher in FRGE than in HRGE.", "type": "CHEMICAL", "entities": [ "allicin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23583806", "text": "Allicin treatment showed reduced production of pro-inflammatory cytokines and NO and increased HO-1 activity.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 74, 76 ] ] }, { "pmid": "23583806", "text": "The results show that the decrease in LPS-induced NO and pro-inflammatory cytokines in RAW 264.7 macrophages through HO-1 induction was greater for FRGE compared with HRGE.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 46, 48 ] ] }, { "pmid": "23583806", "text": "Additionally, the results indicate that allicin is responsible for the anti-inflammatory effect of FRGE.", "type": "CHEMICAL", "entities": [ "allicin" ], "offsets": [ [ 36, 43 ] ] }, { "pmid": "23583806", "text": "Our results suggest a potential therapeutic use of allicin in the treatment of chronic inflammatory disease.", "type": "CHEMICAL", "entities": [ "allicin" ], "offsets": [ [ 47, 54 ] ] }, { "pmid": "18058577", "text": "MORAb-003, a fully humanized monoclonal antibody against the folate receptor alpha, for the potential treatment of epithelial ovarian cancer.\n", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 61, 67 ] ] }, { "pmid": "18058577", "text": "Morphotek Inc is developing MORAb-003, a humanized monoclonal antibody directed against folate receptor alpha, for the potential treatment of ovarian cancer.", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 88, 94 ] ] }, { "pmid": "18058577", "text": "Phase II clinical trialsof MORAb-003, either alone or in combination with platinum/taxane chemotherapy, are underway in ovarian cancer patients experiencing their first disease recurrence.", "type": "CHEMICAL", "entities": [ "platinum", "taxane" ], "offsets": [ [ 74, 82 ], [ 83, 89 ] ] }, { "pmid": "17567713", "text": "Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17567713", "text": "Throughout the world many people use artificial sweeteners (AS) for the purpose of reducing caloric intake.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17567713", "text": "The most prominently used of these molecules include saccharin, aspartame (Nutrasweet), acesulfame-K, and cyclamate.", "type": "CHEMICAL", "entities": [ "saccharin", "aspartame", "Nutrasweet", "acesulfame-K", "cyclamate" ], "offsets": [ [ 53, 62 ], [ 64, 73 ], [ 75, 85 ], [ 88, 100 ], [ 106, 115 ] ] }, { "pmid": "17567713", "text": "Despite the caloric advantage they provide, one key concern in their use is their aversive aftertaste that has been characterized on a sensory level as bitter and/or metallic.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17567713", "text": "Recently, it has been shown that the activation of particular T2R bitter taste receptors is partially involved with the bitter aftertaste sensation of saccharin and acesulfame-K. To more fully understand the biology behind these phenomena we have addressed the question of whether AS could stimulate transient receptor potential vanilloid-1 (TRPV1) receptors, as these receptors are activated by a large range of structurally different chemicals.", "type": "CHEMICAL", "entities": [ "saccharin", "acesulfame-K" ], "offsets": [ [ 151, 160 ], [ 165, 177 ] ] }, { "pmid": "17567713", "text": "Moreover, TRPV1 receptors and/or their variants are found in taste receptor cells and in nerve terminals throughout the oral cavity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17567713", "text": "Hence, TRPV1 activation could be involved in the AS aftertaste or even contribute to the poorly understood metallic taste sensation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17567713", "text": "Using Ca(2+) imaging on TRPV1 receptors heterologously expressed in the human embryonic kidney (HEK) 293 cells and on dissociated primary sensory neurons, we find that in both systems, AS activate TRPV1 receptors, and, moreover, they sensitize these channels to acid and heat.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 6, 12 ] ] }, { "pmid": "17567713", "text": "We also found that TRPV1 receptors are activated by CuSO(4), ZnSO(4), and FeSO(4), three salts known to produce a metallic taste sensation.", "type": "CHEMICAL", "entities": [ "CuSO(4)", "ZnSO(4)", "FeSO(4)" ], "offsets": [ [ 52, 59 ], [ 61, 68 ], [ 74, 81 ] ] }, { "pmid": "17567713", "text": "In summary, our results identify a novel group of compounds that activate TRPV1 and, consequently, provide a molecular mechanism that may account for off tastes of sweeteners and metallic tasting salts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age).", "type": "CHEMICAL", "entities": [ "diethylnitrosamine", "DEN" ], "offsets": [ [ 37, 55 ], [ 57, 60 ] ] }, { "pmid": "23288052", "text": "Second, carbon tetrachloride (CCl(4); 0.2ml/kg, 2/week ip starting at 8 weeks of age) was administered for 9 or 14 weeks to develop advanced liver fibrosis.", "type": "CHEMICAL", "entities": [ "carbon tetrachloride", "CCl(4)" ], "offsets": [ [ 8, 28 ], [ 30, 36 ] ] }, { "pmid": "23288052", "text": "In animals treated with DEN as neonates, presence of liver fibrosis led to more than doubling (to 100%) of the liver tumor incidence as early as 5 months of age.", "type": "CHEMICAL", "entities": [ "DEN" ], "offsets": [ [ 24, 27 ] ] }, { "pmid": "23288052", "text": "This effect was associated with activation of cells with progenitor features in noncancerous liver tissue, including markers of replicative senescence (p16), oncofetal transformation (Afp, H19, and Bex1), and increased \"stemness\" (Prom1 and Epcam).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "In contrast, the dose of DEN used did not modify the extent of liver inflammation, fibrogenesis, oxidative stress, proliferation, or apoptosis induced by subchronic CCl(4) administration.", "type": "CHEMICAL", "entities": [ "DEN", "CCl(4)" ], "offsets": [ [ 25, 28 ], [ 165, 171 ] ] }, { "pmid": "23288052", "text": "This study demonstrates the potential role of liver stem-like cells in the mechanisms of chemical-induced, fibrosis-promoted HCC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "We posit that the combination of genotoxic and fibrogenic insults is a sensible approach to model liver carcinogenesis in experimental animals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288052", "text": "These results may contribute to identification of cirrhotic patients predisposed to HCC by analyzing the expression of hepatic progenitor cell markers in the noncancerous liver tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15974585", "text": "2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.\n", "type": "CHEMICAL", "entities": [ "2-Arylpropionic" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "15974585", "text": "The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15974585", "text": "CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15974585", "text": "(R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis.", "type": "CHEMICAL", "entities": [ "(R)-Ketoprofen" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "15974585", "text": "We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15974585", "text": "The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments.", "type": "CHEMICAL", "entities": [ "alanine" ], "offsets": [ [ 35, 42 ] ] }, { "pmid": "15974585", "text": "The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15974585", "text": "Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.", "type": "CHEMICAL", "entities": [ "repertaxin" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "23221006", "text": "Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex", "type": "CHEMICAL", "entities": [ "carnitine", "phenformin" ], "offsets": [ [ 23, 32 ], [ 60, 70 ] ] }, { "pmid": "23221006", "text": "I respiration in mitochondria.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221006", "text": "Phenformin causes lactic acidosis in clinical situations due to inhibition of mitochondrial respiratory chain complex I. It is reportedly taken up by hepatocytes and exhibits mitochondrial toxicity in the liver.", "type": "CHEMICAL", "entities": [ "Phenformin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23221006", "text": "In this study, uptake of phenformin and [(14)C]tetraethylammonium (TEA) and complex I inhibition by phenformin were examined in isolated liver and heart mitochondria.", "type": "CHEMICAL", "entities": [ "phenformin", "[(14)C]tetraethylammonium", "TEA", "phenformin" ], "offsets": [ [ 25, 35 ], [ 40, 65 ], [ 67, 70 ], [ 100, 110 ] ] }, { "pmid": "23221006", "text": "Uptake of phenformin into isolated rat liver mitochondria was higher than that into heart mitochondria.", "type": "CHEMICAL", "entities": [ "phenformin" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "23221006", "text": "It was inhibited by several cat ionic compounds, which suggests the involvement of multispecific transport system(s).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221006", "text": "Similar characteristics were also observed for uptake of TEA; however, uptake of phenformin into mitochondria of organic cation/carnitine transporter 1 (OCTN1) knockout mice was lower than that in wild-type mice, whereas uptake of TEA was comparable between the two strains, suggesting the involvement of distinct transport mechanisms for these two cations in mitochondria.", "type": "CHEMICAL", "entities": [ "TEA", "phenformin", "carnitine", "TEA" ], "offsets": [ [ 57, 60 ], [ 81, 91 ], [ 128, 137 ], [ 231, 234 ] ] }, { "pmid": "23221006", "text": "Inhibition by phenformin of oxygen consumption via complex", "type": "CHEMICAL", "entities": [ "oxygen", "phenformin" ], "offsets": [ [ 28, 34 ], [ 14, 24 ] ] }, { "pmid": "23221006", "text": "I respiration in isolated rat liver mitochondria was greater than that in heart mitochondria, whereas inhibitory effect of phenformin on complex I respiration was similar in inside-out structured submitochondrial particles prepared from rat livers and hearts.", "type": "CHEMICAL", "entities": [ "phenformin" ], "offsets": [ [ 123, 133 ] ] }, { "pmid": "23221006", "text": "Lactic acidosis provoked by iv infusion of phenformin was weaker in octn1(-/-) mice than that in wild-type mice.", "type": "CHEMICAL", "entities": [ "phenformin" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "23221006", "text": "These observations suggest that uptake of phenformin into liver mitochondria is at least partly mediated by OCTN1 and functionally relevant to its inhibition potential of complex I respiration.", "type": "CHEMICAL", "entities": [ "phenformin" ], "offsets": [ [ 42, 52 ] ] }, { "pmid": "23221006", "text": "This study was, thus, the first to demonstrate OCTN1-mediated mitochondrial transport and toxicity of biguanide in vivo in rodents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23358258", "text": "Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4.\n", "type": "CHEMICAL", "entities": [ "xanthine" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "23358258", "text": "A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes.", "type": "CHEMICAL", "entities": [ "xanthine", "methylene", "xanthine" ], "offsets": [ [ 12, 20 ], [ 44, 53 ], [ 84, 92 ] ] }, { "pmid": "23358258", "text": "As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities.", "type": "CHEMICAL", "entities": [ "4-methyl-quinazoline-2-yl-methyl", "2-aminoethylaminomethyl" ], "offsets": [ [ 96, 128 ], [ 155, 178 ] ] }, { "pmid": "23358258", "text": "Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15224175", "text": "5-HT1B receptors, alpha2A/2C- and,", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15224175", "text": "to a lesser extent, alpha1-adrenoceptors mediate the external carotid vasoconstriction to ergotamine in vagosympathectomised dogs.\n", "type": "CHEMICAL", "entities": [ "ergotamine" ], "offsets": [ [ 90, 100 ] ] }, { "pmid": "15224175", "text": "It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and alpha2-adrenoceptors.", "type": "CHEMICAL", "entities": [ "ergotamine" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "15224175", "text": "The present study has reanalysed this suggestion by using more selective antagonists alone and in combination.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15224175", "text": "Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15224175", "text": "The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 microg/kg; 5-HT1B), BRL15572 (300 microg/kg; 5-HT1D), rauwolscine (300 microg/kg; alpha2), SB224289 + BRL15572 (300 microg/kg each), SB224289 + rauwolscine (300 microg/kg each), BRL15572 + rauwolscine (300 microg/kg each), rauwolscine (300 microg/kg)", "type": "CHEMICAL", "entities": [ "SB224289", "BRL15572", "rauwolscine", "SB224289", "BRL15572", "SB224289", "rauwolscine", "BRL15572", "rauwolscine", "rauwolscine" ], "offsets": [ [ 164, 172 ], [ 198, 206 ], [ 232, 243 ], [ 269, 277 ], [ 280, 288 ], [ 311, 319 ], [ 322, 333 ], [ 356, 364 ], [ 367, 378 ], [ 401, 412 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg; alpha1), SB224289 (300 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin", "SB224289" ], "offsets": [ [ 2, 10 ], [ 36, 44 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg), SB224289 (300 microg/kg) + rauwolscine (300 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin", "SB224289", "rauwolscine" ], "offsets": [ [ 2, 10 ], [ 28, 36 ], [ 55, 66 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg), SB224289 (300 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin", "SB224289" ], "offsets": [ [ 2, 10 ], [ 28, 36 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg) + BRL44408 (1,000 microg/kg; alpha2A), SB224289 (300 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin", "BRL44408", "SB224289" ], "offsets": [ [ 2, 10 ], [ 29, 37 ], [ 66, 74 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg)+ imiloxan (1,000 microg/kg; alpha2B), or SB224289 (300 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin", "imiloxan", "SB224289" ], "offsets": [ [ 2, 10 ], [ 28, 36 ], [ 68, 76 ] ] }, { "pmid": "15224175", "text": "+ prazosin (100 microg/kg)", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 2, 10 ] ] }, { "pmid": "15224175", "text": "+ MK912 (300 microg/kg; alpha2C).", "type": "CHEMICAL", "entities": [ "MK912" ], "offsets": [ [ 2, 7 ] ] }, { "pmid": "15224175", "text": "Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 microg/min), following a cumulative schedule.", "type": "CHEMICAL", "entities": [ "ergotamine" ], "offsets": [ [ 64, 74 ] ] }, { "pmid": "15224175", "text": "In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate.", "type": "CHEMICAL", "entities": [ "ergotamine" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "15224175", "text": "These control responses were: unaffected by SB224289, BRL15572, rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + rauwolscine, rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + rauwolscine; and markedly blocked by SB224289 + rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912.", "type": "CHEMICAL", "entities": [ "SB224289", "BRL15572", "rauwolscine", "SB224289", "BRL15572", "BRL15572", "rauwolscine", "rauwolscine", "prazosin", "SB224289", "prazosin", "SB224289", "prazosin", "imiloxan", "SB224289", "rauwolscine", "SB224289", "rauwolscine", "prazosin", "SB224289", "prazosin", "BRL44408", "SB224289", "prazosin", "MK912" ], "offsets": [ [ 44, 52 ], [ 54, 62 ], [ 64, 75 ], [ 99, 107 ], [ 110, 118 ], [ 120, 128 ], [ 131, 142 ], [ 144, 155 ], [ 158, 166 ], [ 168, 176 ], [ 179, 187 ], [ 192, 200 ], [ 203, 211 ], [ 214, 222 ], [ 244, 252 ], [ 255, 266 ], [ 292, 300 ], [ 303, 314 ], [ 317, 325 ], [ 327, 335 ], [ 338, 346 ], [ 349, 357 ], [ 361, 369 ], [ 372, 380 ], [ 383, 388 ] ] }, { "pmid": "15224175", "text": "Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT1B receptors as well as alpha2A/2C-adrenoceptor subtypes and, to a lesser extent, by alpha1-adrenoceptors.", "type": "CHEMICAL", "entities": [ "ergotamine" ], "offsets": [ [ 56, 66 ] ] }, { "pmid": "11692072", "text": "Influence of the dopamine D2 receptor (DRD2) exon 8 genotype on efficacy of tiapride and clinical outcome of alcohol withdrawal.\n", "type": "CHEMICAL", "entities": [ "alcohol", "dopamine", "tiapride" ], "offsets": [ [ 109, 116 ], [ 17, 25 ], [ 76, 84 ] ] }, { "pmid": "11692072", "text": "We tested the hypothesis that allelic variants of the human dopamine D2 receptor E8 genotype are associated with (i) dopamine D2 antagonist tiapride dose in treatment of alcohol withdrawal (n = 50) and (ii) with anxiety and depression in patients during alcoholism detoxification therapy (admission n = 87; discharge n = 50).", "type": "CHEMICAL", "entities": [ "dopamine", "alcohol", "dopamine" ], "offsets": [ [ 117, 125 ], [ 170, 177 ], [ 60, 68 ] ] }, { "pmid": "11692072", "text": "DRD2 E8 A/A genotype was associated with increased dose of tiapride during a 9-day detoxification therapy and with increased anxiety and depression scores on admission and 2 weeks later.", "type": "CHEMICAL", "entities": [ "tiapride" ], "offsets": [ [ 59, 67 ] ] }, { "pmid": "11692072", "text": "The findings suggest a pharmacogenetic influence of DRD2 E8 genotype on tiapride efficacy in alcohol withdrawal.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11692072", "text": "In an earlier report, DRD2 E8 A/A genotype was associated with reduced responsiveness to the dopamine D2 agonist apomorphine; however, it is not clear whether both findings share the same biological basis.", "type": "CHEMICAL", "entities": [ "dopamine", "apomorphine" ], "offsets": [ [ 93, 101 ], [ 113, 124 ] ] }, { "pmid": "11692072", "text": "Earlier findings concerning association of DRD2 E8 A/A with increased anxiety and depression are replicated for the first time.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23318471", "text": "Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.\n", "type": "CHEMICAL", "entities": [ "Peroxynitrite", "testosterone" ], "offsets": [ [ 0, 13 ], [ 23, 35 ] ] }, { "pmid": "23318471", "text": "Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels.", "type": "CHEMICAL", "entities": [ "androgens", "androgens" ], "offsets": [ [ 146, 155 ], [ 21, 30 ] ] }, { "pmid": "23318471", "text": "Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation.", "type": "CHEMICAL", "entities": [ "testosterone", "TES", "TES" ], "offsets": [ [ 63, 75 ], [ 77, 80 ], [ 155, 158 ] ] }, { "pmid": "23318471", "text": "Mesenteric microvessels were isolated from male Sprague-Dawley rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23318471", "text": "Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol.", "type": "CHEMICAL", "entities": [ "TES", "17β-estradiol" ], "offsets": [ [ 88, 91 ], [ 151, 164 ] ] }, { "pmid": "23318471", "text": "Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite.", "type": "CHEMICAL", "entities": [ "nitrotyrosine", "TES", "peroxynitrite", "TES", "peroxynitrite" ], "offsets": [ [ 36, 49 ], [ 88, 91 ], [ 103, 116 ], [ 185, 188 ], [ 238, 251 ] ] }, { "pmid": "23318471", "text": "As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production.", "type": "CHEMICAL", "entities": [ "TES", "superoxide", "TES", "peroxynitrite", "superoxide", "nitic oxide", "xanthine" ], "offsets": [ [ 170, 173 ], [ 185, 195 ], [ 13, 16 ], [ 49, 62 ], [ 81, 91 ], [ 96, 107 ], [ 114, 122 ] ] }, { "pmid": "23318471", "text": "Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation.", "type": "CHEMICAL", "entities": [ "TES", "phosphoinositide", "androgen", "cGMP" ], "offsets": [ [ 49, 52 ], [ 88, 104 ], [ 182, 190 ], [ 241, 245 ] ] }, { "pmid": "23318471", "text": "These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO.", "type": "CHEMICAL", "entities": [ "androgen", "TES", "peroxynitrite", "xanthine", "superoxide", "NO" ], "offsets": [ [ 143, 151 ], [ 184, 187 ], [ 234, 247 ], [ 260, 268 ], [ 287, 297 ], [ 302, 304 ] ] }, { "pmid": "23318471", "text": "This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 115, 123 ] ] }, { "pmid": "23318471", "text": "We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.", "type": "CHEMICAL", "entities": [ "TES", "cGMP" ], "offsets": [ [ 43, 46 ], [ 58, 62 ] ] }, { "pmid": "12560076", "text": "Mouse brain serine racemase catalyzes specific elimination of L-serine to pyruvate.\n", "type": "CHEMICAL", "entities": [ "serine", "L-serine", "pyruvate" ], "offsets": [ [ 12, 18 ], [ 62, 70 ], [ 74, 82 ] ] }, { "pmid": "12560076", "text": "D-Serine was previously identified in mammalian brain and was shown to be a co-agonist at the 'glycine' site of the N-methyl-D-aspartate (NMDA)-type receptors.", "type": "CHEMICAL", "entities": [ "D-Serine", "N-methyl-D-aspartate", "NMDA", "glycine" ], "offsets": [ [ 0, 8 ], [ 116, 136 ], [ 138, 142 ], [ 95, 102 ] ] }, { "pmid": "12560076", "text": "Racemization of serine is catalyzed by serine racemase, a pyridoxal 5'-phosphate-dependent enzyme expressed mainly in brain and liver.", "type": "CHEMICAL", "entities": [ "serine", "serine", "pyridoxal 5'-phosphate" ], "offsets": [ [ 16, 22 ], [ 39, 45 ], [ 58, 80 ] ] }, { "pmid": "12560076", "text": "NMDA receptor overactivation has been implicated in a number of pathological conditions and inhibitors of serine racemase are thus potentially interesting targets for therapy.", "type": "CHEMICAL", "entities": [ "NMDA", "serine" ], "offsets": [ [ 0, 4 ], [ 106, 112 ] ] }, { "pmid": "12560076", "text": "We expressed recombinant mouse serine racemase in insect cells and purified it to near homogeneity.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 31, 37 ] ] }, { "pmid": "12560076", "text": "The enzyme is a non-covalent homodimer in solution and requires divalent cations Mg(2+), Ca(2+) or Mn(2+) for activity but not for dimerization.", "type": "CHEMICAL", "entities": [ "Mg(2+)", "Ca(2+)", "Mn(2+)" ], "offsets": [ [ 81, 87 ], [ 89, 95 ], [ 99, 105 ] ] }, { "pmid": "12560076", "text": "In addition to the racemization it also catalyzes specific elimination of L-Ser to pyruvate.", "type": "CHEMICAL", "entities": [ "L-Ser", "pyruvate" ], "offsets": [ [ 74, 79 ], [ 83, 91 ] ] }, { "pmid": "12560076", "text": "D-Serine is eliminated much less efficiently.", "type": "CHEMICAL", "entities": [ "D-Serine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12560076", "text": "Both L-serine racemization and elimination activities of serine racemase are of comparable magnitude, display alkaline pH optimum and are negligible below pH 6.5.", "type": "CHEMICAL", "entities": [ "L-serine", "serine", "alkaline" ], "offsets": [ [ 5, 13 ], [ 57, 63 ], [ 110, 118 ] ] }, { "pmid": "17148442", "text": "Ankyrin repeat and suppressors of cytokine signaling box protein asb-9 targets creatine kinase B for degradation.\n", "type": "CHEMICAL", "entities": [ "creatine" ], "offsets": [ [ 79, 87 ] ] }, { "pmid": "17148442", "text": "The suppressors of cytokine signaling (SOCS) proteins inhibit cytokine action by direct interaction with Janus kinases or activated cytokine receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17148442", "text": "In addition to the N-terminal and Src homology 2 domains that mediate these interactions, SOCS proteins contain a C-terminal SOCS box.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 19, 20 ], [ 114, 115 ] ] }, { "pmid": "17148442", "text": "DNA data base searches have identified a number of other protein families that possess a SOCS box, of which the ankyrin repeat and SOCS box-containing (Asb) proteins constitute the largest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17148442", "text": "Although it is known that the SOCS proteins are involved in the negative regulation of cytokine signaling, the biological and biochemical functions of the Asbs are largely undefined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17148442", "text": "Using a proteomics approach, we demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner.", "type": "CHEMICAL", "entities": [ "creatine" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "17148442", "text": "This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17148442", "text": "The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3058238", "text": "Tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer--a randomized study.\n", "type": "CHEMICAL", "entities": [ "Tamoxifen", "fluoxymesterone", "tamoxifen", "danazol" ], "offsets": [ [ 0, 9 ], [ 14, 29 ], [ 37, 46 ], [ 51, 58 ] ] }, { "pmid": "3058238", "text": "A prospective randomized trial of tamoxifen and fluoxymesterone versus tamoxifen and danazol in metastatic breast cancer was conducted from December 1980 to September 1985.", "type": "CHEMICAL", "entities": [ "tamoxifen", "fluoxymesterone", "tamoxifen", "danazol" ], "offsets": [ [ 34, 43 ], [ 48, 63 ], [ 71, 80 ], [ 85, 92 ] ] }, { "pmid": "3058238", "text": "Patients were eligible regardless of site of disease, estrogen receptor status, or age.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 54, 62 ] ] }, { "pmid": "3058238", "text": "Sixty-two of sixty-three randomized patients were evaluable for response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3058238", "text": "Overall response for tamoxifen and fluoxymesterone was 11% with 61% stabilization of disease, versus 12% response rate for tamoxifen and danazol with 59% stabilization.", "type": "CHEMICAL", "entities": [ "tamoxifen", "fluoxymesterone", "tamoxifen", "danazol" ], "offsets": [ [ 21, 30 ], [ 35, 50 ], [ 123, 132 ], [ 137, 144 ] ] }, { "pmid": "3058238", "text": "Toxicities with tamoxifen and fluoxymesterone were greater with an increase in masculinization.", "type": "CHEMICAL", "entities": [ "tamoxifen", "fluoxymesterone" ], "offsets": [ [ 16, 25 ], [ 30, 45 ] ] }, { "pmid": "3058238", "text": "We conclude that the response rates to the combinations of tamoxifen and fluoxymesterone or tamoxifen and danazol reported are equivalent in this study but that the increased toxicity with tamoxifen and fluoxymesterone would make tamoxifen and danazol the treatment of choice if a combination were to be used.", "type": "CHEMICAL", "entities": [ "tamoxifen", "fluoxymesterone", "tamoxifen", "danazol", "tamoxifen", "fluoxymesterone", "tamoxifen", "danazol" ], "offsets": [ [ 59, 68 ], [ 73, 88 ], [ 92, 101 ], [ 106, 113 ], [ 189, 198 ], [ 203, 218 ], [ 230, 239 ], [ 244, 251 ] ] }, { "pmid": "23524316", "text": "Effect of quercetin-rich onion peel extracts on arterial thrombosis in rats.\n", "type": "CHEMICAL", "entities": [ "quercetin" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23524316", "text": "The aim of this study was to examine whether oral supplementation of quercetin-rich onion peel extract (OPE) influences blood coagulation and arterial thrombosis in Sprague-Dawley (SD) rats.", "type": "CHEMICAL", "entities": [ "quercetin" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "23524316", "text": "24 male rats, 5weeks old, were divided into three groups with different diets (C: control, 2mg OPE: chow diet with 2mg OPE supplementation, 10mg OPE: chow diet with 10mg OPE supplementation) for 6weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23524316", "text": "Blood coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (aPTT) and platelet aggregation were examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23524316", "text": "The OPE did not affect blood cholesterol levels but significantly decreased blood triglyceride and glucose levels.", "type": "CHEMICAL", "entities": [ "cholesterol", "triglyceride", "glucose" ], "offsets": [ [ 29, 40 ], [ 82, 94 ], [ 99, 106 ] ] }, { "pmid": "23524316", "text": "PT, aPTT and platelet aggregation were not significantly different among all tested groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23524316", "text": "However, in vivo arterial thrombosis was significantly delayed in groups that were fed 2mg and 10mg OPE diets compared to the control group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23524316", "text": "In addition, the OPE greatly diminished thrombin-induced expression of tissue factor in human umbilical vein endothelial cells (HUVECs), a coagulation initiator.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23524316", "text": "In addition, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways activated by thrombin treatment were prevented by the OPE pre-treatment.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 67, 68 ] ] }, { "pmid": "23524316", "text": "These results indicate that OPE may have anti-thrombotic effects through restricting the induced expression of tissue factor via down-regulating mitogen-activated protein kinase (MAPK) activation upon coagulation stimulus, leading to the prolongation of time for arterial thrombosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "Thyroid hormone receptors/THR genes in human cancer.\n", "type": "CHEMICAL", "entities": [ "Thyroid hormone" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "12668276", "text": "Thyroid hormone (triiodothyronine, T3) is a pleiotropic regulator of growth, differentiation and tissue homeostasis in higher organisms that acts through the control of target gene expression.", "type": "CHEMICAL", "entities": [ "Thyroid hormone", "triiodothyronine" ], "offsets": [ [ 0, 15 ], [ 17, 33 ] ] }, { "pmid": "12668276", "text": "Most, if not all, major T3 actions are mediated by specific high affinity nuclear receptors (TR) which are encoded by two genes, THRA and THRB.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "Several TRalpha and TRbeta receptor isoforms are expressed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "Abundant and contradictory literature exists on the relationship between circulating thyroid hormone levels, thyroid diseases and human cancer.", "type": "CHEMICAL", "entities": [ "thyroid hormone" ], "offsets": [ [ 85, 100 ] ] }, { "pmid": "12668276", "text": "In 1986, a connection between TR and cancer became evident when the chicken TRalpha1 was characterized as the c-erbA proto-oncogene, the cellular counterpart of the retroviral v-erbA oncogene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "V-erbA causes erythroleukemias and sarcomas in birds, and hepatocellular carcinomas in transgenic mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "In recent years, many studies have analyzed the presence of quantitative (abnormal levels) or qualitative (mutations) alterations in the expression of THR genes in different types of human neoplasias.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "While their role in tumor generation or progression is currently unclear, both gross chromosomal and minor mutations (deletions, aberrant splicing, point mutations) and changes in the level of expression of THRA and THRB genes have been found.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668276", "text": "Together with other in vitro data indicating connections between TR and p53, Rb, cyclin D and other cell cycle regulators and oncogenes, these results suggest that THRA and THRB may be involved in human cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17161452", "text": "Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives.\n", "type": "CHEMICAL", "entities": [ "Warfarin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "17161452", "text": "Warfarin is the most widely prescribed oral anticoagulant, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response.", "type": "CHEMICAL", "entities": [ "Warfarin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "17161452", "text": "Information from pharmacogenomics, the study of the interaction of an individual's genotype and drug response, can help optimize drug efficacy while minimizing adverse drug reactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17161452", "text": "Pharmacogenetic analysis of two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 VKORC1, confirmed their influence on warfarin maintenance dose.", "type": "CHEMICAL", "entities": [ "warfarin", "warfarin", "vitamin K epoxide", "warfarin" ], "offsets": [ [ 43, 51 ], [ 80, 88 ], [ 104, 121 ], [ 179, 187 ] ] }, { "pmid": "17161452", "text": "Possession of CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, is associated with a significant decrease in the mean warfarin dose.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 149, 157 ] ] }, { "pmid": "17161452", "text": "Several single nucleotide polymorphisms (SNPs) in VKORC1 are associated with warfarin dose across the normal dose range.", "type": "CHEMICAL", "entities": [ "nucleotide", "warfarin" ], "offsets": [ [ 15, 25 ], [ 77, 85 ] ] }, { "pmid": "17161452", "text": "Haplotypes based on these SNPs explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold greater effect than CYP2C9.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 92, 100 ] ] }, { "pmid": "17161452", "text": "Algorithms incorporating genetic (CYP2C9 and VKORC1), demographic, and clinical factors to estimate the warfarin dosage, could potentially minimize the risk of over dose during warfarin induction.", "type": "CHEMICAL", "entities": [ "warfarin", "warfarin" ], "offsets": [ [ 104, 112 ], [ 177, 185 ] ] }, { "pmid": "21631396", "text": "Pseudoephedrine inhibits T-cell activation by targeting NF-kappaB, NFAT and AP-1 signaling pathways.\n", "type": "CHEMICAL", "entities": [ "Pseudoephedrine" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "21631396", "text": "Pseudoephedrine (PSE) is a stereoisomer of ephedrine that is commonly used as a nasal decongestant in combination with other anti-inflammatory drugs for the symptomatic treatment of some common pathologies such as common cold.", "type": "CHEMICAL", "entities": [ "Pseudoephedrine", "PSE", "ephedrine" ], "offsets": [ [ 0, 15 ], [ 17, 20 ], [ 43, 52 ] ] }, { "pmid": "21631396", "text": "Herein, we describe for the first time the effects of PSE on T-cell activation events.", "type": "CHEMICAL", "entities": [ "PSE" ], "offsets": [ [ 54, 57 ] ] }, { "pmid": "21631396", "text": "We found that PSE inhibits interleukin-2 (IL-2) and tumor necrosis factor (TNF) alpha-gene transcription in stimulated Jurkat cells, a human T-cell leukemia cell line.", "type": "CHEMICAL", "entities": [ "PSE" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "21631396", "text": "To further characterize the inhibitory mechanisms of PSE at the transcriptional level, we examined the transcriptional activities of nuclear factor kappa B (NF-kappaB), nuclear factor of activated T cells (NFAT), and activator protein-1 (AP-1) transcription factors and found that PSE inhibited NF-kappaB-dependent transcriptional activity without affecting either the phosphorylation, the degradation of the cytoplasmic NF-kappaB inhibitory protein, IkappaBalpha or the DNA-binding activity.", "type": "CHEMICAL", "entities": [ "PSE", "PSE" ], "offsets": [ [ 53, 56 ], [ 281, 284 ] ] }, { "pmid": "21631396", "text": "However, phosphorylation of the p65/RelA subunit was clearly inhibited by PSE in stimulated cells.", "type": "CHEMICAL", "entities": [ "PSE" ], "offsets": [ [ 74, 77 ] ] }, { "pmid": "21631396", "text": "In addition, PSE inhibited the transcriptional activity of NFAT without interfering with the calcium-induced NFAT dephosphorylation event, which represents the major signaling pathway for its activation.", "type": "CHEMICAL", "entities": [ "PSE", "calcium" ], "offsets": [ [ 13, 16 ], [ 93, 100 ] ] }, { "pmid": "21631396", "text": "NFAT cooperates with c-Jun, a compound of the AP-1 complex, to activate target genes, and we also found that PSE inhibited both JNK activation and AP-1 transcriptional activity.", "type": "CHEMICAL", "entities": [ "PSE" ], "offsets": [ [ 109, 112 ] ] }, { "pmid": "21631396", "text": "These findings provide new mechanistic insights into the potential immunomodulatory activities of PSE and highlight their potential in designing novel therapeutic strategies to manage inflammatory diseases.", "type": "CHEMICAL", "entities": [ "PSE" ], "offsets": [ [ 98, 101 ] ] }, { "pmid": "15932636", "text": "Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway.\n", "type": "CHEMICAL", "entities": [ "Diethylcarbamazine", "nitric-oxide" ], "offsets": [ [ 0, 18 ], [ 90, 102 ] ] }, { "pmid": "15932636", "text": "BACKGROUND: Diethylcarbamazine (DEC) has been used for many years in the treatment of human lymphatic filariasis.", "type": "CHEMICAL", "entities": [ "Diethylcarbamazine", "DEC" ], "offsets": [ [ 12, 30 ], [ 32, 35 ] ] }, { "pmid": "15932636", "text": "Its mode of action is not well understood, but it is known to interact with the arachidonic acid pathway.", "type": "CHEMICAL", "entities": [ "arachidonic acid" ], "offsets": [ [ 80, 96 ] ] }, { "pmid": "15932636", "text": "Here we have investigated the contribution of the nitric oxide and cyclooxygenase (COX) pathways to the activity of DEC against B. malayi microfilariae in mice.", "type": "CHEMICAL", "entities": [ "nitric oxide", "DEC" ], "offsets": [ [ 50, 62 ], [ 116, 119 ] ] }, { "pmid": "15932636", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "B. malayi microfilariae were injected intravenously into mice and parasitaemia was measured 24 hours later.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "DEC was then administered to BALB/c mice with and without pre-treatment with indomethacin or dexamethasone and the parasitaemia monitored.", "type": "CHEMICAL", "entities": [ "DEC", "indomethacin", "dexamethasone" ], "offsets": [ [ 0, 3 ], [ 77, 89 ], [ 93, 106 ] ] }, { "pmid": "15932636", "text": "To investigate a role for inducible nitric oxide in DEC's activity, DEC and ivermectin were administered to microfilaraemic iNOS-/- mice and their background strain (129/SV).", "type": "CHEMICAL", "entities": [ "nitric oxide", "DEC", "ivermectin" ], "offsets": [ [ 36, 48 ], [ 68, 71 ], [ 76, 86 ] ] }, { "pmid": "15932636", "text": "Western blot analysis was used to determine any effect of DEC on the production of COX and inducible nitric-oxide synthase (iNOS) proteins.", "type": "CHEMICAL", "entities": [ "DEC", "nitric-oxide" ], "offsets": [ [ 58, 61 ], [ 101, 113 ] ] }, { "pmid": "15932636", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "DEC administered alone to BALB/c mice resulted in a rapid and profound reduction in circulating microfilariae within five minutes of treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "Microfilarial levels began to recover after 24 hours and returned to near pre-treatment levels two weeks later, suggesting that the sequestration of microfilariae occurs independently of parasite killing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "Pre-treatment of animals with dexamethasone or indomethacin reduced DEC's efficacy by almost 90% or 56%, respectively, supporting a role for the arachidonic acid and cyclooxygenase pathways in vivo.", "type": "CHEMICAL", "entities": [ "dexamethasone", "indomethacin", "arachidonic acid" ], "offsets": [ [ 30, 43 ], [ 47, 59 ], [ 145, 161 ] ] }, { "pmid": "15932636", "text": "Furthermore, experiments showed that treatment with DEC results in a reduction in the amount of COX-1 protein in peritoneal exudate cells.", "type": "CHEMICAL", "entities": [ "DEC" ], "offsets": [ [ 52, 55 ] ] }, { "pmid": "15932636", "text": "Additionally, in iNOS-/- mice infected with B. malayi microfilariae, DEC showed no activity, whereas the efficacy of another antifilarial drug, ivermectin, was unaffected.", "type": "CHEMICAL", "entities": [ "DEC", "ivermectin" ], "offsets": [ [ 69, 72 ], [ 144, 154 ] ] }, { "pmid": "15932636", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15932636", "text": "These results confirm the important role of the arachidonic acid metabolic pathway in DEC's mechanism of action in vivo and show that in addition to its effects on the 5-lipoxygenase pathway, it targets the cyclooxygenase pathway and COX-1.", "type": "CHEMICAL", "entities": [ "arachidonic acid" ], "offsets": [ [ 48, 64 ] ] }, { "pmid": "15932636", "text": "Moreover, we show for the first time that inducible nitric oxide is essential for the rapid sequestration of microfilariae by DEC.", "type": "CHEMICAL", "entities": [ "nitric oxide", "DEC" ], "offsets": [ [ 52, 64 ], [ 126, 129 ] ] }, { "pmid": "12213829", "text": "SUR-dependent modulation of KATP channels by an N-terminal KIR6.2 peptide.", "type": "CHEMICAL", "entities": [ "KATP", "N" ], "offsets": [ [ 28, 32 ], [ 48, 49 ] ] }, { "pmid": "12213829", "text": "Defining intersubunit gating interactions.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12213829", "text": "Ntp and Ctp, synthetic peptides based on the N- and C-terminal sequences of K(IR)6.0, respectively, were used to probe gating of K(IR)6.0/SUR K(ATP) channels.", "type": "CHEMICAL", "entities": [ "K", "ATP", "N", "C" ], "offsets": [ [ 142, 143 ], [ 144, 147 ], [ 45, 46 ], [ 52, 53 ] ] }, { "pmid": "12213829", "text": "Micromolar Ntp dose-dependently increased the mean open channel probability in ligand-free solution (P(O(max))) and attenuated the ATP inhibition of K(IR)6.2/SUR1, but had no effect on homomeric K(IR)6.2 channels.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 131, 134 ] ] }, { "pmid": "12213829", "text": "Ntp (up to approximately 10(-4) m) did not affect significantly the mean open or \"fast,\" K(+) driving force-dependent, intraburst closed times, verifying that Ntp selectively modulates the ratio of mean burst to interburst times.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 89, 93 ] ] }, { "pmid": "12213829", "text": "Ctp and Rnp, a randomized Ntp, had no effect, indicating that the effects of Ntp are structure specific.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12213829", "text": "Ntp opened K(IR)6.1/SUR1 channels normally silent in the absence of stimulatory Mg(-) nucleotide(s) and attenuated the coupling of high-affinity sulfonylurea binding with K(ATP) pore closure.", "type": "CHEMICAL", "entities": [ "nucleotide(s)", "sulfonylurea", "K", "ATP" ], "offsets": [ [ 86, 99 ], [ 145, 157 ], [ 171, 172 ], [ 173, 176 ] ] }, { "pmid": "12213829", "text": "These effects resemble those seen with N-terminal deletions (DeltaN) of K(IR)6.0, and application of Ntp to DeltaNK(ATP) channels decreased their P(O(max)) and apparent IC(50) for ATP in the absence of Mg(2+).", "type": "CHEMICAL", "entities": [ "ATP", "ATP", "Mg(2+)", "N" ], "offsets": [ [ 116, 119 ], [ 180, 183 ], [ 202, 208 ], [ 39, 40 ] ] }, { "pmid": "12213829", "text": "The results are consistent with a competition between Ntp and the endogenous N terminus for a site of interaction on the cytoplasmic face of the channel or with partial replacement of the deleted N terminus by Ntp, respectively.", "type": "CHEMICAL", "entities": [ "N", "N" ], "offsets": [ [ 77, 78 ], [ 196, 197 ] ] }, { "pmid": "12213829", "text": "The K(IR) N terminus and the TMD0-L0 segment of SUR1 are known to control the P(O(max)).", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 10, 11 ] ] }, { "pmid": "12213829", "text": "The L0 linker has been reported to be required for glibenclamide binding, and DeltaNK(IR)6.2/SUR1 channels exhibit reduced labeling of K(IR) with (125)I-azidoglibenclamide, implying that the K(IR) N terminus and L0 of SUR1 are in proximity.", "type": "CHEMICAL", "entities": [ "glibenclamide", "(125)I-azidoglibenclamide", "N" ], "offsets": [ [ 51, 64 ], [ 146, 171 ], [ 197, 198 ] ] }, { "pmid": "12213829", "text": "We hypothesize that L0 interacts with the K(IR) N terminus in ligand-inhibited K(ATP) channels and put forward a model, based on the architecture of BtuCD, MsbA, and the KcsA channel, in which TMD0-L0 links the MDR-like core of SUR with the K(IR) pore.", "type": "CHEMICAL", "entities": [ "N", "K", "ATP" ], "offsets": [ [ 48, 49 ], [ 79, 80 ], [ 81, 84 ] ] }, { "pmid": "15953344", "text": "Monocarboxylate transporters in the central nervous system: distribution, regulation and function.\n", "type": "CHEMICAL", "entities": [ "Monocarboxylate" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "15953344", "text": "Monocarboxylate transporters (MCTs) are proton-linked membrane carriers involved in the transport of monocarboxylates such as lactate, pyruvate, as well as ketone bodies.", "type": "CHEMICAL", "entities": [ "Monocarboxylate", "monocarboxylates", "lactate", "pyruvate", "ketone" ], "offsets": [ [ 0, 15 ], [ 101, 117 ], [ 126, 133 ], [ 135, 143 ], [ 156, 162 ] ] }, { "pmid": "15953344", "text": "They belong to a larger family of transporters composed of 14 members in mammals based on sequence homologies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "MCTs are found in various tissues including the brain where three isoforms, MCT1, MCT2 and MCT4, have been described.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "Each of these isoforms exhibits a distinct regional and cellular distribution in rodent brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "At the cellular level, MCT1 is expressed by endothelial cells of microvessels, by ependymocytes as well as by astrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "MCT4 expression appears to be specific for astrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "By contrast, the predominant neuronal monocarboxylate transporter is MCT2.", "type": "CHEMICAL", "entities": [ "monocarboxylate" ], "offsets": [ [ 38, 53 ] ] }, { "pmid": "15953344", "text": "Interestingly, part of MCT2 immunoreactivity is located at postsynaptic sites, suggesting a particular role of monocarboxylates and their transporters in synaptic transmission.", "type": "CHEMICAL", "entities": [ "monocarboxylates" ], "offsets": [ [ 111, 127 ] ] }, { "pmid": "15953344", "text": "In addition to variation in expression during development and upon nutritional modifications, new data indicate that MCT expression is regulated at the translational level by neurotransmitters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15953344", "text": "Understanding how transport of monocarboxylates is regulated could be of particular importance not only for neuroenergetics but also for areas such as functional brain imaging, regulation of food intake and glucose homeostasis, or for central nervous system disorders such as ischaemia and neurodegenerative diseases.", "type": "CHEMICAL", "entities": [ "monocarboxylates", "glucose" ], "offsets": [ [ 31, 47 ], [ 207, 214 ] ] }, { "pmid": "23087261", "text": "Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis.\n", "type": "CHEMICAL", "entities": [ "Lysine" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23087261", "text": "Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array of environmental toxins and clinically important drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "Therefore, understanding the regulation of this transporter has profound clinical significance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its internalization from cell surface to intracellular compartments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "However, the underlying mechanisms are poorly understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23087261", "text": "Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 111, 117 ] ] }, { "pmid": "23087261", "text": "Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization.", "type": "CHEMICAL", "entities": [ "Lys" ], "offsets": [ [ 110, 113 ] ] }, { "pmid": "23087261", "text": "Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking.", "type": "CHEMICAL", "entities": [ "Lys" ], "offsets": [ [ 59, 62 ] ] }, { "pmid": "22445601", "text": "Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist.\n", "type": "CHEMICAL", "entities": [ "LY541850" ], "offsets": [ [ 61, 69 ] ] }, { "pmid": "22445601", "text": "Despite the potential therapeutic relevance of group II metabotropic glutamate (mGlu) receptors, there has been a lack of pharmacological tools for separating the roles of mGlu2 and mGlu3 receptor subtypes.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "22445601", "text": "LY541850 was claimed from human mGlu receptors expressed in non-neuronal cells to be a selective orthosteric mGlu2 agonist and mGlu3 antagonist.", "type": "CHEMICAL", "entities": [ "LY541850" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "22445601", "text": "We have verified this pharmacological profile of LY541850 in hippocampal slices.", "type": "CHEMICAL", "entities": [ "LY541850" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "22445601", "text": "Field excitatory post-synaptic potentials (fEPSPs) evoked by stimulation of the temporo-ammonic path (TAP) input to CA1 stratum lacunosum moleculare (SLM) were inhibited by LY541850 in mGlu3-/- mice (EC(50) 38 nM) and wild-type littermates (EC(50) 42 nM) to a similar extent but were not significantly affected in mGlu2-/- mice.", "type": "CHEMICAL", "entities": [ "LY541850" ], "offsets": [ [ 173, 181 ] ] }, { "pmid": "22445601", "text": "The group II agonist, DCG-IV, inhibited the fEPSP in all three genotypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22445601", "text": "Co-application of DCG-IV and LY541850 in mGlu3-/- and wild-type littermates resulted in an additive effect, whereas in mGlu2-/- mice, LY541850 reversed the inhibitory action of DCG-IV.", "type": "CHEMICAL", "entities": [ "LY541850", "LY541850" ], "offsets": [ [ 29, 37 ], [ 134, 142 ] ] }, { "pmid": "22445601", "text": "These results confirm the selective mGlu2 agonist and mGlu3 antagonist actions of LY541850.", "type": "CHEMICAL", "entities": [ "LY541850" ], "offsets": [ [ 82, 90 ] ] }, { "pmid": "22445601", "text": "A similar profile of activity was seen in medial perforant path synapse to the dentate gyrus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22445601", "text": "Systemic administration of LY541850 to wild-type mice, reduced the increase in locomotor activity following both phencyclidine and amphetamine administration.", "type": "CHEMICAL", "entities": [ "LY541850", "phencyclidine", "amphetamine" ], "offsets": [ [ 27, 35 ], [ 113, 126 ], [ 131, 142 ] ] }, { "pmid": "22445601", "text": "These data support the hypothesis that mGlu2 receptors mediate the antipsychotic effects of mixed group II agonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22445601", "text": "This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.", "type": "CHEMICAL", "entities": [ "Glutamate" ], "offsets": [ [ 63, 72 ] ] }, { "pmid": "6227474", "text": "Characterization of rat brain aldosterone receptors reveals high affinity for corticosterone.\n", "type": "CHEMICAL", "entities": [ "aldosterone", "corticosterone" ], "offsets": [ [ 30, 41 ], [ 78, 92 ] ] }, { "pmid": "6227474", "text": "The two [3H]aldosterone-binding proteins of rat brain cytosol were characterized by a dextran-coated charcoal method.", "type": "CHEMICAL", "entities": [ "[3H]aldosterone" ], "offsets": [ [ 8, 23 ] ] }, { "pmid": "6227474", "text": "With molybdate present to stabilize receptors, the affinities of the two sites for [3H]aldosterone in adrenalectomized perfused rat brain cytosols were 0.28 and 18.0 nM at 4 C. High affinity sites comprised 15% of the total receptor number.", "type": "CHEMICAL", "entities": [ "molybdate", "[3H]aldosterone" ], "offsets": [ [ 5, 14 ], [ 83, 98 ] ] }, { "pmid": "6227474", "text": "A small contamination of perfused brain cytosol preparations with corticosteroid-binding globulin (CBG) was found.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6227474", "text": "However, due to the very high affinity of CBG for corticosterone at 4 C, this slight contamination resulted in significant alterations in the apparent affinity of steroids competing for aldosterone-binding sites.", "type": "CHEMICAL", "entities": [ "corticosterone", "steroids", "aldosterone" ], "offsets": [ [ 50, 64 ], [ 163, 171 ], [ 186, 197 ] ] }, { "pmid": "6227474", "text": "Selective precipitation of cytosol receptors with 36% (NH4)2SO4 reduced CBG concentrations to negligible levels.", "type": "CHEMICAL", "entities": [ "(NH4)2SO4" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "6227474", "text": "After blockade of low affinity sites with a highly selective glucocorticoid (RU 26988), the order of steroids in competing for the high affinity receptor was desoxycorticosterone greater than fludrocortisone greater than corticosterone greater than aldosterone greater than progesterone greater than dexamethasone.", "type": "CHEMICAL", "entities": [ "corticosterone", "aldosterone", "progesterone", "dexamethasone", "RU 26988", "steroids", "desoxycorticosterone", "fludrocortisone" ], "offsets": [ [ 221, 235 ], [ 249, 260 ], [ 274, 286 ], [ 300, 313 ], [ 77, 85 ], [ 101, 109 ], [ 158, 178 ], [ 192, 207 ] ] }, { "pmid": "6227474", "text": "Readdition of a small quantity of dialyzed serum to cytosol preparations yielded a profile of steroid binding similar to that of the kidney mineralocorticoid receptor (aldosterone greater than desoxycorticosterone greater than corticosterone).", "type": "CHEMICAL", "entities": [ "steroid", "aldosterone", "desoxycorticosterone", "corticosterone" ], "offsets": [ [ 94, 101 ], [ 168, 179 ], [ 193, 213 ], [ 227, 241 ] ] }, { "pmid": "6227474", "text": "The distribution of both receptors in brain regions of adrenalectomized rats was determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6227474", "text": "Both receptors were at greatest density in the hippocampus and lowest density in the hypothalamus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6227474", "text": "The high affinity site was at greatest density in limbic regions, whereas the low affinity receptor, apparently identical to the glucocorticoid type II receptor, was at greatest density in cortex and cerebellum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6227474", "text": "It is concluded that the high affinity aldosterone receptor of rat brain, which had been identified in preliminary studies as a mineralocorticoid receptor, may bind either corticosterone or aldosterone in vivo.", "type": "CHEMICAL", "entities": [ "aldosterone", "corticosterone", "aldosterone" ], "offsets": [ [ 39, 50 ], [ 172, 186 ], [ 190, 201 ] ] }, { "pmid": "16809928", "text": "Acromegaly: molecular expression of somatostatin receptor subtypes and treatment outcome.\n", "type": "CHEMICAL", "entities": [ "somatostatin" ], "offsets": [ [ 36, 48 ] ] }, { "pmid": "16809928", "text": "About a third of acromegalic patients are resistant to the currently commercially available somatostatin analogs (SA) octreotide and lanreotide.", "type": "CHEMICAL", "entities": [ "octreotide", "lanreotide", "somatostatin" ], "offsets": [ [ 118, 128 ], [ 133, 143 ], [ 92, 104 ] ] }, { "pmid": "16809928", "text": "Such resistance is related to an overall reduction of somatostatin receptor (SSTR) density or to a differentiated expression of SSTR subtypes.", "type": "CHEMICAL", "entities": [ "somatostatin" ], "offsets": [ [ 54, 66 ] ] }, { "pmid": "16809928", "text": "There are five known SSTR subtypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16809928", "text": "SSTR2 and SSTR5 are usually expressed in GH-secreting pituitary tumors, and both octreotide and lanreotide bind preferentially to SSTR2 and, to a lesser extent, to SSTR5.", "type": "CHEMICAL", "entities": [ "octreotide", "lanreotide" ], "offsets": [ [ 81, 91 ], [ 96, 106 ] ] }, { "pmid": "16809928", "text": "SA inhibitory effects on GH secretion and tumor cell proliferation can occur together or be dissociated events, depending on the tumor expression of SSTR subtypes involved in each mechanism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16809928", "text": "The development of specific somatostatin subtypes analogs, mainly for SSTR5, of a SSTR2-SSTR5 bispecific compound, and of a \"universal\" analog with high affinity to SSTR1, 2, 3, and 5 showed preliminary, albeit promising results for the treatment of resistant somatotropic adenomas.", "type": "CHEMICAL", "entities": [ "somatostatin" ], "offsets": [ [ 28, 40 ] ] }, { "pmid": "23373869", "text": "REMNANT UPTAKE AS A POSTOPERATIVE ONCOLOGIC QUALITY INDICATOR.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "The purpose of this study was to examine the utility of remnant uptake on postoperative radioiodine scans as an oncologic indicator after thyroidectomy for differentiated thyroid cancer (DTC).", "type": "CHEMICAL", "entities": [ "radioiodine" ], "offsets": [ [ 88, 99 ] ] }, { "pmid": "23373869", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "We conducted a retrospective review of patients undergoing total thyroidectomy for DTC and subsequent radioactive iodine (RAI) treatment.", "type": "CHEMICAL", "entities": [ "iodine" ], "offsets": [ [ 114, 120 ] ] }, { "pmid": "23373869", "text": "Of the eight surgeons included, three were considered high volume, performing at least 20 thyroidectomies per year.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "Patients with distant metastases at diagnosis or poorly differentiated variants were excluded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "To control for the effect of varying RAI doses, the remnant uptake was analyzed as a ratio of the percentage uptake to the dose received (uptake to dose ratio, UDR).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "Multivariate logistic regression was used to determine the influence of UDR on recurrence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "Of the 223 patients who met inclusion criteria, 21 patients (9.42%) experienced a recurrence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "Those who recurred had a ten-fold higher UDR compared to those who did not recur (0.030 vs. 0.003, p = 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "Similarly, patients with increasing postoperative thyroglobulin measurements (0.339 vs. 0.003, p<0.001) also had significantly greater UDRs compared to those with stable thyroglobulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "The UDRs of high volume surgeons were significantly smaller than low volume surgeons (0.003 vs. 0.025, p = 0.002).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "When combined with other known predictors for recurrence, UDR (OR 3.71, C.I 1.05 - 13.10, p = 0.041) was significantly associated with recurrence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23373869", "text": "High volume surgeons maintained a low level of permanent complications across all UDRs whereas low volume surgeons had greater permanent complications associated with higher uptake.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360412", "text": "Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity.\n", "type": "CHEMICAL", "entities": [ "2,6-dichlorobenzonitrile" ], "offsets": [ [ 36, 60 ] ] }, { "pmid": "23360412", "text": "The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans.", "type": "CHEMICAL", "entities": [ "DCBN", "2,6-dichlorobenzonitrile", "DCBN" ], "offsets": [ [ 118, 122 ], [ 14, 38 ], [ 40, 44 ] ] }, { "pmid": "23360412", "text": "The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5.", "type": "CHEMICAL", "entities": [ "DCBN" ], "offsets": [ [ 33, 37 ] ] }, { "pmid": "23360412", "text": "The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN.", "type": "CHEMICAL", "entities": [ "DCBN" ], "offsets": [ [ 118, 122 ] ] }, { "pmid": "23360412", "text": "In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN.", "type": "CHEMICAL", "entities": [ "DCBN" ], "offsets": [ [ 87, 91 ] ] }, { "pmid": "23360412", "text": "We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models.", "type": "CHEMICAL", "entities": [ "glutathione", "DCBN", "DCBN", "DCBN" ], "offsets": [ [ 36, 47 ], [ 61, 65 ], [ 70, 74 ], [ 112, 116 ] ] }, { "pmid": "23360412", "text": "We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes.", "type": "CHEMICAL", "entities": [ "DCBN" ], "offsets": [ [ 79, 83 ] ] }, { "pmid": "23360412", "text": "The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor.", "type": "CHEMICAL", "entities": [ "8-methoxypsoralen" ], "offsets": [ [ 67, 84 ] ] }, { "pmid": "23360412", "text": "GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg).", "type": "CHEMICAL", "entities": [ "DCBN", "DCBN", "DCBN", "DCBN" ], "offsets": [ [ 97, 101 ], [ 162, 166 ], [ 224, 228 ], [ 3, 7 ] ] }, { "pmid": "23360412", "text": "Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs.", "type": "CHEMICAL", "entities": [ "DCBN" ], "offsets": [ [ 54, 58 ] ] }, { "pmid": "23360412", "text": "Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans.", "type": "CHEMICAL", "entities": [ "DCBN", "DCBN", "DCBN" ], "offsets": [ [ 99, 103 ], [ 116, 120 ], [ 201, 205 ] ] }, { "pmid": "3345199", "text": "Effects of some mono- and bisquaternary ammonium compounds on the reactivatability of soman-inhibited human acetylcholinesterase in vitro.\n", "type": "CHEMICAL", "entities": [ "mono- and bisquaternary ammonium", "soman" ], "offsets": [ [ 16, 48 ], [ 86, 91 ] ] }, { "pmid": "3345199", "text": "Acetylcholinesterase (AChE) inhibited by the organophosphate soman (1,2,2-trimethyl-propylmethylphosphonofluoridate) rapidly becomes resistant to reactivation by oximes due to dealkylation of the soman-enzyme complex.", "type": "CHEMICAL", "entities": [ "oximes", "soman", "organophosphate", "soman", "1,2,2-trimethyl-propylmethylphosphonofluoridate" ], "offsets": [ [ 162, 168 ], [ 196, 201 ], [ 45, 60 ], [ 61, 66 ], [ 68, 115 ] ] }, { "pmid": "3345199", "text": "This reaction is called aging.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3345199", "text": "The effect of the four mono- and bisquaternary ammonium compounds tetramethylammonium (TMA), hexamethonium, decamethonium and suxamethonium on the reactivatability of soman-inhibited, solubilized AChE from human erythrocytes was investigated in vitro.", "type": "CHEMICAL", "entities": [ "mono- and bisquaternary ammonium", "tetramethylammonium", "TMA", "hexamethonium", "decamethonium", "suxamethonium", "soman" ], "offsets": [ [ 23, 55 ], [ 66, 85 ], [ 87, 90 ], [ 93, 106 ], [ 108, 121 ], [ 126, 139 ], [ 167, 172 ] ] }, { "pmid": "3345199", "text": "All compounds were reversible inhibitors of AChE; the respective dissociation constants and the type of inhibition exhibited considerable differences.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3345199", "text": "The affinities to both the active and the allosteric site were considerably higher for suxamethonium (Kii 81.3 microM; Ki 15.9 microM) and decamethonium (Kii 15.4 microM; Ki 4.4 microM) than for TMA (Kii 1 mM; Ki 289.6 microM) and hexamethonium (Kii 4.5 mM; Ki 331.8 microM).", "type": "CHEMICAL", "entities": [ "suxamethonium", "decamethonium", "TMA", "hexamethonium" ], "offsets": [ [ 87, 100 ], [ 139, 152 ], [ 195, 198 ], [ 231, 244 ] ] }, { "pmid": "3345199", "text": "The reactivation experiments were performed in a four-step procedure (soman-inhibition at 0 degree and pH 10, aging at 37 degrees and pH 7.3, reactivation by the oxime HI 6 at 37 degrees and pH 7.3 followed by AChE assay).", "type": "CHEMICAL", "entities": [ "oxime", "soman" ], "offsets": [ [ 162, 167 ], [ 70, 75 ] ] }, { "pmid": "3345199", "text": "After these four steps (total duration 55 min), AChE was inhibited by soman to 95-100%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3345199", "text": "HI 6 could reactivate about 20% of the inhibited enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3345199", "text": "All effectors increased the AChE reactivatability by HI 6 when added before aging was started.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3345199", "text": "The maximal increase in reactivatability was higher in the presence of 1.6 mM suxamethonium (+35.8%) and 150 microM decamethonium (+40%) than of 22 mM TMA (+22.5%) and 8.3 mM hexamethonium (+19.2%).", "type": "CHEMICAL", "entities": [ "suxamethonium", "decamethonium", "TMA", "hexamethonium" ], "offsets": [ [ 78, 91 ], [ 116, 129 ], [ 151, 154 ], [ 175, 188 ] ] }, { "pmid": "3345199", "text": "If the effectors were added after 5 min of aging they increased the activity of soman-inhibited AChE, but to a considerably smaller extent than HI 6.", "type": "CHEMICAL", "entities": [ "soman" ], "offsets": [ [ 80, 85 ] ] }, { "pmid": "3345199", "text": "A good correlation of the respective Kii values and the effective concentrations of these drugs was observed, indicating that an allosteric binding site of AChE might be involved in the protective effect of these drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11278845", "text": "Atp-bound topoisomerase ii as a target for antitumor drugs.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11278845", "text": "Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11278845", "text": "In the current studies, we show that two different classes (ATP-sensitive and -insensitive) of TOP2 poisons can be identified based on their differential sensitivity to the ATP-bound conformation of TOP2.", "type": "CHEMICAL", "entities": [ "ATP", "ATP" ], "offsets": [ [ 60, 63 ], [ 173, 176 ] ] }, { "pmid": "11278845", "text": "First, in the presence of 1 mm ATP or the nonhydrolyzable analog adenosine 5'-(beta,gamma-imino)triphosphate, TOP2-mediated DNA cleavage induced by ATP-sensitive TOP2 poisons (e.g. doxorubicin, etoposide, mitoxantrone, and 4'-(9-acridinylamino)methanesulfon-m-anisidide) was 30-100-fold stimulated, whereas DNA cleavage induced by ATP-insensitive TOP2 poisons (e.g. amonafide, batracylin, and menadione) was only slightly (less than 3-fold) affected.", "type": "CHEMICAL", "entities": [ "ATP", "adenosine 5'-(beta,gamma-imino)triphosphate", "ATP", "doxorubicin", "etoposide", "mitoxantrone", "4'-(9-acridinylamino)methanesulfon-m-anisidide", "ATP", "amonafide", "batracylin", "menadione" ], "offsets": [ [ 31, 34 ], [ 65, 108 ], [ 148, 151 ], [ 181, 192 ], [ 194, 203 ], [ 205, 217 ], [ 223, 269 ], [ 331, 334 ], [ 366, 375 ], [ 377, 387 ], [ 393, 402 ] ] }, { "pmid": "11278845", "text": "In addition, ADP was shown to strongly antagonize TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive TOP2 poisons.", "type": "CHEMICAL", "entities": [ "ADP", "ATP", "ATP" ], "offsets": [ [ 13, 16 ], [ 88, 91 ], [ 110, 113 ] ] }, { "pmid": "11278845", "text": "Second, C427A mutant human TOP2alpha, which exhibits reduced ATPase activity, was shown to exhibit cross-resistance to all ATP-sensitive but not ATP-insensitive TOP2 poisons.", "type": "CHEMICAL", "entities": [ "ATP", "ATP" ], "offsets": [ [ 123, 126 ], [ 145, 148 ] ] }, { "pmid": "11278845", "text": "Third, using ciprofloxacin competition assay, TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive poisons was shown to be antagonized by ciprofloxacin.", "type": "CHEMICAL", "entities": [ "ciprofloxacin", "ATP", "ATP", "ciprofloxacin" ], "offsets": [ [ 13, 26 ], [ 84, 87 ], [ 106, 109 ], [ 161, 174 ] ] }, { "pmid": "11278845", "text": "These results suggest that ATP-bound TOP2 may be the specific target of ATP-sensitive TOP2 poisons.", "type": "CHEMICAL", "entities": [ "ATP", "ATP" ], "offsets": [ [ 27, 30 ], [ 72, 75 ] ] }, { "pmid": "11278845", "text": "Using Lac repressor-operator complexes as roadblocks, we show that ATP-bound TOP2 acts as a circular clamp capable of entering DNA ends and sliding on unobstructed duplex DNA.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 67, 70 ] ] }, { "pmid": "23297831", "text": "Tunable morphology and mesophase formation by naphthalene-containing poly(aryl ether) dendron-based low-molecular-weight fluorescent gels.\n", "type": "CHEMICAL", "entities": [ "naphthalene", "poly(aryl ether)" ], "offsets": [ [ 46, 57 ], [ 69, 85 ] ] }, { "pmid": "23297831", "text": "Novel poly(aryl ether) dendron-based low-molecular-weight organogelaters (LMWG) containing naphthalene units at the core have been synthesized, and the self-assembly of the system has been examined in a variety of solvents and solvent mixtures.", "type": "CHEMICAL", "entities": [ "poly(aryl ether)", "naphthalene" ], "offsets": [ [ 6, 22 ], [ 91, 102 ] ] }, { "pmid": "23297831", "text": "The compounds readily form gels with attractive critical gel concentration values associated with gelation-induced enhanced emission (GIEE).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23297831", "text": "In addition to the remarkable properties of the previously reported anthracene and pyrene analogues (Rajamalli, P.; Prasad, E. Org.", "type": "CHEMICAL", "entities": [ "anthracene", "pyrene" ], "offsets": [ [ 68, 78 ], [ 83, 89 ] ] }, { "pmid": "23297831", "text": "Lett.2011, 13, 3714 and Rajamalli, P.; Prasad, E. Soft Matter2012, 8, 8896), the self-assembled systems exhibit distinctly different structure-property relationships.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23297831", "text": "Unlike the reported ones, the present system forms sheetlike morphology in nonpolar solvent mixtures, giant vesicles in polar solvent mixtures, and lamellar or hexagonal columnar phases in single solvents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23297831", "text": "The unique properties of the self-assembled systems, which were analyzed through electron microscopic (SEM, TEM, AFM) and spectroscopic techniques (POM, fluorescence), are attributed to the replacement of anthracene/pyrene units by naphthalene units.", "type": "CHEMICAL", "entities": [ "anthracene", "pyrene", "naphthalene" ], "offsets": [ [ 205, 215 ], [ 216, 222 ], [ 232, 243 ] ] }, { "pmid": "23297831", "text": "The present work unravels the subtle role of minute structural change in altering the properties of LMWGs based on poly(aryl ether) dendrons.", "type": "CHEMICAL", "entities": [ "poly(aryl ether)" ], "offsets": [ [ 115, 131 ] ] }, { "pmid": "14613270", "text": "Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: relationship to mediators of systemic and local inflammation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "OBJECTIVE: To determine in vivo the extent of damage to, and changes in turnover of, articular cartilage type II collagen (CII) and the proteoglycan aggrecan following the onset of inflammatory arthritis in humans, and to examine the hypothesis that there are direct relationships between cartilage biomarkers of damage/turnover and clinical, histologic, and molecular markers of inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Synovial fluid (SF) and synovial membrane (SM) were obtained by arthroscopy, and a synovitis score was determined, in 32 patients with rheumatoid arthritis (RA) (13 with early untreated disease, 19 with established disease), 18 with psoriatic arthritis (PsA), and 10 with osteoarthritis (OA).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Systemic disease activity markers were recorded, and SM CD3+ T cells, CD4+ T cells, CD68+ macrophages, and lining layer hyperplasia were quantified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "SF levels of tumor necrosis factor alpha (TNFalpha), interleukin-10 (IL-10), matrix metalloproteinase 1 (MMP-1), MMP-3, Col2-3/4C(Long mono) neoepitope (C2C) (reflecting collagenase cleavage of cartilage CII), C-propeptide of type II procollagen (PIICP) (a biosynthesis marker), keratan sulfate (KS), and the 846 epitope of aggrecan (turnover) were measured by enzyme-linked immunosorbent assay or radioimmunoassay.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 287, 294 ] ] }, { "pmid": "14613270", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Levels of cartilage degradation products in early RA or early PsA were not elevated above levels in OA, although in early inflammatory arthritis, TNFalpha and MMP-1 levels were similar to those observed in late inflammatory disease and higher than those in OA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "PIICP was reduced in early RA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Correlations were observed between the SF C2C neoepitope level and the Health Assessment Questionnaire score, C-reactive protein level, plasma viscosity, synovitis score, and SF TNFalpha and MMP-1 levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "KS epitope content was reduced in direct relation to SM macrophage infiltration in the sublining and lining layers and in the presence of elevated SF MMP-3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Both SF MMP-1 and SF MMP-3 levels correlated with CD4+ T cell infiltration and lining layer hyperplasia in the SM, and MMP-1 levels correlated with lining layer CD68 levels, but TNFalpha and IL-10 levels did not.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "Except for CII synthesis, there were no significant changes in extracellular matrix turnover of aggrecan or CII in the early stages of human inflammatory arthritis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "However, the direct correlation between the increases in TNFalpha and MMP-1 production and collagen degradation suggests that collagenase cleavage of cartilage collagen is related to the activities of TNFalpha and MMP-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14613270", "text": "The reduction in CII synthesis in early RA may contribute to the developing pathology, since a lack of synthesis of this molecule would inhibit maintenance of cartilage matrix.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500772", "text": "Activation of ALDH2 with ethanol attenuates diabetes induced myocardial injury in rats.\n", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 25, 32 ] ] }, { "pmid": "23500772", "text": "This study assessed changes in myocardial ALDH2 expression in the diabetic rat, in particular the diabetic rat pretreated with ALDH2 activator ethanol (EtOH).", "type": "CHEMICAL", "entities": [ "ethanol", "EtOH" ], "offsets": [ [ 143, 150 ], [ 152, 156 ] ] }, { "pmid": "23500772", "text": "The rats were divided into six groups: control, EtOH control, diabetic rat at 4th week (DM4W), 8th week (DM8W), 12th week (DM12W) and EtOH+DM8W groups.", "type": "CHEMICAL", "entities": [ "EtOH", "EtOH" ], "offsets": [ [ 48, 52 ], [ 134, 138 ] ] }, { "pmid": "23500772", "text": "Compared with control group, fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were increased in DM groups.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "23500772", "text": "HbA1c level in DM12W group was higher than in DM4W group, HbA1c level in EtOH+DM8W group was lower than in DM8W group.", "type": "CHEMICAL", "entities": [ "EtOH" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "23500772", "text": "Compared with control group, there were no changes of LVDP, HR and ±dp/dtmax in DM4W group, but there were decreased in DM8W and DM12W groups, and increased in the EtOH+DM8W group.", "type": "CHEMICAL", "entities": [ "EtOH" ], "offsets": [ [ 164, 168 ] ] }, { "pmid": "23500772", "text": "In DM groups, SOD activity, ALDH2 mRNA and protein levels were reduced, MDA content was increased compared with control group; which decreased further as diabetes progressed.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 71, 74 ] ] }, { "pmid": "23500772", "text": "Compared with DM8W group, SOD and ALDH2 in EtOH+DM8W group was increased, MDA was decreased.", "type": "CHEMICAL", "entities": [ "EtOH", "MDA" ], "offsets": [ [ 42, 46 ], [ 73, 76 ] ] }, { "pmid": "23500772", "text": "Our results indicated with the development of diabetes, myocardial ALDH2 expression was further decreased accompanying decreased ventricular function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500772", "text": "However, activation of ALDH2 can decrease diabetes induced myocardial injury.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500772", "text": "ALDH2 may be one key endogenous cardiac protective factor in diabetic individuals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines.\n", "type": "CHEMICAL", "entities": [ "quinone", "quinolines" ], "offsets": [ [ 21, 28 ], [ 85, 95 ] ] }, { "pmid": "15078100", "text": "Quinone oxidoreductase 2 (QR2) purified from human red blood cells was recently shown to be a potential target of the quinoline antimalarial compounds", "type": "CHEMICAL", "entities": [ "Quinone", "quinoline" ], "offsets": [ [ 0, 7 ], [ 118, 127 ] ] }, { "pmid": "15078100", "text": "[Graves et al., (2002) Mol. Pharmacol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "62, 1364].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "QR2 catalyzes the two-electron reduction of menadione via the oxidation of N-alkylated or N-ribosylated nicotinamides.", "type": "CHEMICAL", "entities": [ "menadione", "N-alkylated", "N-ribosylated nicotinamides" ], "offsets": [ [ 44, 53 ], [ 75, 86 ], [ 90, 117 ] ] }, { "pmid": "15078100", "text": "To investigate the mechanism and consequences of inhibition of QR2 by the quinolines further, we have used steady-state and transient-state kinetics to define the mechanism of QR2.", "type": "CHEMICAL", "entities": [ "quinolines" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "15078100", "text": "Importantly, we have shown that QR2 when isolated from an overproducing strain of E. coli is kinetically equivalent to the enzyme from the native human red blood cell source.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "We observe ping-pong kinetics consistent with one substrate/inhibitor binding site that shows selectivity for the oxidation state of the FAD cofactor, suggesting that selective inhibition of the liver versus red blood cell forms of malaria may be possible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "The reductant N-methyldihydronicotinamide and the inhibitor primaquine bind exclusively to the oxidized enzyme.", "type": "CHEMICAL", "entities": [ "N-methyldihydronicotinamide", "primaquine" ], "offsets": [ [ 14, 41 ], [ 60, 70 ] ] }, { "pmid": "15078100", "text": "In contrast, the inhibitors quinacrine and chloroquine bind exclusively to the reduced enzyme.", "type": "CHEMICAL", "entities": [ "quinacrine", "chloroquine" ], "offsets": [ [ 28, 38 ], [ 43, 54 ] ] }, { "pmid": "15078100", "text": "The quinone substrate menadione, on the other hand, binds nonspecifically to both forms of the enzyme.", "type": "CHEMICAL", "entities": [ "quinone", "menadione" ], "offsets": [ [ 4, 11 ], [ 22, 31 ] ] }, { "pmid": "15078100", "text": "Single-turnover kinetics of the reductive half-reaction are chemically and kinetically competent and confirm the inhibitor selectivity seen in the steady-state experiments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15078100", "text": "Our studies shed light on the possible in vivo potency of the quinolines and provide a foundation for future studies aimed at creating more potent QR2 inhibitors and at understanding the physiological significance of QR2.", "type": "CHEMICAL", "entities": [ "quinolines" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "23531031", "text": "HISTONE DEACETYLASE INHIBITION AFFECTS SODIUM IODIDE SYMPORTER (NIS) EXPRESSION AND INDUCES ¹³¹I CYTOTOXICITY IN ANAPLASTIC THYROID CANCER CELLS.\n", "type": "CHEMICAL", "entities": [ "SODIUM IODIDE", "¹³¹I" ], "offsets": [ [ 39, 52 ], [ 92, 96 ] ] }, { "pmid": "23531031", "text": "Background: Anaplastic thyroid cancers (ATC) represent only 1-2% of all thyroid tumors, but they account for up to 50% of the mortality.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "Treatment of differentiated thyroid carcinomas is well standardized and the use of radioiodine represents an essential step; in contrast, there is no standardized therapeutic approach for anaplastic tumors and their prognosis is poor.", "type": "CHEMICAL", "entities": [ "radioiodine" ], "offsets": [ [ 80, 91 ] ] }, { "pmid": "23531031", "text": "The resistance of anaplastic thyroid cancer to radioiodine treatment is principally due to the absence of expression of the sodium iodide symporter (NIS), mainly due to epigenetic silencing.", "type": "CHEMICAL", "entities": [ "radioiodine", "sodium iodide" ], "offsets": [ [ 44, 55 ], [ 121, 134 ] ] }, { "pmid": "23531031", "text": "The acetylation status of histones is involved in the epigenetic control of gene expression and is usually disrupted in advanced thyroid cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "Histone deacetylase inhibitors have been demonstrated as potent anticancer drugs with several different effects on cell viability and differentiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "Methods: Stabilized anaplastic thyroid cancer cell lines (BHT-101 and CAL-62) and primary cultures from patients who underwent thyroidectomy for anaplastic thyroid cancer were treated with the histone deacetylase inhibitor LBH589.", "type": "CHEMICAL", "entities": [ "LBH589" ], "offsets": [ [ 220, 226 ] ] }, { "pmid": "23531031", "text": "After treatment, we evaluated the expression and function of NIS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "Gene expression was evaluated by real-time PCR (RT-PCR); NIS promoter activity was determined with a luciferase reporter assay; and protein expression was assessed through immunofluorescence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "We tested the protein function by 125I uptake and efflux experiments; finally the cytotoxic effect of 131I was determined with a clonogenic assay.", "type": "CHEMICAL", "entities": [ "125I", "131I" ], "offsets": [ [ 31, 35 ], [ 99, 103 ] ] }, { "pmid": "23531031", "text": "Results:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531031", "text": "Our results demonstrate that treatment with LBH589 leads to NIS RNA expression as shown by RT-PCR and luciferase assay, and to protein expression as determined by immunofluorescence in vitro and by immunohistochemistry in xenograft tumors.", "type": "CHEMICAL", "entities": [ "LBH589" ], "offsets": [ [ 41, 47 ] ] }, { "pmid": "23531031", "text": "Moreover, 125I uptake and efflux experiments show the correct protein function and iodine retention, that translate into cytotoxicity effects, as demonstrated by a clonogenic assay with 131I .", "type": "CHEMICAL", "entities": [ "125I", "iodine", "131I" ], "offsets": [ [ 7, 11 ], [ 80, 86 ], [ 183, 187 ] ] }, { "pmid": "23531031", "text": "Conclusions: This study supplies a new potential strategy for the treatment of ATC by modifying gene expression with the aim of inducing responsiveness towards radioiodine therapy.", "type": "CHEMICAL", "entities": [ "radioiodine" ], "offsets": [ [ 157, 168 ] ] }, { "pmid": "23165754", "text": "EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 48, 56 ] ] }, { "pmid": "23165754", "text": "In the present study, we examined the role of EphB4 during bone repair after traumatic injury.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively.", "type": "CHEMICAL", "entities": [ "safranin O" ], "offsets": [ [ 155, 165 ] ] }, { "pmid": "23165754", "text": "Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23165754", "text": "Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474645", "text": "Inverted CdSe/CdS/ZnS quantum dot light emitting devices with titanium dioxide as an electron-injection contact.\n", "type": "CHEMICAL", "entities": [ "CdS", "ZnS", "titanium dioxide", "CdSe" ], "offsets": [ [ 14, 17 ], [ 18, 21 ], [ 62, 78 ], [ 9, 13 ] ] }, { "pmid": "23474645", "text": "We demonstrated the fabrication of inverted CdSe/CdS/ZnS quantum dot light emitting devices (QD-LEDs) using titanium dioxide (TiO2) as an electron-injection layer and investigated the operating mechanism by utilizing different hole-transport materials, 4,4-N,N-dicarbazole-biphenyl (CBP) and 4,4',4''-tris(carbazol-9-yl)-triphenylamine (TCTA).", "type": "CHEMICAL", "entities": [ "titanium dioxide", "TiO2", "4,4-N,N-dicarbazole-biphenyl", "CBP", "4,4',4''-tris(carbazol-9-yl)-triphenylamine", "TCTA", "CdSe", "CdS", "ZnS" ], "offsets": [ [ 108, 124 ], [ 126, 130 ], [ 253, 281 ], [ 283, 286 ], [ 292, 335 ], [ 337, 341 ], [ 44, 48 ], [ 49, 52 ], [ 53, 56 ] ] }, { "pmid": "23474645", "text": "A more efficient device with CBP as the hole-transport layer (HTL) was obtained compared with the TCTA based device.", "type": "CHEMICAL", "entities": [ "TCTA" ], "offsets": [ [ 98, 102 ] ] }, { "pmid": "23474645", "text": "The peak efficiency of 6.70 cd A(-1) for the CBP based device was found to be about 74.5% higher than the TCTA based device (3.84 cd A(-1)).", "type": "CHEMICAL", "entities": [ "TCTA" ], "offsets": [ [ 106, 110 ] ] }, { "pmid": "23474645", "text": "The studies on the time-resolved photoluminescence spectra of the QD-HTL composite structures showed that the energy transfer (ET) efficiencies from the two HTLs to the QD layer were similar and the charge separation between QDs and HTLs could be neglected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23474645", "text": "The enhancement in the performance of the CBP based device was attributed to the more efficient hole-injection from CBP to QDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23393220", "text": "Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status.\n", "type": "CHEMICAL", "entities": [ "Monoamine", "Harmaline", "5-Methoxy-N,N-Dimethyltryptamine" ], "offsets": [ [ 37, 46 ], [ 67, 76 ], [ 81, 113 ] ] }, { "pmid": "23393220", "text": "5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name \"5-MEO\") is a newer designer drug belonging to a group of naturally occurring indolealkylamines.", "type": "CHEMICAL", "entities": [ "5-Methoxy-N,N-dimethyltryptamine", "indolealkylamines", "5-MeO-DMT", "5-MEO" ], "offsets": [ [ 0, 32 ], [ 137, 154 ], [ 34, 43 ], [ 60, 65 ] ] }, { "pmid": "23393220", "text": "Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine.", "type": "CHEMICAL", "entities": [ "monoamine", "harmaline", "5-MeO-DMT" ], "offsets": [ [ 59, 68 ], [ 97, 106 ], [ 148, 157 ] ] }, { "pmid": "23393220", "text": "This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine.", "type": "CHEMICAL", "entities": [ "harmaline", "5-MeO-DMT", "harmaline", "5-MeO-DMT", "O", "bufotenine" ], "offsets": [ [ 35, 44 ], [ 49, 58 ], [ 163, 172 ], [ 191, 200 ], [ 201, 202 ], [ 228, 238 ] ] }, { "pmid": "23393220", "text": "Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations.", "type": "CHEMICAL", "entities": [ "harmaline", "5-MeO-DMT" ], "offsets": [ [ 77, 86 ], [ 169, 178 ] ] }, { "pmid": "23393220", "text": "A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice.", "type": "CHEMICAL", "entities": [ "5-MeO-DMT", "harmaline" ], "offsets": [ [ 28, 37 ], [ 81, 90 ] ] }, { "pmid": "23393220", "text": "Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice.", "type": "CHEMICAL", "entities": [ "bufotenine", "Harmaline" ], "offsets": [ [ 51, 61 ], [ 0, 9 ] ] }, { "pmid": "23393220", "text": "Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels.", "type": "CHEMICAL", "entities": [ "harmaline", "bufotenine" ], "offsets": [ [ 22, 31 ], [ 56, 66 ] ] }, { "pmid": "23393220", "text": "The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6.", "type": "CHEMICAL", "entities": [ "harmaline", "bufotenine" ], "offsets": [ [ 33, 42 ], [ 63, 73 ] ] }, { "pmid": "23393220", "text": "Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models.", "type": "CHEMICAL", "entities": [ "5-MeO-DMT", "harmaline", "harmaline", "5-MeO-DMT", "bufotenine" ], "offsets": [ [ 97, 106 ], [ 121, 130 ], [ 163, 172 ], [ 174, 183 ], [ 189, 199 ] ] }, { "pmid": "23393220", "text": "This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.", "type": "CHEMICAL", "entities": [ "harmaline", "5-MeO-DMT", "harmaline", "5-MeO-DMT" ], "offsets": [ [ 49, 58 ], [ 63, 72 ], [ 153, 162 ], [ 163, 172 ] ] }, { "pmid": "23256472", "text": "Iodine-129 microdosing for protein and peptide drug development: erythropoietin as a case study.\n", "type": "CHEMICAL", "entities": [ "Iodine-129" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23256472", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "Microdosing is a technique for studying the behavior of compounds in vivo at 1/100th of the dose of a test substance calculated, based on animal data, to yield a pharmacologic effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "In microdosing, use is made of accelerator MS (AMS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "In this study, we investigated whether (129)I-labeling of proteins with subsequent AMS measurements is a suitable method to perform microdose studies with therapeutic proteins.", "type": "CHEMICAL", "entities": [ "(129)I" ], "offsets": [ [ 39, 45 ] ] }, { "pmid": "23256472", "text": "We used erythropoietin (EPO) as a case study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "In an animal study with (129)I-labeled EPO in Han-Wistar rats, an increase of (129)I-EPO is observed after dose administration.", "type": "CHEMICAL", "entities": [ "(129)I", "(129)I" ], "offsets": [ [ 24, 30 ], [ 78, 84 ] ] }, { "pmid": "23256472", "text": "The half-life was found to be 2 and 5.5 h for two different EPOs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "These results are in accordance with expected values.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "CoNCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256472", "text": "Although further research is required, (129)I-labeling of proteins seems a feasible method for AMS microdose studies with peptide and protein drugs, such as biosimilars.", "type": "CHEMICAL", "entities": [ "(129)I" ], "offsets": [ [ 39, 45 ] ] }, { "pmid": "14505791", "text": "Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists.\n", "type": "CHEMICAL", "entities": [ "cetirizine", "levocetirizine", "histamine" ], "offsets": [ [ 62, 72 ], [ 77, 91 ], [ 97, 106 ] ] }, { "pmid": "14505791", "text": "The potent histamine H(1)-receptor antagonist cetirizine (Zyrtec) is a racemic mixture of levocetirizine (now available under the trademark Xyzal and dextrocetirizine.", "type": "CHEMICAL", "entities": [ "histamine", "Xyzal", "dextrocetirizine", "cetirizine", "Zyrtec", "levocetirizine" ], "offsets": [ [ 11, 20 ], [ 140, 145 ], [ 150, 166 ], [ 46, 56 ], [ 58, 64 ], [ 90, 104 ] ] }, { "pmid": "14505791", "text": "In this Commentary, we examine some biological properties of cetirizine and levocetirizine, namely enantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization, the compared behavior of the two enantiomers, and the potential for interactions with other drugs.", "type": "CHEMICAL", "entities": [ "cetirizine", "levocetirizine" ], "offsets": [ [ 61, 71 ], [ 76, 90 ] ] }, { "pmid": "14505791", "text": "Recent data demonstrate that the antihistaminergic activity of the racemate is primarily due to levocetirizine.", "type": "CHEMICAL", "entities": [ "levocetirizine" ], "offsets": [ [ 96, 110 ] ] }, { "pmid": "14505791", "text": "Levocetirizine is rapidly and extensively absorbed, poorly metabolized, and not subject to racemization.", "type": "CHEMICAL", "entities": [ "Levocetirizine" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "14505791", "text": "Its pharmacokinetic characteristics are comparable after administration alone or in the racemate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14505791", "text": "Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg(-1) vs. 0.60 L kg(-1)).", "type": "CHEMICAL", "entities": [ "dextrocetirizine" ], "offsets": [ [ 60, 76 ] ] }, { "pmid": "14505791", "text": "Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min(-1) vs. 29.2 mL min(-1)).", "type": "CHEMICAL", "entities": [ "dextrocetirizine", "levocetirizine" ], "offsets": [ [ 110, 126 ], [ 54, 68 ] ] }, { "pmid": "14505791", "text": "Our conclusion is that levocetirizine is indeed the eutomer of cetirizine.", "type": "CHEMICAL", "entities": [ "levocetirizine", "cetirizine" ], "offsets": [ [ 23, 37 ], [ 63, 73 ] ] }, { "pmid": "14505791", "text": "The evidence reviewed here confirms preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine.", "type": "CHEMICAL", "entities": [ "levocetirizine" ], "offsets": [ [ 123, 137 ] ] }, { "pmid": "23414235", "text": "Vegfrecine, an Inhibitor of VEGF Receptor Tyrosine Kinases Isolated from the Culture Broth of Streptomyces sp.\n", "type": "CHEMICAL", "entities": [ "Vegfrecine", "Tyrosine" ], "offsets": [ [ 0, 10 ], [ 42, 50 ] ] }, { "pmid": "23414235", "text": "A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp.", "type": "CHEMICAL", "entities": [ "tyrosine", "vegfrecine" ], "offsets": [ [ 33, 41 ], [ 51, 61 ] ] }, { "pmid": "23414235", "text": "MK931-CF8.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23414235", "text": "The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23414235", "text": "Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23414235", "text": "Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15561973", "text": "Substrate specificity of the human renal sodium dicarboxylate cotransporter, hNaDC-3, under voltage-clamp conditions.\n", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 41, 47 ] ] }, { "pmid": "15561973", "text": "Proximal tubule cells extract dicarboxylates from filtrate and blood, using cotransporters located in the brush border [sodium dicarboxylate cotransporter (NaDC-1)] and basolateral cell membrane (NaDC-3).", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 120, 126 ] ] }, { "pmid": "15561973", "text": "We expressed the human NaDC-3 (hNaDC-3) in Xenopus laevis oocytes and characterized it by the two-electrode voltage-clamp technique.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15561973", "text": "At -60 mV, succinate (4 carbons) and glutarate (5 carbons) generated inward currents due to translocation of three sodium ions and one divalent dicarboxylate, whereas oxalate (2 carbons) and malonate (3 carbons) did not.", "type": "CHEMICAL", "entities": [ "succinate", "carbons", "glutarate", "carbons", "sodium", "oxalate", "carbons", "malonate", "carbons" ], "offsets": [ [ 11, 20 ], [ 24, 31 ], [ 37, 46 ], [ 50, 57 ], [ 115, 121 ], [ 167, 174 ], [ 178, 185 ], [ 191, 199 ], [ 203, 210 ] ] }, { "pmid": "15561973", "text": "The cis-dicarboxylate maleate produced currents smaller in magnitude, whereas the trans-dicarboxylate fumarate generated currents similar to succinate.", "type": "CHEMICAL", "entities": [ "cis-dicarboxylate maleate", "trans-dicarboxylate fumarate", "succinate" ], "offsets": [ [ 4, 29 ], [ 82, 110 ], [ 141, 150 ] ] }, { "pmid": "15561973", "text": "The substituted succinate derivatives, malate, 2,2- and 2,3-dimethylsuccinate, and 2,3-dimercaptosuccinate elicited inward currents, whereas aspartate and guanidinosuccinate showed hardly detectable currents.", "type": "CHEMICAL", "entities": [ "succinate", "malate", "2,2- and 2,3-dimethylsuccinate", "2,3-dimercaptosuccinate", "aspartate", "guanidinosuccinate" ], "offsets": [ [ 16, 25 ], [ 39, 45 ], [ 47, 77 ], [ 83, 106 ], [ 141, 150 ], [ 155, 173 ] ] }, { "pmid": "15561973", "text": "The C-5 dicarboxylates glutarate and alpha-ketoglutarate produced larger currents than succinate; glutamate and folate failed to cause inward currents.", "type": "CHEMICAL", "entities": [ "succinate", "glutamate", "folate", "C-5 dicarboxylates glutarate", "alpha-ketoglutarate" ], "offsets": [ [ 87, 96 ], [ 98, 107 ], [ 112, 118 ], [ 4, 32 ], [ 37, 56 ] ] }, { "pmid": "15561973", "text": "Kinetic analysis revealed, at -60 mV, K(0.5) values of 25 +/- 12 microM for succinate and 45 +/- 13 microM for alpha-ketoglutarate, values close to the plasma concentration of these compounds.", "type": "CHEMICAL", "entities": [ "succinate", "alpha-ketoglutarate" ], "offsets": [ [ 76, 85 ], [ 111, 130 ] ] }, { "pmid": "15561973", "text": "For both compounds, the K(0.5) was independent of voltage, whereas the maximal current increased with hyperpolarization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15561973", "text": "As opposed to the rat and flounder orthologs, hNaDC-3 was hardly inhibited by lithium concentrations up to 5 mM.", "type": "CHEMICAL", "entities": [ "lithium" ], "offsets": [ [ 78, 85 ] ] }, { "pmid": "15561973", "text": "In the absence of sodium, however, lithium can mediate succinate-dependent currents.", "type": "CHEMICAL", "entities": [ "sodium", "lithium", "succinate" ], "offsets": [ [ 18, 24 ], [ 35, 42 ], [ 55, 64 ] ] }, { "pmid": "15561973", "text": "The narrow substrate specificity prevents interaction of drugs with dicarboxylate-like structure with hNaDC-3 and ensures sufficient support of the proximal tubule cells with alpha-ketoglutarate for anion secretion via organic anion transporter 1 or 3.", "type": "CHEMICAL", "entities": [ "alpha-ketoglutarate" ], "offsets": [ [ 175, 194 ] ] }, { "pmid": "15866288", "text": "Effects of inhibition of urokinase-type plasminogen activator (u-PA) by amiloride in the cornea and tear fluid of eyes irradiated with UVB.\n", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "15866288", "text": "The purpose of the present study was to test our hypothesis that amiloride, a specific u-PA inhibitor, effectively decreases u-PA activity in cornea as well as in tear fluid and favourably affects corneal healing.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "15866288", "text": "Therefore, comparative histochemical and biochemical studies of u-PA and the effects of amiloride were performed on rabbit corneas and tear fluid using the sensitive fluorogenic substrate Z-Gly-Gly-Arg-7-amino-4-trifluoromethylcoumarin.", "type": "CHEMICAL", "entities": [ "amiloride", "Z-Gly-Gly-Arg-7-amino-4-trifluoromethylcoumarin" ], "offsets": [ [ 88, 97 ], [ 188, 235 ] ] }, { "pmid": "15866288", "text": "Rabbit eyes were repeatedly irradiated with UVB for 9 days and during the irradiation topically treated with amiloride (1 mg/ml saline) or placebo (saline) (dropwise, 5 times daily).", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 109, 118 ] ] }, { "pmid": "15866288", "text": "Results show that in placebo-treated eyes, UVB evoked the appearance of u-PA activity in cornea and tear fluid in early stages of irradiation, and u-PA levels increased during irradiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "Corneal epithelium was gradually lost and remnants of the epithelium as well as keratocytes in the upper part of corneal stroma showed high u-PA activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "Finally, corneas lost their epithelium completely.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "In corneal stroma, numerous u-PA-containing inflammatory cells were present.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "Corneas were vascularized.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "When amiloride was dropped on the eye surface on the first day of irradiation and subsequently daily until the end of the experiment, u-PA activity in both cornea and tear fluid was strongly inhibited.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 5, 14 ] ] }, { "pmid": "15866288", "text": "Corneas were covered with a continuous epithelium until the end of the experiment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "The number of inflammatory cells was significantly decreased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "Corneal vascularization was reduced by 50%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15866288", "text": "In conclusion, early application of amiloride inhibited u-PA activity in UVB-irradiated corneas as well as in tear fluid and diminished the development of corneal pathology.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "20427668", "text": "Rapid glucocorticoid receptor-mediated inhibition of hypothalamic-pituitary-adrenal ultradian activity in healthy males.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20427668", "text": "A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20427668", "text": "We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive.", "type": "CHEMICAL", "entities": [ "corticosteroid" ], "offsets": [ [ 139, 153 ] ] }, { "pmid": "20427668", "text": "Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20427668", "text": "Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon.", "type": "CHEMICAL", "entities": [ "prednisolone", "cortisol" ], "offsets": [ [ 154, 166 ], [ 205, 213 ] ] }, { "pmid": "20427668", "text": "Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20427668", "text": "Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary.", "type": "CHEMICAL", "entities": [ "Prednisolone", "cortisol" ], "offsets": [ [ 0, 12 ], [ 37, 45 ] ] }, { "pmid": "20427668", "text": "Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs.", "type": "CHEMICAL", "entities": [ "corticosteroid" ], "offsets": [ [ 83, 97 ] ] }, { "pmid": "20427668", "text": "Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway.", "type": "CHEMICAL", "entities": [ "Prednisolone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "20427668", "text": "The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 16, 28 ] ] }, { "pmid": "3299141", "text": "Localization of L-glutamate decarboxylase and GABA transaminase immunoreactivity in the sympathetic ganglia of the rat.\n", "type": "CHEMICAL", "entities": [ "L-glutamate", "GABA" ], "offsets": [ [ 16, 27 ], [ 46, 50 ] ] }, { "pmid": "3299141", "text": "The location of L-glutamate decarboxylase and gamma-aminobutyrate (GABA)-transaminase immunoreactivity in the superior cervical ganglion and in the coeliac-superior mesenteric ganglion complex of the rat was studied by an indirect immunofluorescence method and by immunoelectron microscopy, with specific antisera raised in rabbits against the corresponding enzymes.", "type": "CHEMICAL", "entities": [ "L-glutamate", "gamma-aminobutyrate", "GABA" ], "offsets": [ [ 16, 27 ], [ 46, 65 ], [ 67, 71 ] ] }, { "pmid": "3299141", "text": "In light microscopy, several glutamate decarboxylase- or GABA-transaminase-immunoreactive principal nerve cells were detected in the superior cervical ganglion and coeliac-superior mesenteric ganglion complex.", "type": "CHEMICAL", "entities": [ "glutamate", "GABA" ], "offsets": [ [ 29, 38 ], [ 57, 61 ] ] }, { "pmid": "3299141", "text": "In addition, numerous small cells in both the superior cervical ganglion and coeliac-superior mesenteric ganglion complex showed intense immunoreactivity to glutamate decarboxylase or GABA-transaminase.", "type": "CHEMICAL", "entities": [ "glutamate", "GABA" ], "offsets": [ [ 157, 166 ], [ 184, 188 ] ] }, { "pmid": "3299141", "text": "The small cells were 10-20 micron in diameter and resembled in size and morphology the small intensely fluorescent cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3299141", "text": "In consecutive sections, the small glutamate decarboxylase-immunoreactive cell clusters also showed immunoreactivity to tyrosine hydroxylase, suggesting that these cells contain the enzymes for both GABA and catecholamine synthesis.", "type": "CHEMICAL", "entities": [ "tyrosine", "GABA", "catecholamine", "glutamate" ], "offsets": [ [ 120, 128 ], [ 199, 203 ], [ 208, 221 ], [ 35, 44 ] ] }, { "pmid": "3299141", "text": "In the superior cervical ganglion and in the coeliac-superior mesenteric ganglion complex, GABA-transaminase immunoreactivity was also localized in fibre-like processes around and between the principal nerve cells, in nerve trunks traversing the ganglia, and around or in close contact with ganglionic blood vessels.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 91, 95 ] ] }, { "pmid": "3299141", "text": "Furthermore, GABA-transaminase immunoreactivity was observed in fibre-like structures close to the capsule of the ganglia.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 13, 17 ] ] }, { "pmid": "3299141", "text": "Division of the preganglionic nerve trunk of the superior cervical ganglion caused no detectable change in GABA-transaminase immunoreactivity in the ganglion.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 107, 111 ] ] }, { "pmid": "3299141", "text": "In immunoelectron microscopy of the superior cervical ganglion, GABA-transaminase immunoreactivity was localized in nerve fibres in association with neurotubules.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 64, 68 ] ] }, { "pmid": "3299141", "text": "A large number of GABA-transaminase labelled principal nerve cells were detected, containing immunoreactivity evenly distributed in their cytoplasm.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 18, 22 ] ] }, { "pmid": "3299141", "text": "GABA-transaminase immunoreactivity was also observed in satellite cells and their processes in the superior cervical ganglion.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "3299141", "text": "The present immunocytochemical results provide evidence that the rat sympathetic ganglia contain an intrinsic neuronal system showing histochemical markers for GABA synthesis and inactivation, but its functional role in the modulation of ganglionic neurotransmission remains to be established.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 160, 164 ] ] }, { "pmid": "25136065", "text": "Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "DATA SOURCES: A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "References were reviewed to identify additional sources.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "STUDY SELECTION AND DATA EXTRACTION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "DATA SYNTHESIS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 114, 121 ] ] }, { "pmid": "25136065", "text": "Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents.", "type": "CHEMICAL", "entities": [ "metformin", "sulfonylureas", "thiazolidinediones" ], "offsets": [ [ 66, 75 ], [ 77, 90 ], [ 92, 110 ] ] }, { "pmid": "25136065", "text": "Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%.", "type": "CHEMICAL", "entities": [ "sitagliptin", "glimepiride" ], "offsets": [ [ 67, 78 ], [ 84, 95 ] ] }, { "pmid": "25136065", "text": "Noninferiority was not achieved when compared to liraglutide and pioglitazone.", "type": "CHEMICAL", "entities": [ "pioglitazone" ], "offsets": [ [ 65, 77 ] ] }, { "pmid": "25136065", "text": "Weight changes ranged from +0.28 to -1.21 kg.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "Albiglutide is the fourth GLP-1 RA approved in the United States.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "25136065", "text": "It has not been compared head to head with other GLP-1 RAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23177256", "text": "Pharmacophore identification of c-Myc inhibitor 10074-G5.\n", "type": "CHEMICAL", "entities": [ "10074-G5" ], "offsets": [ [ 48, 56 ] ] }, { "pmid": "23177256", "text": "A structure-activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) - which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues - was executed in order to determine its pharmacophore.", "type": "CHEMICAL", "entities": [ "arginine", "10074-G5", "N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine" ], "offsets": [ [ 233, 241 ], [ 75, 83 ], [ 85, 149 ] ] }, { "pmid": "23177256", "text": "Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q).", "type": "CHEMICAL", "entities": [ "7-nitrobenzofurazan", "ortho-biphenyl", "para-carboxyphenyl", "JY-3-094" ], "offsets": [ [ 11, 30 ], [ 85, 99 ], [ 125, 143 ], [ 179, 187 ] ] }, { "pmid": "23177256", "text": "Around five times as potent as the lead with an IC(50) of 33 μM for disruption of the Myc-Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max-Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still.", "type": "CHEMICAL", "entities": [ "JY-3-094", "JY-3-094" ], "offsets": [ [ 107, 115 ], [ 247, 255 ] ] }, { "pmid": "17603755", "text": "Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year.\n", "type": "CHEMICAL", "entities": [ "miglustat" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "17603755", "text": "Niemann-Pick disease type C (NP-C) is a lipid storage disorder characterized by the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system of certain cells in the central nervous system (CNS) and visceral organs.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 113, 124 ] ] }, { "pmid": "17603755", "text": "Clinical symptoms include progressive neurological deterioration and visceral organomegaly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Miglustat, a small iminosugar molecule approved for the treatment of Gaucher disease, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis.", "type": "CHEMICAL", "entities": [ "Miglustat", "glucosylceramide" ], "offsets": [ [ 0, 9 ], [ 106, 122 ] ] }, { "pmid": "17603755", "text": "The physicochemical properties of miglustat allow it to cross the blood-brain barrier and suggest possible benefits in lysosomal storage diseases affecting the CNS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Here, we present findings in two children with NP-C, aged 14 years (patient 1) and 9 years (patient 2), treated with miglustat for 1 year.", "type": "CHEMICAL", "entities": [ "miglustat" ], "offsets": [ [ 117, 126 ] ] }, { "pmid": "17603755", "text": "Before treatment, patient 1 presented with severe difficulties in swallowing and walking, and patient 2 with problems mostly affecting communication and social interaction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Videofluoroscopic studies in patient 1 demonstrated a substantial improvement in swallowing by month 6 of treatment, and ambulation index measurements indicated improved walking.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Mini Mental-State Examination (MMSE) assessments in patient 2 showed cognitive improvement by month 6, which was sustained up to month 12.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Liver/spleen volume and plasma chitotriosidase activities were stabilized in both cases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "There was no weight loss during treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "Patient 1 experienced severe but self-limiting paresthesia, which was not associated with peripheral neuropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17603755", "text": "We conclude that miglustat can provide therapeutic benefits in CNS symptoms and allows stabilization of systemic disease in childhood-onset NP-C. Further follow-up is crucial to determine the long-term maintenance of these effects.", "type": "CHEMICAL", "entities": [ "miglustat" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "23270965", "text": "Safrole-2',3'-oxide induces atherosclerotic plaque vulnerability in apolipoprotein E-knockout mice.\nSafrole-2',3'-oxide (SFO) is the major electrophilic metabolite of safrole (4-allyl-1, 2-methylenedioxybenzene), a natural plant constituent found in essential oils of numerous edible herbs and spices and in food containing these herbs, such as pesto sauce, cola beverages and bologna sausages.", "type": "CHEMICAL", "entities": [ "Safrole-2',3'-oxide", "SFO", "safrole", "4-allyl-1, 2-methylenedioxybenzene", "Safrole-2',3'-oxide" ], "offsets": [ [ 100, 119 ], [ 121, 124 ], [ 167, 174 ], [ 176, 210 ], [ 0, 19 ] ] }, { "pmid": "23270965", "text": "The effects of SFO in mammalian systems, especially the cardiovascular system, are little known.", "type": "CHEMICAL", "entities": [ "SFO" ], "offsets": [ [ 15, 18 ] ] }, { "pmid": "23270965", "text": "Disruption of vulnerable atherosclerotic plaques in atherosclerosis, a chronic inflammatory disease, is the main cause of cardiovascular events.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23270965", "text": "In this study, we investigated SFO-induced atherosclerotic plaque vulnerability (possibility of rupture) in apolipoprotein E-knockout (apoE(-/-))", "type": "CHEMICAL", "entities": [ "SFO" ], "offsets": [ [ 31, 34 ] ] }, { "pmid": "23270965", "text": "mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23270965", "text": "Lipid area in vessel wall reached 59.8% in high dose SFO (SFO-HD) treated group, which is only 31.2% in control group.", "type": "CHEMICAL", "entities": [ "SFO", "SFO" ], "offsets": [ [ 53, 56 ], [ 58, 61 ] ] }, { "pmid": "23270965", "text": "SFO treatment changed the lesion composition to an unstable phenotype, increased the number of apoptotic cells in plaque and the endothelium in plaques was damaged after SFO treatment.", "type": "CHEMICAL", "entities": [ "SFO", "SFO" ], "offsets": [ [ 0, 3 ], [ 170, 173 ] ] }, { "pmid": "23270965", "text": "Furthermore, compared with control groups, the plaque endothelium level of p75(NTR) was 3-fold increased and the liver level of p75(NTR) was 17.4-fold increased by SFO-HD.", "type": "CHEMICAL", "entities": [ "SFO" ], "offsets": [ [ 164, 167 ] ] }, { "pmid": "23270965", "text": "Meanwhile, the serum level of KC (a functional homolog of IL-8 and the main proinflammatory alpha chemokine in mice) in apoE(-/-) mice was up to 357pg/ml in SFO-HD treated group.", "type": "CHEMICAL", "entities": [ "SFO" ], "offsets": [ [ 157, 160 ] ] }, { "pmid": "23270965", "text": "Thus, SFO contributes to the instability of atherosclerotic plaque in apoE(-/-) mice through activating p75(NTR) and IL-8 and cell apoptosis in plaque.", "type": "CHEMICAL", "entities": [ "SFO" ], "offsets": [ [ 6, 9 ] ] }, { "pmid": "9633680", "text": "Mechanism of action of dopaminergic agents in Parkinson's disease.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9633680", "text": "As the substantia nigra degenerates in Parkinson's disease (PD), the nigrostriatal pathway is disrupted, reducing striatal dopamine and producing PD symptoms.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 123, 131 ] ] }, { "pmid": "9633680", "text": "Although dopamine does not readily cross the blood-brain barrier, its precursor, levodopa, does.", "type": "CHEMICAL", "entities": [ "dopamine", "levodopa" ], "offsets": [ [ 9, 17 ], [ 81, 89 ] ] }, { "pmid": "9633680", "text": "Levodopa is absorbed in the small bowel and is rapidly catabolized by aromatic-L-amino-acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT).", "type": "CHEMICAL", "entities": [ "Levodopa", "L-amino-acid", "catechol", "O" ], "offsets": [ [ 0, 8 ], [ 79, 91 ], [ 117, 125 ], [ 126, 127 ] ] }, { "pmid": "9633680", "text": "Because gastric AADC and COMT degrade levodopa, the drug is given with inhibitors of AADC (carbidopa or benserazide), and inhibitors of COMT will also enter clinical use.", "type": "CHEMICAL", "entities": [ "levodopa", "carbidopa", "benserazide" ], "offsets": [ [ 38, 46 ], [ 91, 100 ], [ 104, 115 ] ] }, { "pmid": "9633680", "text": "Although the exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown, most striatal AADC is located in nigrostriatal dopaminergic nerve terminals.", "type": "CHEMICAL", "entities": [ "levodopa", "dopamine" ], "offsets": [ [ 56, 64 ], [ 68, 76 ] ] }, { "pmid": "9633680", "text": "Newly synthesized dopamine is stored in the terminals and then released, stimulating postsynaptic dopamine receptors and mediating the antiparkinsonian action of levodopa.", "type": "CHEMICAL", "entities": [ "dopamine", "levodopa" ], "offsets": [ [ 98, 106 ], [ 162, 170 ] ] }, { "pmid": "9633680", "text": "Dopamine agonists act directly on postsynaptic dopamine receptors, thus obviating the need for metabolic conversion, storage, and release.", "type": "CHEMICAL", "entities": [ "Dopamine", "dopamine" ], "offsets": [ [ 0, 8 ], [ 47, 55 ] ] }, { "pmid": "9633680", "text": "How the actions of dopaminergic drugs produce side effects and how these side effects should be managed are discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16636450", "text": "Soy protein suppresses gene expression of acetyl-coA carboxylase alpha from promoter PI in rat liver.\n", "type": "CHEMICAL", "entities": [ "acetyl-coA" ], "offsets": [ [ 42, 52 ] ] }, { "pmid": "16636450", "text": "Dietary soy protein isolate (SPI) reduces hepatic lipogenesis by suppressing gene expression of lipogenic enzymes, including acetyl-CoA carboxylase (ACC).", "type": "CHEMICAL", "entities": [ "acetyl-CoA" ], "offsets": [ [ 125, 135 ] ] }, { "pmid": "16636450", "text": "In order to elucidate the mechanism of this regulation, the effect of dietary SPI on promoter (PI and PII) specific gene expression of ACC alpha was investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16636450", "text": "Rats were fed experimental diets containing SPI or casein as a nitrogen source.", "type": "CHEMICAL", "entities": [ "nitrogen" ], "offsets": [ [ 63, 71 ] ] }, { "pmid": "16636450", "text": "SPI feeding decreased the hepatic contents of total ACC mRNA as well as triglyceride (TG) content, but dietary SPI affected the amount of sterol-regulatory element binding protein (SREBP)-1 mRNA and protein very little.", "type": "CHEMICAL", "entities": [ "triglyceride", "TG" ], "offsets": [ [ 72, 84 ], [ 86, 88 ] ] }, { "pmid": "16636450", "text": "The amount of ACC mRNA transcribed from PII promoter containing SRE was not significantly affected by dietary protein, while a significant decrease in PI-generated ACC mRNA content was observed in rats fed the SPI diet.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16636450", "text": "These data suggest that SPI feeding decreased the hepatic contents of ACC alpha mRNA mainly by regulating PI promoter via a nuclear factor(s) other than SREBP-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199882", "text": "Polymethoxyflavones as agents that prevent formation of cataract: nobiletin congeners show potent growth inhibitory effects in human lens epithelial cells.\n", "type": "CHEMICAL", "entities": [ "Polymethoxyflavones", "nobiletin" ], "offsets": [ [ 0, 19 ], [ 66, 75 ] ] }, { "pmid": "23199882", "text": "Posterior capsular opacification (PCO) is the most frequent complication and the primary reason for visual decrease after extracapsular cataract surgery.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199882", "text": "The proliferation and migration of leftover lens epithelial cells (LECs) after surgery may contribute to the development of PCO.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199882", "text": "To prevent PCO, a rational approach would be to inhibit both the proliferation and the migration of LECs using nontoxic xenobiotics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199882", "text": "Nobiletin, one of the most abundant polymethoxyflavones (PMFs) in citrus peel, and its synthetic congeners displayed a potent inhibition of LEC proliferation.", "type": "CHEMICAL", "entities": [ "Nobiletin", "polymethoxyflavones", "PMFs" ], "offsets": [ [ 0, 9 ], [ 36, 55 ], [ 57, 61 ] ] }, { "pmid": "23199882", "text": "Structural features which enhance anti-proliferative activity have also been discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23194532", "text": "The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23194532", "text": "The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae) were investigated with a study of carbon tetrachloride (CCl(4))-induced oxidative stress and hepatic fibrosis in male ICR mice.", "type": "CHEMICAL", "entities": [ "carbon tetrachloride", "CCl(4)" ], "offsets": [ [ 129, 149 ], [ 151, 157 ] ] }, { "pmid": "23194532", "text": "Oral administration of green tea extract at doses of 125, 625 and 1250 mg/kg for 8 weeks significantly reduced (p<0.05) the levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls in the liver by at least 28% compared with that was induced by CCl(4) (1 mL/kg) in mice.", "type": "CHEMICAL", "entities": [ "thiobarbituric acid", "carbonyls", "CCl(4)" ], "offsets": [ [ 134, 153 ], [ 194, 203 ], [ 267, 273 ] ] }, { "pmid": "23194532", "text": "Moreover, green tea extract administration significantly increased (p<0.05) the activities of catalase, glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) in the liver.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH", "glutathione", "GSH" ], "offsets": [ [ 104, 115 ], [ 128, 131 ], [ 140, 151 ], [ 163, 166 ] ] }, { "pmid": "23194532", "text": "Our study found that oral administration of green tea extract prevented CCl(4)-induced hepatic fibrosis, as evidenced by a decreased hydroxyproline level in the liver and a reduced incidence of hepatic fibrosis by histological observations.", "type": "CHEMICAL", "entities": [ "CCl(4)", "hydroxyproline" ], "offsets": [ [ 72, 78 ], [ 133, 147 ] ] }, { "pmid": "23194532", "text": "These results indicate that green tea exhibits potent protective effects against CCl(4)-induced oxidative stress and hepatic fibrosis in mice by inhibiting oxidative damage and increasing antioxidant enzyme activities.", "type": "CHEMICAL", "entities": [ "CCl(4)" ], "offsets": [ [ 81, 87 ] ] }, { "pmid": "11732752", "text": "Comparison of vaginal aminopeptidase enzymatic activities in various animals and in humans.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11732752", "text": "The specific enzymatic activity of four different aminopeptidases (aminopeptidase N, leucine aminopeptidase, aminopeptidase A and aminopeptidase B) in vaginal homogenates from rabbit, rat, guinea-pig, sheep and humans was compared.", "type": "CHEMICAL", "entities": [ "leucine" ], "offsets": [ [ 85, 92 ] ] }, { "pmid": "11732752", "text": "The purpose of the study was to find an appropriate animal model that can be used in degradation studies of protein and peptide drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11732752", "text": "Different substrates were used as the relative specific substrates for the determination of aminopeptidase enzymatic activity: 4-methoxy-2-naphthylamide of L-alanine for aminopeptidase N, 4-methoxy-2-naphthylamide of L-leucine for leucine aminopeptidase, 4-methoxy-2-naphthylamide of L-glutamic acid for aminopeptidase A and 4-methoxy-2-naphthylamide of L-arginine for aminopeptidase B. The vaginal aminopeptidase enzymatic activity of different species was determined spectrofluorometrically.", "type": "CHEMICAL", "entities": [ "4-methoxy-2-naphthylamide", "L-alanine", "4-methoxy-2-naphthylamide", "L-leucine", "leucine", "4-methoxy-2-naphthylamide", "L-glutamic acid", "4-methoxy-2-naphthylamide", "L-arginine" ], "offsets": [ [ 127, 152 ], [ 156, 165 ], [ 188, 213 ], [ 217, 226 ], [ 231, 238 ], [ 255, 280 ], [ 284, 299 ], [ 325, 350 ], [ 354, 364 ] ] }, { "pmid": "11732752", "text": "The inhibition of aminopeptidase activity in the presence of bestatin and puromycin inhibitors was also investigated.", "type": "CHEMICAL", "entities": [ "bestatin", "puromycin" ], "offsets": [ [ 61, 69 ], [ 74, 83 ] ] }, { "pmid": "11732752", "text": "The results showed the presence of aminopeptidase enzymatic activity in all vaginal homogenates in the order: sheep > guinea-pig > rabbit > or = human > or = rat.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11732752", "text": "Based on the results of the hydrolysis and inhibition of the 4-methoxy-2-naphthylamide substrates, it was difficult to have an exact decision on the aminopeptidase type in the vaginal homogenates from the species studied.", "type": "CHEMICAL", "entities": [ "4-methoxy-2-naphthylamide" ], "offsets": [ [ 61, 86 ] ] }, { "pmid": "11732752", "text": "It was found that the aminopeptidase activity in rat, rabbit and humans was not statistically different.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11732752", "text": "Therefore, we suggest that rats and rabbits could be used as model animals for vaginal enzymatic activity studies and for determination of the degradation of protein and peptide drugs in the vagina.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23522835", "text": "In silico identification of poly(ADP-ribose)polymerase-1 inhibitors and their chemosensitizing effects against cisplatin-resistant human gastric cancer cells.\n", "type": "CHEMICAL", "entities": [ "cisplatin", "poly(ADP-ribose)" ], "offsets": [ [ 111, 120 ], [ 28, 44 ] ] }, { "pmid": "23522835", "text": "Poly(ADP-ribose)polymerase-1 (PARP-1) enzyme is involved in the repair of DNA damages made by certain anticancer agents.", "type": "CHEMICAL", "entities": [ "Poly(ADP-ribose)" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23522835", "text": "It is suggested that PARP-1 inhibitors potentiate the cytotoxic effects and circumvent the resistance of DNA-modifying anticancer agents such as cisplatin.", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 145, 154 ] ] }, { "pmid": "23522835", "text": "In this study, we conducted virtual screening of Korea Chemical Bank database targeting PARP-1 and identified several potent PARP-1 inhibitors with submicromolar IC50 values (77-79nM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23522835", "text": "We then examined the chemosensitization of cisplatin by pre-treatment of PARP-1 inhibitors in cisplatin-resistant human gastric cancer cells.", "type": "CHEMICAL", "entities": [ "cisplatin", "cisplatin" ], "offsets": [ [ 43, 52 ], [ 94, 103 ] ] }, { "pmid": "23522835", "text": "Our results show that PARP-1 inhibitors suppress the formation of poly(ADP-ribose) and enhance the cytotoxicity of cisplatin.", "type": "CHEMICAL", "entities": [ "poly(ADP-ribose)", "cisplatin" ], "offsets": [ [ 66, 82 ], [ 115, 124 ] ] }, { "pmid": "23231502", "text": "Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles.\n", "type": "CHEMICAL", "entities": [ "prolyl" ], "offsets": [ [ 9, 15 ] ] }, { "pmid": "23231502", "text": "Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23231502", "text": "Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function.", "type": "CHEMICAL", "entities": [ "aldehydes" ], "offsets": [ [ 73, 82 ] ] }, { "pmid": "23231502", "text": "4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues.", "type": "CHEMICAL", "entities": [ "4-Hydroxynonenal", "HNE", "Cys", "His", "Lys" ], "offsets": [ [ 0, 16 ], [ 18, 21 ], [ 100, 103 ], [ 105, 108 ], [ 113, 116 ] ] }, { "pmid": "23231502", "text": "Here, we demonstrate that peptidyl-prolyl cis/trans-isomerase A1 (Pin1), an enzyme that catalyzes the conversion of the peptide bond of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE modification.", "type": "CHEMICAL", "entities": [ "prolyl", "pSer", "pThr", "Pro", "HNE" ], "offsets": [ [ 35, 41 ], [ 136, 140 ], [ 141, 145 ], [ 146, 149 ], [ 225, 228 ] ] }, { "pmid": "23231502", "text": "Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry resulted in detection of Michael adducts at the active site residues His-157 and Cys-113.", "type": "CHEMICAL", "entities": [ "HNE", "His", "Cys" ], "offsets": [ [ 33, 36 ], [ 150, 153 ], [ 162, 165 ] ] }, { "pmid": "23231502", "text": "Time and concentration dependencies indicate that Cys-113 is the primary site of HNE modification.", "type": "CHEMICAL", "entities": [ "Cys", "HNE" ], "offsets": [ [ 50, 53 ], [ 81, 84 ] ] }, { "pmid": "23231502", "text": "Pin1 was adducted in MDA-MB-231 breast cancer cells treated with 8-alkynyl-HNE as judged by click chemistry conjugation with biotin followed by streptavidin-based pulldown and Western blotting with anti-Pin1 antibody.", "type": "CHEMICAL", "entities": [ "biotin", "8-alkynyl-HNE" ], "offsets": [ [ 125, 131 ], [ 65, 78 ] ] }, { "pmid": "23231502", "text": "Furthermore, orbitrap MS data support the adduction of Cys-113 in the Pin1 active site upon HNE treatment of MDA-MB-231 cells.", "type": "CHEMICAL", "entities": [ "Cys", "HNE" ], "offsets": [ [ 55, 58 ], [ 92, 95 ] ] }, { "pmid": "23231502", "text": "siRNA knockdown of Pin1 in MDA-MB-231 cells partially protected the cells from HNE-induced toxicity.", "type": "CHEMICAL", "entities": [ "HNE" ], "offsets": [ [ 79, 82 ] ] }, { "pmid": "23231502", "text": "Recent studies indicate that Pin1 is an important molecular target for the chemopreventive effects of green tea polyphenols.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 112, 123 ] ] }, { "pmid": "23231502", "text": "The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16484281", "text": "Withdrawal from free-choice ethanol consumption results in increased packing density of glutamine synthetase-immunoreactive astrocytes in the prelimbic cortex of alcohol-preferring rats.\n", "type": "CHEMICAL", "entities": [ "alcohol", "ethanol", "glutamine" ], "offsets": [ [ 162, 169 ], [ 28, 35 ], [ 88, 97 ] ] }, { "pmid": "16484281", "text": "Excess activation of glutamatergic neurotransmission in the cerebral cortex following ethanol withdrawal is considered to contribute to significant behavioural disturbances, and to alcohol craving.", "type": "CHEMICAL", "entities": [ "alcohol", "ethanol" ], "offsets": [ [ 181, 188 ], [ 86, 93 ] ] }, { "pmid": "16484281", "text": "Astrocytes may play a role in these manifestations because astrocytes are essential in the regulation of released glutamate and its conversion to glutamine through the enzyme glutamine synthetase (GS).", "type": "CHEMICAL", "entities": [ "glutamate", "glutamine", "glutamine" ], "offsets": [ [ 114, 123 ], [ 146, 155 ], [ 175, 184 ] ] }, { "pmid": "16484281", "text": "However, it is unclear if withdrawal from free-choice ethanol drinking causes changes in the numbers of astrocytes expressing GS or the cytoskeletal protein of astrocytes glial fibrillary acidic protein (GFAP).", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 54, 61 ] ] }, { "pmid": "16484281", "text": "Alcohol-preferring (P) rats exposed to free-choice ethanol drinking were either maintained without forced interruption of ethanol drinking, subjected to a 3-day withdrawal period at the end of 2 months, or subjected to three 3-day withdrawal periods along 6 months.", "type": "CHEMICAL", "entities": [ "Alcohol", "ethanol", "ethanol" ], "offsets": [ [ 0, 7 ], [ 51, 58 ], [ 122, 129 ] ] }, { "pmid": "16484281", "text": "At 2 months, P rats were also compared with alcohol-naive alcohol non-preferring rats (NP) rats.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 44, 51 ], [ 58, 65 ] ] }, { "pmid": "16484281", "text": "Packing density of GS and GFAP-immunoreactive (IR) astrocytes was measured in sections from the prelimbic cortex (PLC) using the optical disector probe.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16484281", "text": "An alcohol deprivation effect was observed in P rats with withdrawals during a 6-month ethanol drinking period.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 3, 10 ] ] }, { "pmid": "16484281", "text": "Ethanol withdrawal significantly increased the packing density of GS- and GFAP-IR astrocytes in the PLC of P rats as compared with P rats with continuous access to ethanol.", "type": "CHEMICAL", "entities": [ "Ethanol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "16484281", "text": "In addition, there was a positive correlation between the pre-withdrawal ethanol consumption and the packing density of GS-IR astrocytes.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 73, 80 ] ] }, { "pmid": "16484281", "text": "The present results suggest the involvement of astrocytes in the regulation of the glutamatergic activation associated with withdrawal from free-choice ethanol consumption and point to differential adaptations of GS and GFAP to prolonged alcohol drinking in the PLC of P rats.", "type": "CHEMICAL", "entities": [ "ethanol", "alcohol" ], "offsets": [ [ 152, 159 ], [ 238, 245 ] ] }, { "pmid": "23274887", "text": "Fetal PGC-1α overexpression programs adult pancreatic β-cell dysfunction.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "Here we have investigated the molecular mechanisms underlying this regulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "23274887", "text": "Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274887", "text": "Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221868", "text": "Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state.\n", "type": "CHEMICAL", "entities": [ "Rufinamide", "sodium" ], "offsets": [ [ 0, 10 ], [ 116, 122 ] ] }, { "pmid": "23221868", "text": "BACKGROUND: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 26, 32 ] ] }, { "pmid": "23221868", "text": "Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated.", "type": "CHEMICAL", "entities": [ "Sodium" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23221868", "text": "Getting new molecules to clinical use is laborious.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221868", "text": "We here propose a drug already marketed as anticonvulsant, rufinamide.", "type": "CHEMICAL", "entities": [ "rufinamide" ], "offsets": [ [ 59, 69 ] ] }, { "pmid": "23221868", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221868", "text": "We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice.", "type": "CHEMICAL", "entities": [ "rufinamide", "amitriptyline" ], "offsets": [ [ 37, 47 ], [ 51, 64 ] ] }, { "pmid": "23221868", "text": "We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine.", "type": "CHEMICAL", "entities": [ "rufinamide", "sodium", "sodium", "amitriptyline", "mexiletine" ], "offsets": [ [ 26, 36 ], [ 40, 46 ], [ 121, 127 ], [ 202, 215 ], [ 220, 230 ] ] }, { "pmid": "23221868", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221868", "text": "In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect.", "type": "CHEMICAL", "entities": [ "amitriptyline", "rufinamide" ], "offsets": [ [ 15, 28 ], [ 252, 262 ] ] }, { "pmid": "23221868", "text": "Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 +/- 0.03 g (mean +/- SD) to 1.99 +/- 0.26 g for rufinamide and 0.25 +/- 0.22 g to 1.92 +/- 0.85 g for amitriptyline).", "type": "CHEMICAL", "entities": [ "amitriptyline", "rufinamide", "amitriptyline", "Rufinamide" ], "offsets": [ [ 15, 28 ], [ 154, 164 ], [ 208, 221 ], [ 0, 10 ] ] }, { "pmid": "23221868", "text": "All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 85, 91 ] ] }, { "pmid": "23221868", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23221868", "text": "At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both.", "type": "CHEMICAL", "entities": [ "amitriptyline" ], "offsets": [ [ 39, 52 ] ] }, { "pmid": "23221868", "text": "Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline.", "type": "CHEMICAL", "entities": [ "amitriptyline" ], "offsets": [ [ 81, 94 ] ] }, { "pmid": "23221868", "text": "Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.", "type": "CHEMICAL", "entities": [ "Rufinamide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23298258", "text": "All-trans retinoic acid protects hepatocellular carcinoma cells against serum-starvation-induced cell death by upregulating collagen 8A2.\n", "type": "CHEMICAL", "entities": [ "All-trans retinoic acid" ], "offsets": [ [ 0, 23 ] ] }, { "pmid": "23298258", "text": "As a therapeutic or chemopreventative agent for various cancers, all-trans retinoic acid (atRA) has been reported to inhibit growth, induce apoptosis or cause differentiation.", "type": "CHEMICAL", "entities": [ "all-trans retinoic acid", "atRA" ], "offsets": [ [ 65, 88 ], [ 90, 94 ] ] }, { "pmid": "23298258", "text": "It was found that atRA could protect hepatocellular carcinoma (HCC) cells against cell death induced by serum starvation.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 18, 22 ] ] }, { "pmid": "23298258", "text": "Furthermore, it was found that atRA could enhance cell adhesion, but had no effect on the cell cycle and apoptosis.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 31, 35 ] ] }, { "pmid": "23298258", "text": "Using an Illumina Human HT-12 v4 expression microarray, 207 upregulated and 173 downregulated genes were identified in HepG2 cells treated with atRA.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 144, 148 ] ] }, { "pmid": "23298258", "text": "The most upregulated genes are cytochrome P450 family 26", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "subfamily A polypeptide 1 (CYP26A1), histidine triad nucleotide binding protein 3 (HINT3), miR-1282 and cytochrome P450 family 26", "type": "CHEMICAL", "entities": [ "histidine" ], "offsets": [ [ 37, 46 ] ] }, { "pmid": "23298258", "text": "subfamily B polypeptide 1 (CYP26B1), which showed more than fivefold greater expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "Using Gene Ontology analysis, the greatest significance was found in extracellular-matrix-related molecular functions and the cellular component in upregulated genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "The upregulation of collagen 8A2 (COL8A2) was further confirmed using quantitative RT-PCR and western blotting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "Knockdown of COL8A2 blocked enhancement in the early stage of cell adhesion by atRA treatment.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 79, 83 ] ] }, { "pmid": "23298258", "text": "Re-expression of COL8A2 in COL8A2-knocked-down HCC cells reversed the effect of small interfering RNA-COL8A2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "In addition, COL8A2 could increase HCC cell migration and invasion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298258", "text": "Thus, COL8A2 was identified as the key protein involved in the enhancement of cell adhesion of atRA under serum-free conditions.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 95, 99 ] ] }, { "pmid": "23298258", "text": "In conclusion, atRA protects HCC cells against serum-starvation-induced cell death by enhancing cell adhesion, and COL8A2 plays an important role in HCC cell migration and invasion.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 15, 19 ] ] }, { "pmid": "12699699", "text": "Cloning and expression of a heme binding protein from the genome of Saccharomyces cerevisiae.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12699699", "text": "The YLR205c gene of Saccharomyces cerevisiae does not show significant sequence identity to any known gene, except for heme oxygenase (22% to human HO-1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12699699", "text": "The YLR205 ORF was cloned and overexpressed in both Escherichia coli and S. cerevisiae.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12699699", "text": "Both expression systems yielded proteins that bound heme tightly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12699699", "text": "The isolated YLR205c protein underwent reduction in the presence of either NADPH-cytochrome P450 reductase or NADH-putidaredoxin-putidaredoxin reductase but did not exhibit heme oxygenase activity.", "type": "CHEMICAL", "entities": [ "NADPH", "NADH" ], "offsets": [ [ 75, 80 ], [ 110, 114 ] ] }, { "pmid": "12699699", "text": "The protein exhibited modest H(2)O(2)-dependent peroxidase activities with guaiacol, potassium iodide, and 2,2(')-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS).", "type": "CHEMICAL", "entities": [ "H(2)O(2)", "guaiacol", "potassium iodide", "2,2(')-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid", "ABTS" ], "offsets": [ [ 29, 37 ], [ 75, 83 ], [ 85, 101 ], [ 107, 162 ], [ 164, 168 ] ] }, { "pmid": "12699699", "text": "Thus, YLR205c codes for a hemoprotein of unknown physiological function that exhibits peroxidase activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435367", "text": "Transcriptional regulation of human ferredoxin 1 in ovarian granulosa cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435367", "text": "Ferredoxin 1 (FDX1; adrenodoxin) is an iron-sulfur protein that is involved in various metabolic processes, including steroid hormone synthesis in mammalian tissues.", "type": "CHEMICAL", "entities": [ "steroid", "steroid hormone", "iron", "sulfur" ], "offsets": [ [ 118, 125 ], [ 118, 133 ], [ 39, 43 ], [ 44, 50 ] ] }, { "pmid": "23435367", "text": "We investigated the transcriptional regulation of FDX1 in ovarian granulosa cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435367", "text": "Previously, we reported that the NR5A family, including steroidogenic factor-1 (SF-1) and liver receptor homolog-1 could induce differentiation of human mesenchymal stem cells (hMSCs) into steroidogenic cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435367", "text": "A ChIP assay showed that SF-1 could bind to the FDX1 promoter in differentiated hMSCs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435367", "text": "Luciferase reporter assays showed that transcription of FDX1 was synergistically activated by the NR5A family and 8Br-cAMP treatment through two SF-1 binding sites and a CRE-like sequence in a human ovarian granulosa cell line, KGN.", "type": "CHEMICAL", "entities": [ "8Br-cAMP" ], "offsets": [ [ 114, 122 ] ] }, { "pmid": "23435367", "text": "Knockdown of FDX1 attenuated progesterone production in KGN cells.", "type": "CHEMICAL", "entities": [ "progesterone" ], "offsets": [ [ 29, 41 ] ] }, { "pmid": "23435367", "text": "These results indicate transcription of FDX1 is regulated by the NR5A family and cAMP signaling, and participates in steroid hormone production in ovarian granulosa cells.", "type": "CHEMICAL", "entities": [ "cAMP", "steroid" ], "offsets": [ [ 81, 85 ], [ 117, 124 ] ] }, { "pmid": "10752671", "text": "Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes.\n", "type": "CHEMICAL", "entities": [ "flutamide" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "10752671", "text": "Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes.", "type": "CHEMICAL", "entities": [ "Flutamide" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10752671", "text": "Negative responses were obtained in all the in vivo assays as well as in the in vitro assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10752671", "text": "In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes.", "type": "CHEMICAL", "entities": [ "flutamide" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "10752671", "text": "In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats.", "type": "CHEMICAL", "entities": [ "flutamide" ], "offsets": [ [ 27, 36 ] ] }, { "pmid": "10752671", "text": "There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks.", "type": "CHEMICAL", "entities": [ "flutamide" ], "offsets": [ [ 110, 119 ] ] }, { "pmid": "10752671", "text": "In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.", "type": "CHEMICAL", "entities": [ "flutamide", "flutamide" ], "offsets": [ [ 235, 244 ], [ 342, 351 ] ] }, { "pmid": "22874922", "text": "Novel non-canonical TGF-β signaling networks: emerging roles in airway smooth muscle phenotype and function.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22874922", "text": "The airway smooth muscle (ASM) plays an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22874922", "text": "ASM cells express a wide range of receptors involved in contraction, growth, matrix protein production and the secretion of cytokines and chemokines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22874922", "text": "Transforming growth factor beta (TGF-β) is one of the major players in determining the structural and functional abnormalities of the ASM in asthma and COPD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22874922", "text": "It is increasingly evident that TGF-β functions as a master switch, controlling a network of intracellular and autocrine signaling loops that effect ASM phenotype and function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22874922", "text": "In this review, the various elements that participate in non-canonical TGF-β signaling, including MAPK, PI3K, WNT/β-catenin, and Ca(2+), are discussed, focusing on their effect on ASM phenotype and function.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 126, 132 ] ] }, { "pmid": "22874922", "text": "In addition, new aspects of ASM biology and their possible association with non-canonical TGF-β signaling will be discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "Oxidative status in ICU patients with septic shock.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "The aim of this pilot study was to investigate variability of oxidative stress during sepsis evolution.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "ICU patients with the diagnosis of septic shock were included.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "Thiobarbituric-acid reactive substances, total antioxidant capacity, protein carbonyls in plasma, reduced, oxidized glutathione and catalase activity in erythrocyte lysate were assessed in the 1st, 3rd, 5th and 8thday after sepsis appearance.", "type": "CHEMICAL", "entities": [ "Thiobarbituric-acid", "carbonyls", "glutathione" ], "offsets": [ [ 0, 19 ], [ 77, 86 ], [ 116, 127 ] ] }, { "pmid": "23542126", "text": "A total of 17 patients were divided in two groups: survivors (n=7) and non-survivors (n=10).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "APACHE II was 11.5±5.4 and 19.9±4.97 in survivors and non-survivors respectively (p=0.005), while mean age and SOFA score at sepsis diagnosis, were similar between the two groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "GSH levels, catalase activity and protein carbonyls presented significant different course in time between survivors and non-survivors (p<0.05).", "type": "CHEMICAL", "entities": [ "carbonyls" ], "offsets": [ [ 40, 49 ] ] }, { "pmid": "23542126", "text": "Catalase activity was significantly higher in survivors (238.8±51.5) than non-survivors (166.4±40.2; p=0.005), while protein carbonyls levels were significantly lower in survivors (0.32±0.09) than non-survivors (0.48±0.16; p=0.036) on the 1stday.", "type": "CHEMICAL", "entities": [ "carbonyls" ], "offsets": [ [ 123, 132 ] ] }, { "pmid": "23542126", "text": "Yet, non-survivors exhibited a declining course in GSH levels during time, while GSH levels were maintained in survivors.", "type": "CHEMICAL", "entities": [ "GSH", "GSH" ], "offsets": [ [ 45, 48 ], [ 75, 78 ] ] }, { "pmid": "23542126", "text": "Conclusively, a longstanding antioxidant deficiency in non-surviving patients was noted.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542126", "text": "This phenomenon was clearly prominent in patients' erythrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "NADPH Oxidase NOX5-S and Nuclear Factor κB1 Mediate Acid-Induced Microsomal Prostaglandin E Synthase-1 Expression in Barrett's Esophageal Adenocarcinoma Cells.\n", "type": "CHEMICAL", "entities": [ "NADPH", "Prostaglandin E" ], "offsets": [ [ 0, 5 ], [ 76, 91 ] ] }, { "pmid": "23439561", "text": "The mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2" ], "offsets": [ [ 31, 47 ], [ 49, 53 ] ] }, { "pmid": "23439561", "text": "We have shown that COX-2 mediates acid-induced PGE2 production.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "23439561", "text": "The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known.", "type": "CHEMICAL", "entities": [ "prostaglandin E", "PGE2" ], "offsets": [ [ 3, 18 ], [ 64, 68 ] ] }, { "pmid": "23439561", "text": "We found that microsomal PGES1 (mPGES1), mPGES2, and cytosolic PGES (cPGES) were present in FLO EA cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels but had little or no effect on mPGES2 or cPGES mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation.", "type": "CHEMICAL", "entities": [ "PGE2", "thymidine" ], "offsets": [ [ 92, 96 ], [ 112, 121 ] ] }, { "pmid": "23439561", "text": "Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production.", "type": "CHEMICAL", "entities": [ "NADPH", "calcium", "thymidine", "PGE2" ], "offsets": [ [ 12, 17 ], [ 53, 60 ], [ 160, 169 ], [ 189, 193 ] ] }, { "pmid": "23439561", "text": "Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a nuclear factor κB (NF-κB) in vivo activation reporter plasmid pNF-κB-Luc.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "Knockdown of NF-κB1 p50 by p50 siRNA significantly decreased acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production.", "type": "CHEMICAL", "entities": [ "thymidine", "PGE2" ], "offsets": [ [ 101, 110 ], [ 130, 134 ] ] }, { "pmid": "23439561", "text": "Two novel NF-κB binding elements, GGAGTCTCCC and CGGGACACCC, were identified in the mPGES1 gene promoter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "We conclude that mPGES1 mediates acid-induced increase in PGE2 production and cell proliferation.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 52, 56 ] ] }, { "pmid": "23439561", "text": "Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-κB1 p50.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439561", "text": "Microsomal PGES1 may be a potential target to prevent or treat EA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23318726", "text": "Butein protects human dental pulp cells from hydrogen peroxide-induced oxidative toxicity via Nrf2 pathway-dependent heme oxygenase-1 expressions.\n", "type": "CHEMICAL", "entities": [ "Butein", "hydrogen peroxide" ], "offsets": [ [ 0, 6 ], [ 45, 62 ] ] }, { "pmid": "23318726", "text": "Rhus verniciflua Stokes is a plant that is native to East Asian countries, such as Korea, China, and Japan.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23318726", "text": "Butein, a plant polyphenol, is one of the major active components of R. verniciflua.", "type": "CHEMICAL", "entities": [ "Butein", "polyphenol" ], "offsets": [ [ 0, 6 ], [ 16, 26 ] ] }, { "pmid": "23318726", "text": "Reactive oxygen species (ROS), produced via dental adhesive bleaching agents and pulpal disease, can cause oxidative stress.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 9, 15 ] ] }, { "pmid": "23318726", "text": "Here, we found that butein possesses cytoprotective effects on hydrogen peroxide (H2O2)-induced dental cell death.", "type": "CHEMICAL", "entities": [ "butein", "hydrogen peroxide", "H2O2" ], "offsets": [ [ 20, 26 ], [ 63, 80 ], [ 82, 86 ] ] }, { "pmid": "23318726", "text": "H2O2 is a representative ROS and causes cell death through necrosis in human dental pulp (HDP) cells.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23318726", "text": "H2O2-induced cytotoxicity and production of ROS were blocked in the presence of butein, and these effects were dose dependent.", "type": "CHEMICAL", "entities": [ "H2O2", "butein" ], "offsets": [ [ 0, 4 ], [ 80, 86 ] ] }, { "pmid": "23318726", "text": "Butein also increased heme oxygenase-1 (HO-1) protein expression and HO activity.", "type": "CHEMICAL", "entities": [ "Butein", "heme" ], "offsets": [ [ 0, 6 ], [ 22, 26 ] ] }, { "pmid": "23318726", "text": "In addition, butein-dependent HO-1 expression was required for the inhibition of H2O2-induced cell death and ROS generation.", "type": "CHEMICAL", "entities": [ "butein", "H2O2" ], "offsets": [ [ 13, 19 ], [ 81, 85 ] ] }, { "pmid": "23318726", "text": "Furthermore, butein treatment caused nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (AREs).", "type": "CHEMICAL", "entities": [ "butein" ], "offsets": [ [ 13, 19 ] ] }, { "pmid": "23318726", "text": "Treatment of HDP cells with a c-Jun NH2-terminal kinase (JNK) inhibitor also reduced butein-induced HO-1 expression, and butein treatment led to increased JNK phosphorylation.", "type": "CHEMICAL", "entities": [ "NH2", "butein", "butein" ], "offsets": [ [ 36, 39 ], [ 85, 91 ], [ 121, 127 ] ] }, { "pmid": "23318726", "text": "These results indicate that butein may be used to prevent functional dental cell death and thus may be useful as a pulpal disease agent.", "type": "CHEMICAL", "entities": [ "butein" ], "offsets": [ [ 28, 34 ] ] }, { "pmid": "7986344", "text": "Folding pathway of guanidine-denatured disulfide-intact wild-type and mutant bovine pancreatic ribonuclease A.\n", "type": "CHEMICAL", "entities": [ "guanidine", "disulfide" ], "offsets": [ [ 19, 28 ], [ 39, 48 ] ] }, { "pmid": "7986344", "text": "The refolding kinetics of guanidine-denatured disulfide-intact bovine pancreatic ribonuclease A (RNase A) and its proline-42-to-alanine mutant (Pro42Ala) have been studied by monitoring tyrosine burial and 2'-cytidine monophosphate (2'CMP) inhibitor binding.", "type": "CHEMICAL", "entities": [ "proline", "alanine", "tyrosine", "2'-cytidine monophosphate", "2'CMP", "guanidine", "disulfide" ], "offsets": [ [ 114, 121 ], [ 128, 135 ], [ 186, 194 ], [ 206, 231 ], [ 233, 238 ], [ 26, 35 ], [ 46, 55 ] ] }, { "pmid": "7986344", "text": "The folding rate for wild-type RNase A is faster in the presence of the inhibitor 2'CMP than in its absence, indicating that the transition-state structure in the rate-determining step is stabilized by 2'CMP.", "type": "CHEMICAL", "entities": [ "2'CMP", "2'CMP" ], "offsets": [ [ 82, 87 ], [ 202, 207 ] ] }, { "pmid": "7986344", "text": "The folding rate monitored by 2'CMP binding to the major slow-folding species of Pro42Ala", "type": "CHEMICAL", "entities": [ "2'CMP" ], "offsets": [ [ 30, 35 ] ] }, { "pmid": "7986344", "text": "RNase A is faster than the folding rate monitored by tyrosine burial; however, the folding rate monitored by inhibitor binding to the minor slow-folding species is decreased significantly over the folding rate monitored by tyrosine burial, indicating that the major and minor slow-folding species of Pro42Ala fold to the native state with different transition-state conformations in the rate-determining step.", "type": "CHEMICAL", "entities": [ "tyrosine", "tyrosine" ], "offsets": [ [ 53, 61 ], [ 223, 231 ] ] }, { "pmid": "23592839", "text": "Nutrient signaling in protein homeostasis: an increase in quantity at the expense of quality.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23592839", "text": "The discovery that rapamycin extends the life span of diverse organisms has triggered many studies aimed at identifying the underlying molecular mechanisms.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 19, 28 ] ] }, { "pmid": "23592839", "text": "Mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and may regulate organismal aging by controlling mRNA translation.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "23592839", "text": "However, how inhibiting mTORC1 and decreasing protein synthesis can extend life span remains an unresolved issue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23592839", "text": "We showed that constitutively active mTORC1 signaling increased general protein synthesis but unexpectedly reduced the quality of newly synthesized polypeptides.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23592839", "text": "We demonstrated that constitutively active mTORC1 decreased translation fidelity by increasing the speed of ribosomal elongation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23592839", "text": "Conversely, rapamycin treatment restored the quality of newly synthesized polypeptides mainly by slowing the rate of ribosomal elongation.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23592839", "text": "We also found distinct roles for mTORC1 downstream targets in maintaining protein homeostasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23592839", "text": "Loss of S6 kinases, but not 4E-BP family proteins, which are both involved in regulation of translation, attenuated the effects of rapamycin on the quality of newly translated proteins.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 131, 140 ] ] }, { "pmid": "23592839", "text": "Our results reveal a mechanistic connection between mTORC1 and protein quality, highlighting the central role of nutrient signaling in growth and aging.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23264615", "text": "Cortisol and interferon tau regulation of endometrial function and conceptus development in female sheep.\n", "type": "CHEMICAL", "entities": [ "Cortisol" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23264615", "text": "During early pregnancy in sheep, the elongating conceptus secretes interferon-τ (IFNT) and the conceptus as well as endometrial epithelia produce prostaglandins (PG) via PG synthase 2 (PTGS2) and cortisol via hydroxysteroid (11-β) dehydrogenase 1 (HSD11B1).", "type": "CHEMICAL", "entities": [ "prostaglandins", "cortisol", "hydroxysteroid" ], "offsets": [ [ 146, 160 ], [ 196, 204 ], [ 209, 223 ] ] }, { "pmid": "23264615", "text": "Ovarian progesterone induces and PG and IFNT stimulates endometrial HSD11B1 expression and keto-reductase activity as well as many epithelial genes that govern trophectoderm proliferation, migration, and attachment during elongation.", "type": "CHEMICAL", "entities": [ "progesterone", "keto" ], "offsets": [ [ 6, 18 ], [ 89, 93 ] ] }, { "pmid": "23264615", "text": "The primary aim of these studies was to test the hypothesis that HSD11B1-derived cortisol has a biological role in endometrial function and conceptus development during early pregnancy in sheep.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 79, 87 ] ] }, { "pmid": "23264615", "text": "In study 1, cyclic ewes received vehicle, cortisol, PF 915275 (PF; a selective inhibitor of HSD11B1), cortisol and PF, meloxicam (a selective inhibitor of PTGS2), cortisol and meloxicam, recombinant ovine IFNT, or IFNT and PF into the uterus from day 10 to day14 after estrus.", "type": "CHEMICAL", "entities": [ "cortisol", "PF 915275", "cortisol", "meloxicam", "cortisol", "meloxicam" ], "offsets": [ [ 40, 48 ], [ 50, 59 ], [ 100, 108 ], [ 117, 126 ], [ 161, 169 ], [ 174, 183 ] ] }, { "pmid": "23264615", "text": "Cortisol and IFNT stimulated endometrial HSD11B1 expression and activity, increased endometrial PTGS2 activity and the amount of PG in the uterine lumen, and up-regulated many conceptus elongation-related genes in the endometrium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23264615", "text": "Some effects of cortisol and IFNT were mediated by PTGS2-derived PG.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "23264615", "text": "In study 2, bred ewes received PF 915275 or recombinant ovine IFNT and into the uterus from day 10 to day 14 after mating.", "type": "CHEMICAL", "entities": [ "PF 915275" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "23264615", "text": "Inhibition of HSD11B1 activity in utero prevented conceptus elongation, whereas IFNT rescued conceptus elongation in PF-infused ewes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23264615", "text": "These results suggest that HSD11B1-derived cortisol mediates, in part, actions of ovarian progesterone and the conceptus on endometrial function and support the hypothesis that IFNT, PG, and cortisol coordinately regulate endometrial functions important for conceptus elongation and implantation during early pregnancy in sheep.", "type": "CHEMICAL", "entities": [ "cortisol", "progesterone", "cortisol" ], "offsets": [ [ 41, 49 ], [ 88, 100 ], [ 189, 197 ] ] }, { "pmid": "7944828", "text": "2-(2-Aminoethyl)-quinoline (D-1997): a novel agonist at 5-hydroxytryptamine1-like receptors in the canine basilar artery.\n", "type": "CHEMICAL", "entities": [ "2-(2-Aminoethyl)-quinoline", "D-1997", "5-hydroxytryptamine" ], "offsets": [ [ 0, 26 ], [ 28, 34 ], [ 56, 75 ] ] }, { "pmid": "7944828", "text": "This study aimed to investigate the mechanisms involved in the contractile effects produced by the novel quinoline derivative, 2-(2-aminoethyl)-quinoline (D-1997), in the canine isolated basilar artery.", "type": "CHEMICAL", "entities": [ "quinoline", "2-(2-aminoethyl)-quinoline", "D-1997" ], "offsets": [ [ 105, 114 ], [ 127, 153 ], [ 155, 161 ] ] }, { "pmid": "7944828", "text": "For comparison, the effects of D-1997 were also evaluated on rat aorta.", "type": "CHEMICAL", "entities": [ "D-1997" ], "offsets": [ [ 31, 37 ] ] }, { "pmid": "7944828", "text": "Canine basilar artery and rat aortic rings were prepared and mounted in organ baths to record isometric tension changes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7944828", "text": "The contractile effects of D-1997 in the basilar artery were compared with those produced by 5-hydroxytryptamine (5-HT) and the 5-HT receptor agonist quipazine.", "type": "CHEMICAL", "entities": [ "D-1997", "5-hydroxytryptamine", "5-HT", "5-HT", "quipazine" ], "offsets": [ [ 27, 33 ], [ 93, 112 ], [ 114, 118 ], [ 128, 132 ], [ 150, 159 ] ] }, { "pmid": "7944828", "text": "Thus, 4-HT (10(-10)-10(-6)M), D-1997 (3.1 x 10(-8)-10(-4) M) and quipazine (3.1 x 10(-7)-10(-4) M) each caused concentration-dependent contractions of the canine basilar artery with a rank order of agonist potency of 5-HT > D-1997 > quipazine.", "type": "CHEMICAL", "entities": [ "4-HT", "D-1997", "quipazine", "5-HT", "D-1997", "quipazine" ], "offsets": [ [ 6, 10 ], [ 30, 36 ], [ 65, 74 ], [ 217, 221 ], [ 224, 230 ], [ 233, 242 ] ] }, { "pmid": "7944828", "text": "5-HT and D-1997 exhibited similar maximum effects which were higher than that of quipazine.", "type": "CHEMICAL", "entities": [ "5-HT", "D-1997", "quipazine" ], "offsets": [ [ 0, 4 ], [ 9, 15 ], [ 81, 90 ] ] }, { "pmid": "7944828", "text": "Similar concentrations of D-1997 failed to produce contraction in rat aorta.", "type": "CHEMICAL", "entities": [ "D-1997" ], "offsets": [ [ 26, 32 ] ] }, { "pmid": "7944828", "text": "The effects of D-1997 in the basilar artery were not modified by incubation with either the 5-HT2 receptor antagonist ketanserin (0.01-1 microM), the 5-HT3 and 5-HT4 receptor antagonist ICS205930 (tropisetron; 0.1-10 microM), the 5-HT1A receptor antagonist spiroxatrine (0.01-1 microM), the beta-adrenoceptor blocker with high affinity for 5-HT1A and 5-HT1B binding sites (+/-)-pindolol (0.01-1 microM), or the alpha 1-adrenoceptor antagonist prazosin (0.01-1 microM).", "type": "CHEMICAL", "entities": [ "ketanserin", "tropisetron", "spiroxatrine", "(+/-)-pindolol", "prazosin", "D-1997" ], "offsets": [ [ 118, 128 ], [ 197, 208 ], [ 257, 269 ], [ 372, 386 ], [ 443, 451 ], [ 15, 21 ] ] }, { "pmid": "7944828", "text": "In contrast, the D-1997-induced responses were potently and concentration-dependently antagonized by the mixed 5-HT1-like and 5-HT2 receptor antagonist methiothepin (0.01-1 microM).", "type": "CHEMICAL", "entities": [ "D-1997", "methiothepin" ], "offsets": [ [ 17, 23 ], [ 152, 164 ] ] }, { "pmid": "7944828", "text": "It is concluded that D-1997 contracts the canine basilar artery by stimulating 5-HT1-like receptors unrelated to either the 5-HT1A or 5-HT1B receptor subtypes.", "type": "CHEMICAL", "entities": [ "D-1997" ], "offsets": [ [ 21, 27 ] ] }, { "pmid": "7944828", "text": "The compound seems to be devoid of 5-HT2 receptor agonist properties in rat aorta.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23229512", "text": "Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis.\n", "type": "CHEMICAL", "entities": [ "Vitamin K2" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23229512", "text": "Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Vitamin K2", "VK2", "menaquinone" ], "offsets": [ [ 0, 10 ], [ 12, 15 ], [ 17, 28 ] ] }, { "pmid": "23229512", "text": "Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23229512", "text": "Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis.", "type": "CHEMICAL", "entities": [ "VK2" ], "offsets": [ [ 77, 80 ] ] }, { "pmid": "23229512", "text": "VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis.", "type": "CHEMICAL", "entities": [ "VK2" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23229512", "text": "Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death.", "type": "CHEMICAL", "entities": [ "VK2" ], "offsets": [ [ 180, 183 ] ] }, { "pmid": "23229512", "text": "Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak.", "type": "CHEMICAL", "entities": [ "VK2-2,3 epoxide", "VK2", "cysteine" ], "offsets": [ [ 10, 25 ], [ 58, 61 ], [ 99, 107 ] ] }, { "pmid": "23229512", "text": "Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction.", "type": "CHEMICAL", "entities": [ "VK2" ], "offsets": [ [ 68, 71 ] ] }, { "pmid": "23229512", "text": "Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23229512", "text": "This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.", "type": "CHEMICAL", "entities": [ "VK2" ], "offsets": [ [ 64, 67 ] ] }, { "pmid": "23142538", "text": "Effect of developmental dioxin exposure on methylation and expression of specific imprinted genes in mice.\n", "type": "CHEMICAL", "entities": [ "dioxin" ], "offsets": [ [ 24, 30 ] ] }, { "pmid": "23142538", "text": "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disruptor affecting the reproductive system in humans.", "type": "CHEMICAL", "entities": [ "2,3,7,8-Tetrachlorodibenzo-p-dioxin", "TCDD" ], "offsets": [ [ 0, 35 ], [ 37, 41 ] ] }, { "pmid": "23142538", "text": "The aim of this study was to evaluate the effects of TCDD administered to pregnant mice at two different doses (2-10 ng/kg/day), on imprinted genes in the male offspring.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "23142538", "text": "The degree of methylation and the mRNA expression of Snrpn, Peg3 and Igf2r were analyzed in the sperm, skeletal muscle and liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142538", "text": "TCDD administration (10 ng/kg/day) decreased the sperm count in the male offspring.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23142538", "text": "It did not affect methylation but increased mRNA expression of Snrpn, Peg3, Igf2r and Air ncRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142538", "text": "In muscle and liver, TCDD (10 ng/kg/day) induced increases in methylation and decreases in mRNA expression of Igf2r.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 21, 25 ] ] }, { "pmid": "23142538", "text": "These results show that the robust effects of TCDD on the mRNA expression of Snrpn, Peg3 and Igf2r genes in the sperm and of Igf2r in the muscle and liver are unrelated to changes in methylation in their respective genes.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "20624440", "text": "Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells.\n", "type": "CHEMICAL", "entities": [ "Rasagiline" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "20624440", "text": "Rasagiline is a propargylamine and irreversible monoamine oxidase (MAO) B inhibitor used for the treatment of Parkinson's disease (PD).", "type": "CHEMICAL", "entities": [ "Rasagiline", "propargylamine", "monoamine" ], "offsets": [ [ 0, 10 ], [ 16, 30 ], [ 48, 57 ] ] }, { "pmid": "20624440", "text": "It has demonstrated neuroprotective properties in laboratory studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20624440", "text": "Current concepts of PD aetiopathogenesis include the role of alpha-synuclein, protein aggregation, free radical metabolism and mitochondrial dysfunction in contributing to cell death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20624440", "text": "We have used a combination of alpha-synuclein and free radical mediated toxicity in a dopaminergic cell line to provide a model of nigral toxicity in order to investigate the potential molecular mechanisms that mediate rasagiline protection.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 219, 229 ] ] }, { "pmid": "20624440", "text": "We demonstrate that rasagiline protects against cell death induced by the combination of free radicals generated by paraquat and either wild-type or A53T mutant alpha-synuclein over-expression.", "type": "CHEMICAL", "entities": [ "rasagiline", "paraquat" ], "offsets": [ [ 20, 30 ], [ 116, 124 ] ] }, { "pmid": "20624440", "text": "This protection was associated with a reduction in caspase 3 activation, a reduction in superoxide generation and a trend to ameliorate the fall in mitochondrial membrane potential.", "type": "CHEMICAL", "entities": [ "superoxide" ], "offsets": [ [ 88, 98 ] ] }, { "pmid": "20624440", "text": "Rasagiline induced an increase in cellular glutathione levels.", "type": "CHEMICAL", "entities": [ "Rasagiline", "glutathione" ], "offsets": [ [ 0, 10 ], [ 43, 54 ] ] }, { "pmid": "20624440", "text": "The results support a role for rasagiline in protecting dopaminergic cells against free radical mediated damage and apoptosis in the presence of alpha-synuclein over-expression.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 31, 41 ] ] }, { "pmid": "20624440", "text": "The data are of relevance to the interpretation of the potential mechanisms of action of rasagiline in explaining the results of disease modification trials in PD.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 89, 99 ] ] }, { "pmid": "19337422", "text": "Tolvaptan and its potential in the treatment of hyponatremia.\n", "type": "CHEMICAL", "entities": [ "Tolvaptan" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "19337422", "text": "Tolvaptan is a selective arginine vasopressin (AVP) V(2) receptor blocker used to induce free water diuresis in the treatment of euvolemic or hypervolemic hyponatremia.", "type": "CHEMICAL", "entities": [ "Tolvaptan", "arginine vasopressin", "AVP" ], "offsets": [ [ 0, 9 ], [ 25, 45 ], [ 47, 50 ] ] }, { "pmid": "19337422", "text": "Currently the orally active medication is in the final stages prior to approval by the FDA for outpatient therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19337422", "text": "It appears to be safe and effective at promoting aquaresis and raising serum sodium levels in both short- and long-term studies.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 77, 83 ] ] }, { "pmid": "19337422", "text": "Tolvaptan is also effective for treatment of congestive heart failure (CHF) exacerbation, but whether there are long standing beneficial effects on CHF is still controversial.", "type": "CHEMICAL", "entities": [ "Tolvaptan" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "19337422", "text": "Prolonged use of tolvaptan leads to increased endogenous levels of AVP and perhaps over-stimulation of V(1A) receptors.", "type": "CHEMICAL", "entities": [ "tolvaptan", "AVP" ], "offsets": [ [ 17, 26 ], [ 67, 70 ] ] }, { "pmid": "19337422", "text": "Theoretically this activation could lead to increased afterload and cardiac myocyte fibrosis, causing progression of CHF.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19337422", "text": "However, after 52 weeks of tolvaptan therapy there was no worsening of left ventricular dilatation.", "type": "CHEMICAL", "entities": [ "tolvaptan" ], "offsets": [ [ 27, 36 ] ] }, { "pmid": "19337422", "text": "In addition, tolvaptan is metabolized by the CYP3A4 system; thus physicians should be aware of the potential for increased interactions with other medications.", "type": "CHEMICAL", "entities": [ "tolvaptan" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "19337422", "text": "Tolvaptan is a breakthrough in the therapy of hyponatremia as it directly combats elevated AVP levels associated with the syndrome of inappropriate secretion of antidiuretic hormone, congestive heart failure, and cirrhosis of the liver.", "type": "CHEMICAL", "entities": [ "Tolvaptan", "AVP" ], "offsets": [ [ 0, 9 ], [ 91, 94 ] ] }, { "pmid": "11156594", "text": "alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P.\n1.", "type": "CHEMICAL", "entities": [ "gonadotrophin-releasing hormone" ], "offsets": [ [ 34, 65 ] ] }, { "pmid": "11156594", "text": "Peptidergic neurones accumulate amines via an unusual uptake process, designated", "type": "CHEMICAL", "entities": [ "amines" ], "offsets": [ [ 32, 38 ] ] }, { "pmid": "11156594", "text": "Transport-P. [(3)H]-prazosin binds to alpha(1) adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10(-7)", "type": "CHEMICAL", "entities": [ "prazosin", "[(3)H]-prazosin" ], "offsets": [ [ 110, 118 ], [ 13, 28 ] ] }, { "pmid": "11156594", "text": "M.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11156594", "text": "However, at greater concentrations of prazosin, there is a paradoxical accumulation of [(3)H]-prazosin which we have attributed to Transport-P. Uptake of prazosin via Transport-P is detectable at 10(-10)", "type": "CHEMICAL", "entities": [ "prazosin", "[(3)H]-prazosin", "prazosin" ], "offsets": [ [ 38, 46 ], [ 87, 102 ], [ 154, 162 ] ] }, { "pmid": "11156594", "text": "M prazosin concentration, is linear up to 10(-7)", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 2, 10 ] ] }, { "pmid": "11156594", "text": "M and at greater concentrations becomes non-linear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11156594", "text": "In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10(-7)", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 40, 53 ] ] }, { "pmid": "11156594", "text": "In noradrenergic neurones and in non-neuronal cells, there is no uptake of prazosin in concentrations up to 10(-6) M, suggesting that Transport-P is a specialised function of peptidergic neurones.", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 75, 83 ] ] }, { "pmid": "11156594", "text": "2. Using a mouse peptidergic (gonadotrophin-releasing hormone, GnRH) neuronal cell line which possesses Transport-P, we have studied the interaction of alpha(1) adrenoceptors with Transport-P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the alpha(1B) sub-type of adrenoceptors is present in GnRH cells.", "type": "CHEMICAL", "entities": [ "GnRH", "gonadotrophin-releasing hormone", "GnRH" ], "offsets": [ [ 332, 336 ], [ 30, 61 ], [ 63, 67 ] ] }, { "pmid": "11156594", "text": "3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11156594", "text": "In COS cells transfected with alpha(1b) adrenoceptor cDNA and in DDT(1) MF-2 cells which express native alpha(1B) adrenoceptors, [(3)H]-prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10(-6) M.", "type": "CHEMICAL", "entities": [ "[(3)H]-prazosin", "prazosin", "prazosin" ], "offsets": [ [ 129, 144 ], [ 173, 181 ], [ 223, 231 ] ] }, { "pmid": "11156594", "text": "In DDT(1) MF-2 cells, [(3)H]-prazosin was displaced likewise by a series of alpha(1) adrenergic agonists, none of which increased the binding of [(3)H]-prazosin.", "type": "CHEMICAL", "entities": [ "[(3)H]-prazosin", "[(3)H]-prazosin" ], "offsets": [ [ 22, 37 ], [ 145, 160 ] ] }, { "pmid": "11156594", "text": "Hence, the prazosin paradox is not due to some function of alpha(1) adrenoceptors, such as internalization of ligand-receptor complexes.", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 11, 19 ] ] }, { "pmid": "11156594", "text": "4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11156594", "text": "In neurones which possess Transport-P, transfection with alpha(1b) adrenoceptor cDNA resulted in over-expression of alpha(1B) adrenoceptors, but the prazosin paradox was unaltered.", "type": "CHEMICAL", "entities": [ "prazosin" ], "offsets": [ [ 149, 157 ] ] }, { "pmid": "11156594", "text": "Thus, alpha(1) adrenoceptors and Transport-P mediate distinct functions in peptidergic neurones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats.\n", "type": "CHEMICAL", "entities": [ "Fisetin", "streptozotocin" ], "offsets": [ [ 0, 7 ], [ 57, 71 ] ] }, { "pmid": "23277230", "text": "Persistent hyperglycemia is associated with chronic oxidative stress which contributes to the development and progression of diabetes-associated complications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "The sensitivity of pancreatic β-cells to oxidative stress has been attributed to their low content of antioxidants compared with other tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Bioactive compounds with potent antidiabetic properties have been shown to ameliorate hyperglycemia mediated oxidative stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Recently, we have reported that oral administration of fisetin (10 mg/Kg b.w.), a bioflavonoid found to be present in strawberries, persimmon, to STZ-induced experimental diabetic rats significantly improved normoglycemia.", "type": "CHEMICAL", "entities": [ "fisetin", "bioflavonoid", "STZ" ], "offsets": [ [ 54, 61 ], [ 81, 93 ], [ 145, 148 ] ] }, { "pmid": "23277230", "text": "The present study was aimed to evaluate the antioxidant potential of fisetin in both in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "23277230", "text": "Diabetes was induced by single intraperitoneal injection of streptozotocin (50 mg/kg body weight).", "type": "CHEMICAL", "entities": [ "streptozotocin" ], "offsets": [ [ 58, 72 ] ] }, { "pmid": "23277230", "text": "Fisetin was administered orally for 30 days.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "At the end of the study, all animals were killed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Blood samples were collected for the biochemical estimations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "The antioxidant status was evaluated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Histological examinations were performed on pancreatic tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23277230", "text": "Fisetin treatment showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), NF-kB p65 unit (in pancreas) and IL-1β (plasma), serum nitric oxide (NO) with an elevation in plasma insulin.", "type": "CHEMICAL", "entities": [ "glucose", "nitric oxide", "NO" ], "offsets": [ [ 66, 73 ], [ 163, 175 ], [ 177, 179 ] ] }, { "pmid": "23277230", "text": "The treatment also improved the antioxidant status in pancreas as well as plasma of diabetic rats indicating the antioxidant potential of fisetin.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 133, 140 ] ] }, { "pmid": "23277230", "text": "In addition, the results of DPPH and ABTS assays substantiate the free radical scavenging activity of fisetin.", "type": "CHEMICAL", "entities": [ "DPPH", "ABTS", "fisetin" ], "offsets": [ [ 23, 27 ], [ 32, 36 ], [ 97, 104 ] ] }, { "pmid": "23277230", "text": "Histological studies of the pancreas also evidenced the tissue protective nature of fisetin.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 79, 86 ] ] }, { "pmid": "23277230", "text": "It is concluded that, fisetin possesses antioxidant and anti-inflammatory property and may be considered as an adjunct for the treatment of diabetes.", "type": "CHEMICAL", "entities": [ "fisetin" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "6872937", "text": "Inhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018.\n", "type": "CHEMICAL", "entities": [ "LY117018" ], "offsets": [ [ 103, 111 ] ] }, { "pmid": "6872937", "text": "The aim of the study was to determine whether the dihydroxylated antiestrogen LY117018, with a high affinity for the estrogen receptor and low intrinsic estrogenic activity, could inhibit the uterotropic actions of steroidal", "type": "CHEMICAL", "entities": [ "LY117018" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "6872937", "text": "[estradiol-17 beta (E2)] and nonsteroidal", "type": "CHEMICAL", "entities": [ "estradiol-17 beta", "E2" ], "offsets": [ [ 1, 18 ], [ 20, 22 ] ] }, { "pmid": "6872937", "text": "[ICI 3188 and trianisylchloroethylene (TACE)] estrogens in immature rats and also the uterotropic actions of tamoxifen and monohydroxytamoxifen in the ovariectomized mouse and immature rat.", "type": "CHEMICAL", "entities": [ "trianisylchloroethylene", "TACE", "tamoxifen", "monohydroxytamoxifen" ], "offsets": [ [ 14, 37 ], [ 39, 43 ], [ 109, 118 ], [ 123, 143 ] ] }, { "pmid": "6872937", "text": "In the first series of experiments, LY117018 was compared with monohydroxytamoxifen.", "type": "CHEMICAL", "entities": [ "LY117018", "monohydroxytamoxifen" ], "offsets": [ [ 36, 44 ], [ 63, 83 ] ] }, { "pmid": "6872937", "text": "Both antiestrogens inhibited the uterotropic actions of E2 (0.32 micrograms daily), ICI 3188 (5 micrograms daily), and TACE (40 and 160 micrograms daily) in a dose-related manner (0.32-82 micrograms daily).", "type": "CHEMICAL", "entities": [ "E2" ], "offsets": [ [ 56, 58 ] ] }, { "pmid": "6872937", "text": "The potency of the antiestrogens against E2 and ICI 3188 was similar, however, at higher doses (20.48 and 82 micrograms daily) LY117018 reduced uterine weights to below the lowest level achieved by monohydroxytamoxifen.", "type": "CHEMICAL", "entities": [ "LY117018", "monohydroxytamoxifen" ], "offsets": [ [ 127, 135 ], [ 198, 218 ] ] }, { "pmid": "6872937", "text": "In contrast, LY117018 was less effective against the long acting estrogen TACE.", "type": "CHEMICAL", "entities": [ "LY117018" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "6872937", "text": "The competitive interaction of LY117018 with tamoxifen and monohydroxytamoxifen was compared in 3-day ovariectomized mouse and immature rat uterine weight tests.", "type": "CHEMICAL", "entities": [ "LY117018", "tamoxifen", "monohydroxytamoxifen" ], "offsets": [ [ 31, 39 ], [ 45, 54 ], [ 59, 79 ] ] }, { "pmid": "6872937", "text": "Tamoxifen and monohydroxytamoxifen were fully estrogenic in the mouse (5 micrograms daily) and partially estrogenic in the rat (1.5-20 micrograms daily).", "type": "CHEMICAL", "entities": [ "Tamoxifen", "monohydroxytamoxifen" ], "offsets": [ [ 0, 9 ], [ 14, 34 ] ] }, { "pmid": "6872937", "text": "LY117018 was a partial estrogen in the mouse and a weekly active partial estrogen in the rat (2.5-120 micrograms daily).", "type": "CHEMICAL", "entities": [ "LY117018" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "6872937", "text": "LY117018 produced dose-related decreases in the uterine weight increases induced by tamoxifen and monohydroxytamoxifen in both species.", "type": "CHEMICAL", "entities": [ "LY117018", "tamoxifen", "monohydroxytamoxifen" ], "offsets": [ [ 0, 8 ], [ 84, 93 ], [ 98, 118 ] ] }, { "pmid": "6872937", "text": "However, in the rat, LY117018 was more effective against the less potent compound tamoxifen, at a 6:1 dosage ratio compared with a 24:1 dosage ratio required for the potent compound monohydroxytamoxifen.", "type": "CHEMICAL", "entities": [ "LY117018", "tamoxifen", "monohydroxytamoxifen" ], "offsets": [ [ 21, 29 ], [ 82, 91 ], [ 182, 202 ] ] }, { "pmid": "6872937", "text": "LY117018 had a short duration of action as an antiestrogen when compared with monohydroxytamoxifen.", "type": "CHEMICAL", "entities": [ "LY117018", "monohydroxytamoxifen" ], "offsets": [ [ 0, 8 ], [ 78, 98 ] ] }, { "pmid": "6872937", "text": "LY117018 (120 micrograms) was only completely effective as an antiestrogen if administered repeatedly with E2 whereas a single injection of monohydroxytamoxifen (120 micrograms) was sufficient to inhibit fully E2 action in the uterus for up to 4 days.", "type": "CHEMICAL", "entities": [ "LY117018", "E2", "monohydroxytamoxifen", "E2" ], "offsets": [ [ 0, 8 ], [ 107, 109 ], [ 140, 160 ], [ 210, 212 ] ] }, { "pmid": "6872937", "text": "Because LY117018 has a shorter duration of action than monohydroxytamoxifen, a high dosage ratio of LY117018 over monohydroxytamoxifen is required to maintain effective competitive antagonism in the uterus.", "type": "CHEMICAL", "entities": [ "LY117018", "monohydroxytamoxifen", "LY117018", "monohydroxytamoxifen" ], "offsets": [ [ 8, 16 ], [ 55, 75 ], [ 100, 108 ], [ 114, 134 ] ] }, { "pmid": "6872937", "text": "Overall, these findings suggest that monohydroxytamoxifen and LY117018 probably act through the same mechanism of action via the estrogen receptor.", "type": "CHEMICAL", "entities": [ "monohydroxytamoxifen", "LY117018" ], "offsets": [ [ 37, 57 ], [ 62, 70 ] ] }, { "pmid": "23423570", "text": "High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: New insights on impaired diabetic wound healing.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 5, 12 ] ] }, { "pmid": "23423570", "text": "Impaired wound healing frequently occurs in patients with diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "Interluekin-8 (IL-8) production by keratinocyte is responsible for recruiting neutrophils during healing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "Intense inflammation is associated with diabetic wounds while reduction of neutrophil infiltration is associated with enhanced healing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "We hypothesized that increased neutrophil recruitment by keratinocytes may contribute to the delayed healing of diabetic wound.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "Using cultured human keratinocytes and diabetic rat model, the current study showed that high-glucose environment enhanced IL-8 production via epidermal growth factor receptor (EGFR) -extracelluar signal-regulated kinase (ERK) pathway in a reactive oxygen species (ROS)-dependent manner in keratinocytes.", "type": "CHEMICAL", "entities": [ "glucose", "oxygen" ], "offsets": [ [ 94, 101 ], [ 249, 255 ] ] }, { "pmid": "23423570", "text": "In addition, diabetic rat skin showed enhanced EGFR, ERK and IL-8 expression as compared to control rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "The dermal neutrophil infiltration of the wound, as represented by expression of myeloperoxidase level, was also significantly higher in diabetic rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423570", "text": "Treating diabetic rats with dapsone, an agent known to inhibit neutrophil function, was associated with improved healing.", "type": "CHEMICAL", "entities": [ "dapsone" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "23423570", "text": "In conclusion, IL-8 production and neutrophil infiltration are increased in high-glucose environment due to elevated ROS level and contributed to impaired wound healing in diabetic skin.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "23423570", "text": "Targeting these dysfunctions may present novel therapeutic approaches.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313794", "text": "Effects of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) on histopathology, oxidative stress, and expression of c-fos, c-jun and p16 in rat stomachs.\n", "type": "CHEMICAL", "entities": [ "2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine", "PhIP" ], "offsets": [ [ 11, 61 ], [ 63, 67 ] ] }, { "pmid": "23313794", "text": "2-Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) is one of the most abundant heterocyclic amines (HCAs) generated from overcooking meat at high temperatures.", "type": "CHEMICAL", "entities": [ "2-Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine", "HCAs", "PhIP", "heterocyclic amines" ], "offsets": [ [ 0, 50 ], [ 107, 111 ], [ 52, 56 ], [ 86, 105 ] ] }, { "pmid": "23313794", "text": "To understand the possible mechanism of PhIP-associated stomach cancer, the effects of PhIP on morphology, oxidative stress, gene expression of c-fos, c-jun and p16 in rat stomachs were investigated.", "type": "CHEMICAL", "entities": [ "PhIP", "PhIP" ], "offsets": [ [ 40, 44 ], [ 87, 91 ] ] }, { "pmid": "23313794", "text": "The results showed that (1) 15mg/kg body weight PhIP induced obvious histopathological changes in gastric mucosa; (2) PhIP (10 and/or 15mg/kg) significantly decreased superoxide dismutase (SOD) and glutathioneperoxidase (GPx) activities, while increased catalase (CAT) activity compared with the control.", "type": "CHEMICAL", "entities": [ "PhIP", "PhIP", "superoxide" ], "offsets": [ [ 48, 52 ], [ 118, 122 ], [ 167, 177 ] ] }, { "pmid": "23313794", "text": "With the elevated doses of PhIP, malondialdehyde (MDA) contents, protein carbonyl (PCO) contents and DNA-protein crosslinks (DPC) coefficients were significantly raised in a dose-dependent manner; (3) PhIP at the doses of 10mg/kg and/or 15mg/kg significantly inhibited p16 mRNA and protein expression, whereas enhanced c-fos and c-jun expression relative to control.", "type": "CHEMICAL", "entities": [ "PhIP", "malondialdehyde", "MDA", "carbonyl", "PhIP" ], "offsets": [ [ 27, 31 ], [ 33, 48 ], [ 50, 53 ], [ 73, 81 ], [ 201, 205 ] ] }, { "pmid": "23313794", "text": "The data indicated that PhIP could cause stomach injury, oxidative stress in rat stomachs as well as the activation of c-fos and c-jun and inactivation of p16, which may play a role in the pathogenesis of PhIP-associated stomach cancer.", "type": "CHEMICAL", "entities": [ "PhIP", "PhIP" ], "offsets": [ [ 24, 28 ], [ 205, 209 ] ] }, { "pmid": "23542578", "text": "A novel method for preparing complete antigens of gonyautoxin 2,3 and their feature of immunogenicity.\n", "type": "CHEMICAL", "entities": [ "gonyautoxin 2,3" ], "offsets": [ [ 50, 65 ] ] }, { "pmid": "23542578", "text": "In this paper, a novel method was proposed to prepare artificial antigens of gonyaulax parlaytic shellfish toxin 2 and 3 (GTX2,3).", "type": "CHEMICAL", "entities": [ "GTX2,3" ], "offsets": [ [ 122, 128 ] ] }, { "pmid": "23542578", "text": "An intermediate GTX2,3-aldehyde was first synthesized by activating the NH2 group of the 2nd and 8th amino acid residues with three different aldehydes and two artificial complete antigens GTX2,3-aldehyde-bovine serum albumin (BSA) and GTX2,3-aldehyde- keyhole limpet hemocyanin (KLH) were then prepared by cross-linking the intermediate with BSA or KLH.", "type": "CHEMICAL", "entities": [ "GTX2,3-aldehyde", "NH2", "amino acid", "aldehydes", "GTX2,3-aldehyde", "GTX2,3-aldehyde" ], "offsets": [ [ 16, 31 ], [ 72, 75 ], [ 101, 111 ], [ 142, 151 ], [ 189, 204 ], [ 236, 251 ] ] }, { "pmid": "23542578", "text": "The successful preparation of the two complete antigens was confirmed by UV spectral scanning, HPLC, production of antibodies with titer of 1.28 × 10(4) from mice immunized with the two complete antigens, indirect ELISA and Western-blot.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542578", "text": "In conclusion, the synthesized complete antigens have strong immunogenicity, which provides a solid foundation for preparing GTX2,3 monoclonal antibody and rapid detection kit.", "type": "CHEMICAL", "entities": [ "GTX2,3" ], "offsets": [ [ 122, 128 ] ] }, { "pmid": "12003347", "text": "Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines.\n", "type": "CHEMICAL", "entities": [ "Tetrahydrobiopterin", "nitric oxide", "pteridines" ], "offsets": [ [ 0, 19 ], [ 23, 35 ], [ 75, 85 ] ] }, { "pmid": "12003347", "text": "Ever since the discovery that (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) is a cofactor of NOS, its function has been the object of intense research and occasional controversy.", "type": "CHEMICAL", "entities": [ "(6R)-5,6,7,8-tetrahydro-L-biopterin", "BH4" ], "offsets": [ [ 30, 65 ], [ 67, 70 ] ] }, { "pmid": "12003347", "text": "Only in the last couple of years a consensus has been reached on what constitutes the main role of BH4 in NO synthesis.", "type": "CHEMICAL", "entities": [ "BH4", "NO" ], "offsets": [ [ 99, 102 ], [ 106, 108 ] ] }, { "pmid": "12003347", "text": "In this review we aim to provide an outline of the various ways in which BH4 affects NOS catalysis.", "type": "CHEMICAL", "entities": [ "BH4" ], "offsets": [ [ 73, 76 ] ] }, { "pmid": "12003347", "text": "First we give a brief general description of the structure and catalytic mechanism of NOS, with special emphasis on those aspects of catalysis that are actively debated, and that directly or indirectly involve BH4.", "type": "CHEMICAL", "entities": [ "BH4" ], "offsets": [ [ 210, 213 ] ] }, { "pmid": "12003347", "text": "Foremost among those issues is uncoupled catalysis, i.e. the NOS-catalyzed oxidation of NADPH in the absence of substrate or pterin that does not result in NO production.", "type": "CHEMICAL", "entities": [ "NADPH", "NO" ], "offsets": [ [ 88, 93 ], [ 156, 158 ] ] }, { "pmid": "12003347", "text": "We also shortly discuss the ongoing debate on whether NO is the actual reaction product of NOS catalysis, as well as the phenomenon of NO-mediated autoinhibition.", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 54, 56 ], [ 135, 137 ] ] }, { "pmid": "12003347", "text": "We describe the function of BH4 in aromatic amino acid hydroxylation, and discuss the allosteric and structural effects that BH4 exerts on NOS.", "type": "CHEMICAL", "entities": [ "BH4", "BH4", "aromatic amino acid" ], "offsets": [ [ 125, 128 ], [ 28, 31 ], [ 35, 54 ] ] }, { "pmid": "12003347", "text": "Next we turn our attention to what is now becoming accepted as the central function of BH4: its capacity to act as a 1-electron donor during reductive activation of the oxyferrous complex of the heme.", "type": "CHEMICAL", "entities": [ "BH4", "oxyferrous" ], "offsets": [ [ 87, 90 ], [ 169, 179 ] ] }, { "pmid": "12003347", "text": "Finally, we illustrate how BH4 might transform the NOS dimer into an efficient S-nitrosoglutathione synthase,and briefly touch on some more speculative aspects of the role of BH4 in NO synthesis.", "type": "CHEMICAL", "entities": [ "BH4", "S-nitrosoglutathione", "BH4", "NO" ], "offsets": [ [ 27, 30 ], [ 79, 99 ], [ 175, 178 ], [ 182, 184 ] ] }, { "pmid": "1375507", "text": "Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism.\n", "type": "CHEMICAL", "entities": [ "Prostacyclin", "cyclic AMP" ], "offsets": [ [ 0, 12 ], [ 101, 111 ] ] }, { "pmid": "1375507", "text": "Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1375507", "text": "The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells.", "type": "CHEMICAL", "entities": [ "prostacyclin" ], "offsets": [ [ 77, 89 ] ] }, { "pmid": "1375507", "text": "Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-1 beta, or 5 ng/ml tumor necrosis factor-alpha for 4 hours led to increased tissue factor procoagulant activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1375507", "text": "Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents.", "type": "CHEMICAL", "entities": [ "iloprost", "ciprostene", "carbacyclin" ], "offsets": [ [ 34, 42 ], [ 44, 54 ], [ 60, 71 ] ] }, { "pmid": "1375507", "text": "Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor.", "type": "CHEMICAL", "entities": [ "Iloprost", "iloprost", "prostacyclin" ], "offsets": [ [ 0, 8 ], [ 127, 135 ], [ 160, 172 ] ] }, { "pmid": "1375507", "text": "An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression.", "type": "CHEMICAL", "entities": [ "cicaprost" ], "offsets": [ [ 27, 36 ] ] }, { "pmid": "1375507", "text": "Carbacyclin and ciprostene were 100 times less potent.", "type": "CHEMICAL", "entities": [ "Carbacyclin", "ciprostene" ], "offsets": [ [ 0, 11 ], [ 16, 26 ] ] }, { "pmid": "1375507", "text": "Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1375507", "text": "Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP.", "type": "CHEMICAL", "entities": [ "Iloprost", "cyclic AMP" ], "offsets": [ [ 0, 8 ], [ 58, 68 ] ] }, { "pmid": "1375507", "text": "This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase.", "type": "CHEMICAL", "entities": [ "isobutylmethylxanthine" ], "offsets": [ [ 31, 53 ] ] }, { "pmid": "1375507", "text": "The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP.", "type": "CHEMICAL", "entities": [ "isobutylmethylxanthine", "forskolin", "ibutyryl cyclic AMP", "dibutyryl cyclic GMP" ], "offsets": [ [ 88, 110 ], [ 127, 136 ], [ 142, 161 ], [ 170, 190 ] ] }, { "pmid": "1375507", "text": "These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.", "type": "CHEMICAL", "entities": [ "prostacyclin", "cyclic AMP" ], "offsets": [ [ 27, 39 ], [ 171, 181 ] ] }, { "pmid": "11071707", "text": "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.\n", "type": "CHEMICAL", "entities": [ "Amphetamine", "dopamine", "serotonin", "norepinephrine" ], "offsets": [ [ 0, 11 ], [ 106, 114 ], [ 119, 128 ], [ 59, 73 ] ] }, { "pmid": "11071707", "text": "A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates, in animal models, the reinforcing effects of central nervous system stimulants such as cocaine and amphetamine.", "type": "CHEMICAL", "entities": [ "cocaine", "amphetamine", "dopamine", "DA" ], "offsets": [ [ 176, 183 ], [ 188, 199 ], [ 65, 73 ], [ 75, 77 ] ] }, { "pmid": "11071707", "text": "The role DA plays in mediating amphetamine-type subjective effects of stimulants in humans remains to be established.", "type": "CHEMICAL", "entities": [ "DA", "amphetamine" ], "offsets": [ [ 9, 11 ], [ 31, 42 ] ] }, { "pmid": "11071707", "text": "Both amphetamine and cocaine increase norepinephrine (NE) via stimulation of release and inhibition of reuptake, respectively.", "type": "CHEMICAL", "entities": [ "amphetamine", "cocaine", "norepinephrine", "NE" ], "offsets": [ [ 5, 16 ], [ 21, 28 ], [ 38, 52 ], [ 54, 56 ] ] }, { "pmid": "11071707", "text": "If increases in NE mediate amphetamine-type subjective effects of stimulants in humans, then one would predict that stimulant medications that produce amphetamine-type subjective effects in humans should share the ability to increase NE.", "type": "CHEMICAL", "entities": [ "NE", "amphetamine", "amphetamine", "NE" ], "offsets": [ [ 16, 18 ], [ 27, 38 ], [ 151, 162 ], [ 234, 236 ] ] }, { "pmid": "11071707", "text": "To test this hypothesis, we determined, using in vitro methods, the neurochemical mechanism of action of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), (+)-methamphetamine, ephedrine, phentermine, and aminorex.", "type": "CHEMICAL", "entities": [ "amphetamine", "3,4-methylenedioxymethamphetamine", "MDMA", "(+)-methamphetamine", "ephedrine", "phentermine", "aminorex" ], "offsets": [ [ 105, 116 ], [ 118, 151 ], [ 153, 157 ], [ 160, 179 ], [ 181, 190 ], [ 192, 203 ], [ 209, 217 ] ] }, { "pmid": "11071707", "text": "As expected, their rank order of potency for DA release was similar to their rank order of potency in published self-administration studies.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 45, 47 ] ] }, { "pmid": "11071707", "text": "Interestingly, the results demonstrated that the most potent effect of these stimulants is to release NE.", "type": "CHEMICAL", "entities": [ "NE" ], "offsets": [ [ 102, 104 ] ] }, { "pmid": "11071707", "text": "Importantly, the oral dose of these stimulants, which produce amphetamine-type subjective effects in humans, correlated with the their potency in releasing NE, not DA, and did not decrease plasma prolactin, an effect mediated by DA release.", "type": "CHEMICAL", "entities": [ "amphetamine", "NE", "DA", "DA" ], "offsets": [ [ 62, 73 ], [ 156, 158 ], [ 164, 166 ], [ 229, 231 ] ] }, { "pmid": "11071707", "text": "These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in humans.", "type": "CHEMICAL", "entities": [ "NE", "amphetamine" ], "offsets": [ [ 27, 29 ], [ 52, 63 ] ] }, { "pmid": "15526004", "text": "Genetic risk factors for infection in patients with early rheumatoid arthritis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15526004", "text": "We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept.", "type": "CHEMICAL", "entities": [ "methotrexate" ], "offsets": [ [ 173, 185 ] ] }, { "pmid": "15526004", "text": "Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 49, 59 ] ] }, { "pmid": "15526004", "text": "At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15526004", "text": "Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15526004", "text": "There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15526004", "text": "These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360475", "text": "Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents.\n", "type": "CHEMICAL", "entities": [ "tryptanthrins" ], "offsets": [ [ 66, 79 ] ] }, { "pmid": "23360475", "text": "The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb).", "type": "CHEMICAL", "entities": [ "tryptanthrin", "tryptanthrin" ], "offsets": [ [ 104, 116 ], [ 20, 32 ] ] }, { "pmid": "23360475", "text": "However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360475", "text": "Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds.", "type": "CHEMICAL", "entities": [ "tryptanthrin" ], "offsets": [ [ 38, 50 ] ] }, { "pmid": "23360475", "text": "Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360475", "text": "The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360475", "text": "Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents.", "type": "CHEMICAL", "entities": [ "tryptanthrin", "tryptanthrin" ], "offsets": [ [ 47, 59 ], [ 166, 178 ] ] }, { "pmid": "23360475", "text": "However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360475", "text": "Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.", "type": "CHEMICAL", "entities": [ "tryptanthrin" ], "offsets": [ [ 128, 140 ] ] }, { "pmid": "23179966", "text": "Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins.\n", "type": "CHEMICAL", "entities": [ "Serotonin", "glutamate", "serotonin", "dopamine" ], "offsets": [ [ 0, 9 ], [ 10, 19 ], [ 24, 33 ], [ 34, 42 ] ] }, { "pmid": "23179966", "text": "The physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment.", "type": "CHEMICAL", "entities": [ "serotonin", "glutamate", "serotonin", "dopamine" ], "offsets": [ [ 49, 58 ], [ 59, 68 ], [ 73, 82 ], [ 83, 91 ] ] }, { "pmid": "23179966", "text": "Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers.", "type": "CHEMICAL", "entities": [ "glutamate", "serotonin", "5-HT", "5-HT" ], "offsets": [ [ 21, 30 ], [ 54, 63 ], [ 64, 68 ], [ 218, 222 ] ] }, { "pmid": "23179966", "text": "Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 62, 66 ] ] }, { "pmid": "23179966", "text": "Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state.", "type": "CHEMICAL", "entities": [ "N-methyl-D-aspartate", "NMDA", "5-HT" ], "offsets": [ [ 119, 139 ], [ 141, 145 ], [ 157, 161 ] ] }, { "pmid": "23179966", "text": "Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 174, 182 ] ] }, { "pmid": "23179966", "text": "Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission.", "type": "CHEMICAL", "entities": [ "dopamine", "serotonin", "glutamate" ], "offsets": [ [ 147, 155 ], [ 157, 166 ], [ 172, 181 ] ] }, { "pmid": "23179966", "text": "Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics.", "type": "CHEMICAL", "entities": [ "glutamate", "dopamine", "serotonin" ], "offsets": [ [ 53, 62 ], [ 63, 71 ], [ 72, 81 ] ] }, { "pmid": "23179966", "text": "The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies.", "type": "CHEMICAL", "entities": [ "serotonin", "glutamate", "serotonin", "dopamine" ], "offsets": [ [ 61, 70 ], [ 71, 80 ], [ 85, 94 ], [ 95, 103 ] ] }, { "pmid": "12955294", "text": "The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder.\n", "type": "CHEMICAL", "entities": [ "serotonin", "sertraline" ], "offsets": [ [ 4, 13 ], [ 94, 104 ] ] }, { "pmid": "12955294", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "A common polymorphism (5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder.", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin" ], "offsets": [ [ 185, 194 ], [ 66, 75 ] ] }, { "pmid": "12955294", "text": "We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm.", "type": "CHEMICAL", "entities": [ "sertraline" ], "offsets": [ [ 58, 68 ] ] }, { "pmid": "12955294", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele.", "type": "CHEMICAL", "entities": [ "sertraline" ], "offsets": [ [ 128, 138 ] ] }, { "pmid": "12955294", "text": "METHODS: HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week, placebo-controlled study in elderly depressed subjects.", "type": "CHEMICAL", "entities": [ "sertraline" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "12955294", "text": "Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the sertraline and placebo groups ( n=206).", "type": "CHEMICAL", "entities": [ "sertraline" ], "offsets": [ [ 112, 122 ] ] }, { "pmid": "12955294", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2, as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele ( P=0.01 at both weeks).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "No significant difference was observed in the placebo group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12955294", "text": "These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs.", "type": "CHEMICAL", "entities": [ "serotonin", "sertraline" ], "offsets": [ [ 52, 61 ], [ 108, 118 ] ] }, { "pmid": "23085085", "text": "Histone deacetylase 3 is required for maintenance of bone mass during aging.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression.", "type": "CHEMICAL", "entities": [ "acetyl", "lysine" ], "offsets": [ [ 63, 69 ], [ 82, 88 ] ] }, { "pmid": "23085085", "text": "Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the osteocalcin (OCN) promoter driving Cre expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Hdac3 CKO(OCN) mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "The Hdac3 CKO(OCN) mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Bone resorption was lower, not higher, in the Hdac3 CKO(OCN) mice, suggesting that primary defects in osteoblasts caused the reduced bone mass.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Indeed, reductions in bone formation were observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Osteoblasts and osteocytes from Hdac3 CKO(OCN) mice showed increased DNA damage and reduced functional activity in vivo and in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085085", "text": "Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults.\n", "type": "CHEMICAL", "entities": [ "Xeloda", "fluoropyrimidine carbamate", "capecitabine" ], "offsets": [ [ 102, 108 ], [ 61, 87 ], [ 88, 100 ] ] }, { "pmid": "15132128", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "The fluoropyrimidine carbamate (capecitabine) is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (TP) inside target tissues.", "type": "CHEMICAL", "entities": [ "fluoropyrimidine carbamate", "capecitabine", "5-fluorouracil", "5-FU", "thymidine" ], "offsets": [ [ 4, 30 ], [ 32, 44 ], [ 62, 76 ], [ 78, 82 ], [ 87, 96 ] ] }, { "pmid": "15132128", "text": "5-FU interferes with DNA synthesis by blocking thymidylate synthase (TS) but is inactivated by dihydropyrimidine dehydrogenase (DPD).", "type": "CHEMICAL", "entities": [ "5-FU", "thymidylate", "dihydropyrimidine" ], "offsets": [ [ 0, 4 ], [ 47, 58 ], [ 95, 112 ] ] }, { "pmid": "15132128", "text": "Favorable enzyme profiles (high TP and low DPD) generate high intratumor levels of 5-FU that are effective against many tumors, especially those with low TS.", "type": "CHEMICAL", "entities": [ "5-FU" ], "offsets": [ [ 83, 87 ] ] }, { "pmid": "15132128", "text": "Capecitabine has not been tested against thyroid cancers, and it is not known to what extent thyroid cancers express TP, TS or DPD.", "type": "CHEMICAL", "entities": [ "Capecitabine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "15132128", "text": "METHODS: To test this, we determined TP, TS and DPD in 19 thyroid cancers from young patients (14 papillary, 4 follicular, 1 medullary) by immunohistochemistry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "After approval by the Human Use Committee, the intensity of TP, TS, and DPD staining was determined by two independent examiners and graded (absent=0 to intense=3) with >90% concordance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "TS was detected in 7/19 cancers (37%), TP in 14/19 cancers (74%) and DPD in 14/19 cancers (74%).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "In six tumors, TP was more intense that DPD, suggesting capecitabine sensitivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance.", "type": "CHEMICAL", "entities": [ "capecitabine" ], "offsets": [ [ 82, 94 ] ] }, { "pmid": "15132128", "text": "Overall, 6/19 tumors (32% of the total) had a favorable expression profile, and all of them were papillary cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15132128", "text": "The results support the hypothesis that capecitabine is activated in the majority of differentiated thyroid cancers and that 32% have favorable expression of all three enzymes (TP, TS, and DPD).", "type": "CHEMICAL", "entities": [ "capecitabine" ], "offsets": [ [ 40, 52 ] ] }, { "pmid": "8667211", "text": "Nonsteroidal anti-inflammatory drugs activate carbonic anhydrase by a direct mechanism of action.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8667211", "text": "Previous studies by this research team proved that vasodilating prostaglandins (PGs) E1, E2 and I2 inhibit carbonic anhydrase (CA) in vitro and in vivo, which suggested involvement of CA in gastric acid secretion inhibition and the increase of gastric mucosa blood flow produced by this group of PGs.", "type": "CHEMICAL", "entities": [ "PGs", "prostaglandins", "PGs" ], "offsets": [ [ 296, 299 ], [ 64, 78 ], [ 80, 83 ] ] }, { "pmid": "8667211", "text": "Relying on these findings, as well as on our clinical observations, we studied in vitro and in vivo the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on CA I and CA II.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8667211", "text": "We also followed in vitro the effects on these isozymes of NSAIDs associated to histamine, Ca, PGE2 and acetazolamide.", "type": "CHEMICAL", "entities": [ "histamine", "Ca", "acetazolamide" ], "offsets": [ [ 80, 89 ], [ 91, 93 ], [ 104, 117 ] ] }, { "pmid": "8667211", "text": "The results show that the NSAIDs used here, which reduce the activity of cyclooxygenase and PG production, activated CA I and CA II in a dose-dependent manner by a mechanism of the noncompetitive type.", "type": "CHEMICAL", "entities": [ "PG" ], "offsets": [ [ 92, 94 ] ] }, { "pmid": "8667211", "text": "Histamine and Ca added to NSAIDs amplified the activating effect of the latter on CA II.", "type": "CHEMICAL", "entities": [ "Histamine", "Ca" ], "offsets": [ [ 0, 9 ], [ 14, 16 ] ] }, { "pmid": "8667211", "text": "Association of PGE2 or acetazolamide to NSAIDs reduced NSAID-induced activation of CA I and CA II.", "type": "CHEMICAL", "entities": [ "acetazolamide" ], "offsets": [ [ 23, 36 ] ] }, { "pmid": "8667211", "text": "Indomethacin abolished the inhibitory effect of acetazolamide on CA I and CA II.", "type": "CHEMICAL", "entities": [ "acetazolamide", "Indomethacin" ], "offsets": [ [ 48, 61 ], [ 0, 12 ] ] }, { "pmid": "8667211", "text": "Our data imply that between CA and cyclooxygenase there is an inverse relationship, CA activation being accompanied by reduction of cyclooxygenase activity, a reduction achieved by the pH modifications induced by CA activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8667211", "text": "In this way, cyclooxygenase, inhibition occurs \"via CA,\" with the pH variations it brings about.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "We characterized in this study the pharmacokinetics and antitumor efficacy of histidine-lysine (HK):siRNA nanoplexes modified with PEG and a cyclic RGD (cRGD) ligand targeting αvβ3", "type": "CHEMICAL", "entities": [ "PEG", "histidine", "lysine" ], "offsets": [ [ 131, 134 ], [ 78, 87 ], [ 88, 94 ] ] }, { "pmid": "23360232", "text": "and αvβ5 integrins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "With noninvasive imaging, systemically administered surface-modified HK:siRNA nanoplexes showed nearly 4-fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HK:siRNA nanoplexes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "We then determined whether the surface-modified HK:siRNA nanoplex carrier was more effective in reducing MDA-MB-435 tumor growth with an siRNA targeting Raf-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "Repeated systemic administration of the selected surface modified HK:siRNA nanoplexes targeting Raf-1 showed 35% greater inhibition of tumor growth than unmodified HK:siRNA nanoplexes and 60% greater inhibition of tumor growth than untreated mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "The improved blood pharmacokinetic results and tumor localization observed with the integrin-targeting surface modification of HK:siRNA nanoplexes correlated with greater tumor growth inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23360232", "text": "This investigation reveals that through control of targeting ligand surface display in association with a steric PEG layer, modified HK: siRNA nanoplexes show promise to advance RNAi therapeutics in oncology and potentially other critical diseases.", "type": "CHEMICAL", "entities": [ "PEG" ], "offsets": [ [ 109, 112 ] ] }, { "pmid": "17651117", "text": "Inhibition of platelet receptors involved in neutrophil-platelet interaction in model cardiopulmonary bypass.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "We investigated the interactions between neutrophils, platelets, and artificial surfaces, and whether blocking of relevant receptors on platelets reduced unwanted activation responses in model cardiopulmonary bypass.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "Isolated neutrophils and platelets resuspended in heparin-anticoagulated plasma were recirculated with and without blocking antibodies to CD62P, CD42b, or junctional adhesion molecule C (JAM-C) in polyvinyl chloride tubing using a roller pump.", "type": "CHEMICAL", "entities": [ "polyvinyl chloride" ], "offsets": [ [ 197, 215 ] ] }, { "pmid": "17651117", "text": "Platelet adhesion to the tubing was inhibited by anti-CD42b and anti-CD62P, and adhesion of neutrophils by anti-JAM-C. Formation of platelet-neutrophil and platelet aggregates was reduced by anti-CD62P. Anti-JAM-C decreased platelet-neutrophil aggregation at low concentrations and platelet macroaggregates at high concentrations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "Anti-CD62P increased neutrophil", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "CD11b expression but not degranulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "Anti-JAM-C substantially increased neutrophil degranulation and slightly increased CD11b expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "Platelet activation increased when CD62P was blocked and decreased with anti-CD42b antibody.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "High-dose anti-JAM-C reduced platelet activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17651117", "text": "In conclusion, inhibiting platelet and neutrophil-platelet interactions had useful effects but no single blocking antibody seemed capable of inducing only beneficial effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers.\n", "type": "CHEMICAL", "entities": [ "nabumetone", "meloxicam", "thromboxane B2" ], "offsets": [ [ 31, 41 ], [ 45, 54 ], [ 64, 78 ] ] }, { "pmid": "12047490", "text": "AIMS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function.", "type": "CHEMICAL", "entities": [ "nabumetone", "meloxicam" ], "offsets": [ [ 26, 36 ], [ 41, 50 ] ] }, { "pmid": "12047490", "text": "METHODS: Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out.", "type": "CHEMICAL", "entities": [ "nabumetone", "meloxicam" ], "offsets": [ [ 132, 142 ], [ 166, 175 ] ] }, { "pmid": "12047490", "text": "After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function.", "type": "CHEMICAL", "entities": [ "indomethacin" ], "offsets": [ [ 51, 63 ] ] }, { "pmid": "12047490", "text": "COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100.", "type": "CHEMICAL", "entities": [ "TXB2" ], "offsets": [ [ 64, 68 ] ] }, { "pmid": "12047490", "text": "Data are reported as median with range.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "Paired variables were analysed using Wilcoxons signed rank test.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05).", "type": "CHEMICAL", "entities": [ "meloxicam", "TXB2", "nabumetone", "indomethacin" ], "offsets": [ [ 189, 198 ], [ 0, 4 ], [ 97, 107 ], [ 112, 124 ] ] }, { "pmid": "12047490", "text": "Closure times increased significantly after administration of all three medications (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01).", "type": "CHEMICAL", "entities": [ "nabumetone", "meloxicam", "indomethacin" ], "offsets": [ [ 70, 80 ], [ 85, 94 ], [ 160, 172 ] ] }, { "pmid": "12047490", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12047490", "text": "In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former.", "type": "CHEMICAL", "entities": [ "nabumetone", "thromboxane" ], "offsets": [ [ 34, 44 ], [ 54, 65 ] ] }, { "pmid": "12047490", "text": "However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.", "type": "CHEMICAL", "entities": [ "nabumetone", "meloxicam", "indomethacin" ], "offsets": [ [ 14, 24 ], [ 29, 38 ], [ 107, 119 ] ] }, { "pmid": "12826271", "text": "Diclofenac inhibits proliferation and differentiation of neural stem cells.\n", "type": "CHEMICAL", "entities": [ "Diclofenac" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12826271", "text": "Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical situations as anti-inflammatory, analgesic and antipyretic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12826271", "text": "However, it is still unknown whether NSAIDs have effects on the development of the central nervous system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12826271", "text": "In the present study, we investigated the effects of NSAIDs on neural stem cell (NSC) proliferation and differentiation into neurons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12826271", "text": "In contrast to aspirin, naproxen, indomethacin and ibuprofen, treatment with diclofenac (10 microM) for 2 days induced the death of NSCs in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "aspirin", "naproxen", "indomethacin", "ibuprofen", "diclofenac" ], "offsets": [ [ 15, 22 ], [ 24, 32 ], [ 34, 46 ], [ 51, 60 ], [ 77, 87 ] ] }, { "pmid": "12826271", "text": "Diclofenac also inhibited the proliferation of NSCs and their differentiation into neurons.", "type": "CHEMICAL", "entities": [ "Diclofenac" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12826271", "text": "Treatment with diclofenac resulted in nuclear condensation (a morphological change due to apoptosis of NSCs)", "type": "CHEMICAL", "entities": [ "diclofenac" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "12826271", "text": "24hr after the treatment and activated caspase-3 after 6 hr, indicating that diclofenac may cause apoptosis of neuronal cells via activation of the caspase cascade.", "type": "CHEMICAL", "entities": [ "diclofenac" ], "offsets": [ [ 77, 87 ] ] }, { "pmid": "12826271", "text": "These results suggest that diclofenac may affect the development of the central nervous system.", "type": "CHEMICAL", "entities": [ "diclofenac" ], "offsets": [ [ 27, 37 ] ] }, { "pmid": "23563205", "text": "Correlation between activation of PPARγ and resistin downregulation in a mouse adipocyte cell line by a series of thiazolidinediones.\n", "type": "CHEMICAL", "entities": [ "thiazolidinediones" ], "offsets": [ [ 114, 132 ] ] }, { "pmid": "23563205", "text": "The present study shows significant correlations between the EC50 for PPARγ activation in a reporter gene cell line and resistin downregulation in mouse adipocytes, and between the IC50 for resistin downregulation and the already published minimum effective dose for antihyperglycemic activity in a mouse model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563205", "text": "These correlations indicate that PPARγ mediated downregulation of resistin might promote insulin sensitivity and that downregulation of resistin in mouse adipocytes provides an adequate and possibly more direct bioassay for screening of newly developed antihyperglycemic compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563205", "text": "Because of the higher throughput of the PPARγ the resistin downregulation assays seems most suitable to be used as a second tier in a tiered screening strategy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Identification of aldo-keto reductases as NRF2-target marker genes in human cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Transcription factor NF-E2-related factor 2 (NRF2) plays a crucial role in the cellular defense against oxidative/electrophilic stress by up-regulating multiple antioxidant genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Numerous studies with genetically modified animals have demonstrated that Nrf2 is a sensitivity determining factor upon the exposure to environmental chemicals including carcinogens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Moreover, recent studies have demonstrated that polymorphism in the human NRF2 promoter is associated with higher risks for developing acute lung injury, gastric mucosal inflammation, and nephritis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Therefore, the identification of reliable and effective human target genes of NRF2 may allow the monitoring of NRF2 activity and to predict individual sensitivity to environmental stress-induced damage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "For this purpose, we investigated genes that are tightly controlled by NRF2 to establish markers for NRF2 activity in human cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Firstly, in the normal human renal epithelial HK-2 cells, the measurement of the expression of 30 previously reported NRF2 target genes in response to NRF2 inducers (sulforaphane, tert-butylhydroquinone, cinnamic aldehyde, and hydrogen peroxide) showed that the aldo-keto reductase (AKR) 1C1 is highly inducible by all treatments.", "type": "CHEMICAL", "entities": [ "sulforaphane", "tert-butylhydroquinone", "cinnamic aldehyde", "hydrogen peroxide" ], "offsets": [ [ 166, 178 ], [ 180, 202 ], [ 204, 221 ], [ 227, 244 ] ] }, { "pmid": "23305850", "text": "Accordantly, the basal and inducible expressions of AKRs were significantly attenuated in NRF2-silenced HK-2 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Whereas, cells with stable KEAP1 knockdown, which causes a modest NRF2 activation, demonstrated substantially increased levels of AKR1A1, 1B1, 1B10, 1C1, 1C2, and 1C3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "Secondly, the linkage between NRF2 and the AKRs was confirmed in human monocytic leukemia cell line U937, which can be a model of peripherally available blood cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "The treatment of U937 cells with NRF2 inducers including sulforaphane effectively elevated the expression of AKR1B1, 1B10, 1C1, 1C2, and 1C3.", "type": "CHEMICAL", "entities": [ "sulforaphane" ], "offsets": [ [ 57, 69 ] ] }, { "pmid": "23305850", "text": "Whereas, the levels of both the basal and sulforaphane-inducible expression of AKR1C1 were significantly reduced in NRF2-silenced stable U937 cells compared to the control cells.", "type": "CHEMICAL", "entities": [ "sulforaphane" ], "offsets": [ [ 42, 54 ] ] }, { "pmid": "23305850", "text": "Similarly, the inducible expression of AKR1C1 was observed in another human monocytic leukemia cell line THP-1 as well as in human primary blood CD14(+) monocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305850", "text": "In conclusion, together with the high inducibility and NRF2 dependency shown in renal epithelial cells as well as in peripherally available blood cells, current findings suggest that AKRs can be utilized as a marker of NRF2 activity in human cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19683471", "text": "Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation.\n", "type": "CHEMICAL", "entities": [ "serine", "serine" ], "offsets": [ [ 121, 127 ], [ 68, 74 ] ] }, { "pmid": "19683471", "text": "Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 34, 40 ] ] }, { "pmid": "19683471", "text": "Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 125, 131 ] ] }, { "pmid": "19683471", "text": "Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19683471", "text": "Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19683471", "text": "These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10446934", "text": "Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes.\n", "type": "CHEMICAL", "entities": [ "Angiotensin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "10446934", "text": "The intrarenal factors responsible for hypertension in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes are unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10446934", "text": "The pressure-natriuresis and -diuresis relationships in response to chronic angiotensin-converting enzyme (ACE) inhibition and AT1 receptor blockade were evaluated.", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 76, 87 ] ] }, { "pmid": "10446934", "text": "Renal renin-angiotensin and nitric oxide (NO) system gene expression was also investigated.", "type": "CHEMICAL", "entities": [ "angiotensin", "nitric oxide", "NO" ], "offsets": [ [ 12, 23 ], [ 28, 40 ], [ 42, 44 ] ] }, { "pmid": "10446934", "text": "Six-week-old dTGR were treated for 3 wk with submaximal doses of cilazapril (10 mg/kg, orally) or losartan (10 mg/kg, orally) or with the drug combination.", "type": "CHEMICAL", "entities": [ "cilazapril", "losartan" ], "offsets": [ [ 65, 75 ], [ 98, 106 ] ] }, { "pmid": "10446934", "text": "In untreated dTGR, pressure-natriuresis relationships were maximally shifted rightward by approximately 70 to 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10446934", "text": "Submaximal cilazapril and losartan dosages both decreased systolic BP by 30 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmHg.", "type": "CHEMICAL", "entities": [ "cilazapril", "losartan" ], "offsets": [ [ 11, 21 ], [ 26, 34 ] ] }, { "pmid": "10446934", "text": "Cilazapril increased RBF and GFR to values observed in normotensive control animals but did not significantly affect fractional sodium excretion (FENa) or fractional water excretion (FEH2O) curves.", "type": "CHEMICAL", "entities": [ "sodium", "Cilazapril" ], "offsets": [ [ 128, 134 ], [ 0, 10 ] ] }, { "pmid": "10446934", "text": "In contrast, losartan had no significant effect on RBF or GFR but shifted the FENa and FEH2O curves leftward.", "type": "CHEMICAL", "entities": [ "losartan" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "10446934", "text": "The cilazapril and losartan combination completely normalized BP and shifted the pressure-natriuresis curves leftward more than did either drug alone.", "type": "CHEMICAL", "entities": [ "cilazapril", "losartan" ], "offsets": [ [ 4, 14 ], [ 19, 27 ] ] }, { "pmid": "10446934", "text": "When cilazapril and losartan were administered at higher doses (30 mg/kg, orally), the two drugs equally shifted the pressure-natriuresis curves leftward, by 50 mmHg.", "type": "CHEMICAL", "entities": [ "cilazapril", "losartan" ], "offsets": [ [ 5, 15 ], [ 20, 28 ] ] }, { "pmid": "10446934", "text": "Both drugs increased RBF and GFR; however, only losartan shifted FENa and FEH2O curves leftward.", "type": "CHEMICAL", "entities": [ "losartan" ], "offsets": [ [ 48, 56 ] ] }, { "pmid": "10446934", "text": "Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losartan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT1A receptor genes were observed.", "type": "CHEMICAL", "entities": [ "losartan", "cilazapril" ], "offsets": [ [ 95, 103 ], [ 108, 118 ] ] }, { "pmid": "10446934", "text": "Endothelial NO synthase expression was increased by cilazapril but not by losartan.", "type": "CHEMICAL", "entities": [ "NO", "cilazapril", "losartan" ], "offsets": [ [ 12, 14 ], [ 52, 62 ], [ 74, 82 ] ] }, { "pmid": "10446934", "text": "Neither inducible NO synthase nor neural", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 18, 20 ] ] }, { "pmid": "10446934", "text": "NO synthase gene expression was affected by drug treatments.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 0, 2 ] ] }, { "pmid": "10446934", "text": "Therefore, submaximal ACE inhibition enhanced sodium excretion mainly by increasing RBF and GFR, whereas submaximal AT1 receptor blockade decreased tubular sodium and water reabsorption.", "type": "CHEMICAL", "entities": [ "sodium", "sodium" ], "offsets": [ [ 46, 52 ], [ 156, 162 ] ] }, { "pmid": "10446934", "text": "The combination of the two drugs produced an additive effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10446934", "text": "The ACE inhibitor effects may involve increased endothelial", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10446934", "text": "NO synthase expression, perhaps related to the inhibition of bradykinin degradation.", "type": "CHEMICAL", "entities": [ "NO", "bradykinin" ], "offsets": [ [ 0, 2 ], [ 61, 71 ] ] }, { "pmid": "12123767", "text": "A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine.\n", "type": "CHEMICAL", "entities": [ "mexiletine" ], "offsets": [ [ 77, 87 ] ] }, { "pmid": "12123767", "text": "OBJECTIVE: Mutations in the cardiac sodium channel gene, SCN5A, cause congenital long QT syndrome (LQT3), Brugada syndrome, idiopathic ventricular fibrillation, and conduction disease by distinct cellular and clinical electrophysiological phenotypes.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "12123767", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "Postmortem molecular analysis of SCN5A was conducted on an infant who presented shortly after birth with self-terminating torsades de pointes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "The infant was treated with lidocaine, propranolol, and mexiletine and was stable for 16 months manifesting only a prolonged QT interval.", "type": "CHEMICAL", "entities": [ "lidocaine", "propranolol", "mexiletine" ], "offsets": [ [ 28, 37 ], [ 39, 50 ], [ 56, 66 ] ] }, { "pmid": "12123767", "text": "The infant collapsed suddenly following presumed viral gastroenteritis, was found in 2:1 AV block, and was subsequently declared brain dead.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "Genomic DNA was subjected to SCN5A mutational analyses and DNA sequencing revealing a novel, spontaneous germline missense mutation, M1766L.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "The M1766L mutation was engineered into the hH1a clone by site-directed mutagenesis, transfected into embryonic kidney cells (HEK-293), and studied by voltage clamp.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "The M1766L mutation caused a significant decrease in the sodium channel expression.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 57, 63 ] ] }, { "pmid": "12123767", "text": "Co-expression with beta1 subunit, incubation at low temperature, and most effectively incubation with mexiletine partially 'rescued' the defective expression.", "type": "CHEMICAL", "entities": [ "mexiletine" ], "offsets": [ [ 102, 112 ] ] }, { "pmid": "12123767", "text": "In addition to this pronounced loss of function, M1766L also showed a 10-fold increase in the persistent late sodium current.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 110, 116 ] ] }, { "pmid": "12123767", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12123767", "text": "These findings suggest that M1766L-SCN5A channel dysfunction may contribute to the basis of lethal arrhythmias, displays an overlapping electrophysiological phenotype, and represents the first sodium channelopathy rescued by drug.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 193, 199 ] ] }, { "pmid": "23219339", "text": "Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptors.\n", "type": "CHEMICAL", "entities": [ "NMDA", "oxymatrine" ], "offsets": [ [ 114, 118 ], [ 27, 37 ] ] }, { "pmid": "23219339", "text": "Oxymatrine (OMT) is a major bioactive component derived from Sophora flavescens Ait (kushen), which is widely used in Chinese medicine.", "type": "CHEMICAL", "entities": [ "Oxymatrine", "OMT" ], "offsets": [ [ 0, 10 ], [ 12, 15 ] ] }, { "pmid": "23219339", "text": "Recent studies have shown that it has neuroprotective effects; however, its underlying mechanisms remain unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219339", "text": "We focus on the mechanisms of pharmacologic action in OMT by detecting its pharmacological properties against focal cerebral ischemia in vivo and NMDA-induced neurotoxicity in vitro.", "type": "CHEMICAL", "entities": [ "OMT", "NMDA" ], "offsets": [ [ 54, 57 ], [ 146, 150 ] ] }, { "pmid": "23219339", "text": "OMT prevented cerebral ischemic injury in mice induced via a 2 h middle cerebral artery occlusion and a 24 h reperfusion, in vivo.", "type": "CHEMICAL", "entities": [ "OMT" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23219339", "text": "In vitro cultured neurons challenged with N-methyl-D-aspartate (NMDA, 200 μM) for 30 min showed significant decrease in the viability of neurons; however, OMT was able to protect neurons against induced neurotoxicity via NMDA exposure.", "type": "CHEMICAL", "entities": [ "N-methyl-D-aspartate", "NMDA", "OMT", "NMDA" ], "offsets": [ [ 42, 62 ], [ 64, 68 ], [ 155, 158 ], [ 221, 225 ] ] }, { "pmid": "23219339", "text": "Western blot analysis revealed that OMT decreased the expression of Bax and repaired the balance of pro- and anti-apoptotic proteins.", "type": "CHEMICAL", "entities": [ "OMT" ], "offsets": [ [ 35, 38 ] ] }, { "pmid": "23219339", "text": "Furthermore, OMT significantly reversed the up-regulation of NR2B and inhibited the calcium overload in the cultured neurons after challenging the NMDA.", "type": "CHEMICAL", "entities": [ "calcium", "NMDA", "OMT" ], "offsets": [ [ 83, 90 ], [ 146, 150 ], [ 12, 15 ] ] }, { "pmid": "23219339", "text": "OMT showed partial protection in the cortical neurons via down-regulation of NR2B containing NMDA receptors and up-regulation of Bcl-2 family.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 92, 96 ] ] }, { "pmid": "23219339", "text": "Our results provide new insights into the development of natural therapeutic anti-oxidants against ischemia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454300", "text": "Phenotypic analysis of ovine antigen presenting cells loaded with nanoparticles migrating from the site of vaccination.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454300", "text": "Virus-sized particulate adjuvants such as ISCOMs, polystyrene nanoparticles and virus-like particles have been shown to target dendritic cells, resulting in the activation of T and B cells in vivo.", "type": "CHEMICAL", "entities": [ "polystyrene" ], "offsets": [ [ 50, 61 ] ] }, { "pmid": "23454300", "text": "Using an ovine pseudo-afferent lymph cannulation model to capture APC that traffic from the site of injection to the local lymph node, we show that 40-50nm nanoparticles are taken up at the site of injection by dendritic cells (DCs) migrating to the draining lymph node.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454300", "text": "These DCs can express CD11c, CD1b, CD5, MHC class II and CD8.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454300", "text": "Nanoparticles transported by DCs migrating from the site of injection to the local lymph node therefore needs to be considered as a new mechanism underlying the immunogenicity of virus-sized vaccine delivery systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "Emodin-6-O-β-D-glucoside inhibits HMGB1-induced inflammatory responses in vitro and in vivo.\n", "type": "CHEMICAL", "entities": [ "Emodin-6-O-β-D-glucoside" ], "offsets": [ [ 0, 24 ] ] }, { "pmid": "23146691", "text": "High mobility group box 1 (HMGB1) protein acts as a potent proinflammatory cytokine and is involved in the pathogenesis of several vascular diseases, such as, systemic vasculitis and sepsis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "Emodin-6-O-β-D-glucoside (EG) is a new active compound from Reynoutria japonica, and its biologic activities have not been previously investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "In this study, we first investigated the antiinflammatory activities of EG on HMGB1-mediated proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and in a murine cecal ligation and puncture (CLP)-model of sepsis in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "EG was found to suppress the release of HMGB1, the production of tumor necrosis factor (TNF)-α, and the activation of nuclear factor-κB (NF-κB) by HMGB1 in HUVECs, and to inhibit HMGB1-mediated hyperpermeability and leukocyte migration in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "In the CLP model, HMGB1 was highly released, but this release was prevented by EG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "Furthermore, EG also increased the survival times of CLP administered mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146691", "text": "Collectively, this study shows EG can protect barrier integrity and inhibit HMGB1-mediated inflammatory responses, which suggests a potential use as a therapy for sepsis or septic shock.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "Copy number variations of the human histamine H4 receptor gene are associated with systemic lupus erythematosus.\n", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "20618322", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "Systemic lupus erythematosus (SLE) is a complex genetic disease; the histamine H4 receptor (HRH4) has been shown to be related to different kinds of autoimmune disorders; and copy number variations (CNVs) have been found to be associated with various types of diseases.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "20618322", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "To explore a possible association between HRH4 (formerly H4R) CNVs and the risk of SLE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "Genomic DNA and RNA from 340 patients with SLE and 392 healthy controls were extracted, and CNVs and mRNA levels of HRH4 were examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "The expression of HRH4 mRNA was significantly increased in patients with SLE compared with controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "Amplification of HRH4 copy numbers significantly increased the risk of SLE [P < 0.001, odds ratio (OR) 2.26, 95% confidence interval (CI) 1.50-3.40].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "HRH4 amplifications also positively correlated with the incidence of arthritis (P = 0.019, OR 1.96, 95% CI 1.11-3.47), and proteinuria (P < 0.001, OR 2.95, 95% CI 1.73-5.00) and antinuclear antibody abnormalities (P < 0.001, OR 2.97, 95% CI 1.66-5.33).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "Deletions of HRH4 copy numbers were protective against proteinuria (P = 0.03, OR 0.50, 95% CI 0.26-0.94).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20618322", "text": "CONCLUSION: CNVs of the HRH4 gene are associated with SLE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19228178", "text": "Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders.\n", "type": "CHEMICAL", "entities": [ "ramelteon" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "19228178", "text": "An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19228178", "text": "However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA(A)) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia.", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid" ], "offsets": [ [ 55, 78 ] ] }, { "pmid": "19228178", "text": "Ramelteon (Rozerem; Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT(1)/MT(2) receptor agonist.", "type": "CHEMICAL", "entities": [ "Ramelteon", "Rozerem", "melatonin" ], "offsets": [ [ 0, 9 ], [ 11, 18 ], [ 111, 120 ] ] }, { "pmid": "19228178", "text": "Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT(1) and MT(2) receptors, which are primarily located in the suprachiasmatic nucleus, the body's \"master clock.\"", "type": "CHEMICAL", "entities": [ "ramelteon", "melatonin" ], "offsets": [ [ 70, 79 ], [ 117, 126 ] ] }, { "pmid": "19228178", "text": "As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades.", "type": "CHEMICAL", "entities": [ "ramelteon" ], "offsets": [ [ 9, 18 ] ] }, { "pmid": "19228178", "text": "Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia.", "type": "CHEMICAL", "entities": [ "Ramelteon" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15843826", "text": "Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis.\n", "type": "CHEMICAL", "entities": [ "retinoid", "Am80", "Tamibarotene" ], "offsets": [ [ 41, 49 ], [ 50, 54 ], [ 56, 68 ] ] }, { "pmid": "15843826", "text": "In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15843826", "text": "We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15843826", "text": "Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15843826", "text": "We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs.", "type": "CHEMICAL", "entities": [ "retinoid", "Am80", "Tamibarotene" ], "offsets": [ [ 60, 68 ], [ 69, 73 ], [ 75, 87 ] ] }, { "pmid": "15843826", "text": "Am80 is specific for the retinoic-acid receptor-alpha/beta, and has therapeutic effects in all-trans retinoic acid resistant acute promyelocytic leukemia.", "type": "CHEMICAL", "entities": [ "Am80", "retinoic-acid", "all-trans retinoic acid" ], "offsets": [ [ 0, 4 ], [ 25, 38 ], [ 91, 114 ] ] }, { "pmid": "15843826", "text": "Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF.", "type": "CHEMICAL", "entities": [ "Am80" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "15843826", "text": "Am80 showed little growth inhibition of bone marrow stromal cells (BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells.", "type": "CHEMICAL", "entities": [ "Am80" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "15843826", "text": "Am80 inhibited VEGF-induced phosphorylation of VEGF receptor.", "type": "CHEMICAL", "entities": [ "Am80" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "15843826", "text": "In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80.", "type": "CHEMICAL", "entities": [ "Am80" ], "offsets": [ [ 141, 145 ] ] }, { "pmid": "15843826", "text": "These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.", "type": "CHEMICAL", "entities": [ "Am80" ], "offsets": [ [ 40, 44 ] ] }, { "pmid": "9231746", "text": "Mechanisms of inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by dihydropyridine calcium antagonists.\n", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "9231746", "text": "Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interaction between the cyclic nucleotide and Ca2+ second-messenger systems.", "type": "CHEMICAL", "entities": [ "nucleotide", "Ca2+", "nucleotide" ], "offsets": [ [ 147, 157 ], [ 162, 166 ], [ 28, 38 ] ] }, { "pmid": "9231746", "text": "CaMPDE exists as tissue-specific isozymes, and initially these isozymes were designated according to their respective subunit molecular mass.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9231746", "text": "A variety of pharmacological agents have been used to inhibit CaMPDE, and this inhibition occurs mostly via Ca2+-dependent association with the proteins.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 108, 112 ] ] }, { "pmid": "9231746", "text": "We have examined the effect of dihydropyridine Ca2+-channel blockers felodipine and nicardipine on CaMPDE.", "type": "CHEMICAL", "entities": [ "dihydropyridine", "Ca2+", "felodipine", "nicardipine" ], "offsets": [ [ 31, 46 ], [ 47, 51 ], [ 69, 79 ], [ 84, 95 ] ] }, { "pmid": "9231746", "text": "The results suggest that the 63-kDa (PDE 1B1) and 60-kDa (PDE 1A2) CaMPDE isozymes are inhibited by felodipine and nicardipine by partial competitive inhibition and that these two Ca2+ antagonists appear to counteract each other.", "type": "CHEMICAL", "entities": [ "felodipine", "nicardipine", "Ca2+" ], "offsets": [ [ 100, 110 ], [ 115, 126 ], [ 180, 184 ] ] }, { "pmid": "9231746", "text": "This study further demonstrates the existence of a specific site, distinct from the active site on CaMPDE, that exhibits high-affinity binding of these drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9231746", "text": "Felodipine and nicardipine have similar affinities for 60-kDa CaMPDE isozymes but bring about different levels of enzyme inhibition, suggesting the possibility of designing specific drugs that can protect the enzyme from inhibition by dihydropyridine Ca2+-channel blockers.", "type": "CHEMICAL", "entities": [ "nicardipine", "dihydropyridine", "Ca2+", "Felodipine" ], "offsets": [ [ 15, 26 ], [ 235, 250 ], [ 251, 255 ], [ 0, 10 ] ] }, { "pmid": "23481176", "text": "Efficient MRI labeling of endothelial progenitor cells: Design of thiolated surface stabilized superparamagnetic iron oxide nanoparticles.\n", "type": "CHEMICAL", "entities": [ "iron oxide" ], "offsets": [ [ 113, 123 ] ] }, { "pmid": "23481176", "text": "The aim of this study was to design thiolated surface stabilized superparamagnetic iron oxide nanoparticles (TSS-SPIONs) for efficient internalization with high MRI sensitivity.", "type": "CHEMICAL", "entities": [ "iron oxide" ], "offsets": [ [ 83, 93 ] ] }, { "pmid": "23481176", "text": "TSS-SPIONs were developed by chelation between thiolated chitosan-thioglycolic acid (chitosan-TGA) hydrogel and iron ions (Fe(2+)/Fe(3+)).", "type": "CHEMICAL", "entities": [ "thioglycolic acid", "TGA", "iron", "Fe(2+)", "Fe(3+)" ], "offsets": [ [ 66, 83 ], [ 94, 97 ], [ 112, 116 ], [ 123, 129 ], [ 130, 136 ] ] }, { "pmid": "23481176", "text": "Likely, unmodified chitosan hydrogel SPIONs (UC-SPIONs) and uncoated SPIONs were used as control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481176", "text": "Moreover, TSS-SPIONs were investigated regarding to their iron core size, hydrodynamic diameter, zeta potential, iron contents, molar relaxivities (r1 and r2), and cellular internalization.", "type": "CHEMICAL", "entities": [ "iron", "iron" ], "offsets": [ [ 58, 62 ], [ 113, 117 ] ] }, { "pmid": "23481176", "text": "TSS-SPIONs demonstrated an iron oxide core diameter (crystallite size by XRD) of 3.1±0.02nm, a hydrodynamic diameter of 94±20nm, a zeta potential of +21±5mV, and an iron content of 3.6±0.9mg/mL. In addition, internalization of TSS-SPIONs into human endothelial progenitor cells (EPC) from umbilical cord blood was more than threefold and 17-fold higher in contrast to UC-SPIONs and SPIONs, respectively.", "type": "CHEMICAL", "entities": [ "iron oxide", "iron" ], "offsets": [ [ 27, 37 ], [ 165, 169 ] ] }, { "pmid": "23481176", "text": "With twofold lower incubation iron concentration of TSS-SPIONs, more than threefold higher internalization was achieved as compared to Resovist®.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 26, 30 ] ] }, { "pmid": "23481176", "text": "Also, cell viability of more than 90% was observed in the presence of TSS-SPIONs after 24h.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481176", "text": "The molar MR relaxivities (r2) value at 1.5T was threefold higher than that of Resovist® and demonstrated that TSS-SPIONs have the potential as very effective T2 contrast-enhancement agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23481176", "text": "According to these findings, TSS-SPIONs with efficient internalization, lower cytotoxicity, and high MRI sensitivity seem to be promising for cell tracking.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23260346", "text": "Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23260346", "text": "Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23260346", "text": "Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23260346", "text": "Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis.", "type": "CHEMICAL", "entities": [ "darapladib" ], "offsets": [ [ 63, 73 ] ] }, { "pmid": "23260346", "text": "The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported.", "type": "CHEMICAL", "entities": [ "darapladib", "serine" ], "offsets": [ [ 21, 31 ], [ 89, 95 ] ] }, { "pmid": "23260346", "text": "Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23260346", "text": "We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity.", "type": "CHEMICAL", "entities": [ "darapladib", "carbamate" ], "offsets": [ [ 18, 28 ], [ 72, 81 ] ] }, { "pmid": "23260346", "text": "Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14725487", "text": "Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol.\n", "type": "CHEMICAL", "entities": [ "Arformoterol", "R,R-eformoterol", "R,R-formoterol", "(R,R)-eformoterol", "(R,R)-formoterol", "arformoterol tartrate", "eformoterol", "formoterol" ], "offsets": [ [ 0, 12 ], [ 117, 132 ], [ 134, 148 ], [ 14, 31 ], [ 33, 49 ], [ 51, 72 ], [ 74, 85 ], [ 96, 106 ] ] }, { "pmid": "14725487", "text": "Sepracor in the US is developing arformoterol", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 33, 45 ] ] }, { "pmid": "14725487", "text": "[R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol].", "type": "CHEMICAL", "entities": [ "formoterol", "eformoterol", "R,R-formoterol" ], "offsets": [ [ 75, 85 ], [ 87, 98 ], [ 1, 15 ] ] }, { "pmid": "14725487", "text": "This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14725487", "text": "Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 23, 35 ] ] }, { "pmid": "14725487", "text": "In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol.", "type": "CHEMICAL", "entities": [ "levosalbutamol", "arformoterol" ], "offsets": [ [ 157, 171 ], [ 176, 188 ] ] }, { "pmid": "14725487", "text": "Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 42, 54 ] ] }, { "pmid": "14725487", "text": "Phase III trials of arformoterol began in September 2001.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 20, 32 ] ] }, { "pmid": "14725487", "text": "The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14725487", "text": "However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 162, 174 ] ] }, { "pmid": "14725487", "text": "In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14725487", "text": "Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 47, 59 ] ] }, { "pmid": "14725487", "text": "Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 136, 148 ] ] }, { "pmid": "14725487", "text": "In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14725487", "text": "In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 66, 78 ] ] }, { "pmid": "23402364", "text": "Role of nitric oxide in the chemistry and anticancer activity of etoposide (VP-16,213).\n", "type": "CHEMICAL", "entities": [ "etoposide", "VP-16,213", "nitric oxide" ], "offsets": [ [ 65, 74 ], [ 76, 85 ], [ 8, 20 ] ] }, { "pmid": "23402364", "text": "Originally identified as an innate cytotoxin, nitric oxide ((·)NO) formation in tumors can influence chemotherapy and exacerbate cancer progression.", "type": "CHEMICAL", "entities": [ "nitric oxide", "(·)NO" ], "offsets": [ [ 46, 58 ], [ 60, 65 ] ] }, { "pmid": "23402364", "text": "Here, we examined the hypothesis that (·)NO generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16).", "type": "CHEMICAL", "entities": [ "(·)NO", "Etoposide", "VP-16" ], "offsets": [ [ 37, 42 ], [ 136, 145 ], [ 147, 152 ] ] }, { "pmid": "23402364", "text": "The UV-vis spectrum of VP-16 was not changed by exposure of VP-16 to (·)NO in aqueous buffer.", "type": "CHEMICAL", "entities": [ "VP-16", "VP-16", "(·)NO" ], "offsets": [ [ 21, 26 ], [ 58, 63 ], [ 67, 72 ] ] }, { "pmid": "23402364", "text": "In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner.", "type": "CHEMICAL", "entities": [ "o-quinone- and nitroso-VP-16", "chloroform", "oxygen" ], "offsets": [ [ 55, 83 ], [ 132, 142 ], [ 150, 156 ] ] }, { "pmid": "23402364", "text": "Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to (·)NO in chloroform in the presence of oxygen.", "type": "CHEMICAL", "entities": [ "VP-16", "VP-16", "H2O2", "(·)NO", "chloroform", "oxygen" ], "offsets": [ [ 40, 45 ], [ 70, 75 ], [ 103, 107 ], [ 133, 138 ], [ 142, 152 ], [ 172, 178 ] ] }, { "pmid": "23402364", "text": "Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV-vis indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates.", "type": "CHEMICAL", "entities": [ "VP-16", "phenoxy", "o-quinone", "VP-16", "nitroxide", "iminoxyl", "nitrogen oxide" ], "offsets": [ [ 32, 37 ], [ 126, 133 ], [ 150, 159 ], [ 163, 168 ], [ 190, 199 ], [ 201, 209 ], [ 221, 235 ] ] }, { "pmid": "23402364", "text": "Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells.", "type": "CHEMICAL", "entities": [ "VP-16" ], "offsets": [ [ 21, 26 ] ] }, { "pmid": "23402364", "text": "LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells.", "type": "CHEMICAL", "entities": [ "nitric oxide", "VP-16" ], "offsets": [ [ 22, 34 ], [ 78, 83 ] ] }, { "pmid": "23402364", "text": "Furthermore, (·)NO products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity.", "type": "CHEMICAL", "entities": [ "(·)NO", "VP-16" ], "offsets": [ [ 9, 14 ], [ 63, 68 ] ] }, { "pmid": "23402364", "text": "Together, these observations suggest that the formation of (·)NO in tumors (associated macrophages) can contribute to VP-16 resistance via the detoxification of VP-16.", "type": "CHEMICAL", "entities": [ "(·)NO", "VP-16", "VP-16" ], "offsets": [ [ 54, 59 ], [ 113, 118 ], [ 156, 161 ] ] }, { "pmid": "11319232", "text": "Acyl-CoA synthetase isoforms 1, 4, and 5 are present in different subcellular membranes in rat liver and can be inhibited independently.\n", "type": "CHEMICAL", "entities": [ "Acyl-CoA" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "11319232", "text": "Inhibition studies have suggested that acyl-CoA synthetase (ACS, EC ) isoforms might regulate the use of acyl-CoAs by different metabolic pathways.", "type": "CHEMICAL", "entities": [ "acyl-CoAs", "acyl-CoA" ], "offsets": [ [ 105, 114 ], [ 39, 47 ] ] }, { "pmid": "11319232", "text": "In order to determine whether the subcellular locations differed for each of the three ACSs present in liver and whether these isoforms were regulated independently, non-cross-reacting peptide antibodies were raised against ACS1, ACS4, and ACS5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11319232", "text": "ACS1 was identified in endoplasmic reticulum, mitochondria-associated membrane (MAM), and cytosol, but not in mitochondria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11319232", "text": "ACS4 was present primarily in MAM, and the 76-kDa ACS5 protein was located in mitochondrial membrane.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11319232", "text": "Consistent with these locations, N-ethylmaleimide, an inhibitor of ACS4, inhibited ACS activity 47% in MAM and 28% in endoplasmic reticulum.", "type": "CHEMICAL", "entities": [ "N-ethylmaleimide" ], "offsets": [ [ 33, 49 ] ] }, { "pmid": "11319232", "text": "Troglitazone, a second ACS4 inhibitor, inhibited ACS activity <10% in microsomes and mitochondria and 45% in MAM.", "type": "CHEMICAL", "entities": [ "Troglitazone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "11319232", "text": "Triacsin C, a competitive inhibitor of both ACS1 and ACS4, inhibited ACS activity similarly in endoplasmic reticulum, MAM, and mitochondria, suggesting that a hitherto unidentified triacsin-sensitive ACS is present in mitochondria.", "type": "CHEMICAL", "entities": [ "triacsin", "Triacsin C" ], "offsets": [ [ 181, 189 ], [ 0, 10 ] ] }, { "pmid": "11319232", "text": "ACS1, ACS4, and ACS5 were regulated independently by fasting and re-feeding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11319232", "text": "Fasting rats for 48 h resulted in a decrease in ACS4 protein, and an increase in ACS5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11319232", "text": "Re-feeding normal chow or a high sucrose diet for 24 h after a 48-h fast increased both ACS1 and ACS4 protein expression 1.5-2.0-fold, consistent with inhibition studies.", "type": "CHEMICAL", "entities": [ "sucrose" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "11319232", "text": "These results suggest that ACS1 and ACS4 may be linked to triacylglycerol synthesis.", "type": "CHEMICAL", "entities": [ "triacylglycerol" ], "offsets": [ [ 58, 73 ] ] }, { "pmid": "11319232", "text": "Taken together, the data suggest that acyl-CoAs may be functionally channeled to specific metabolic pathways through different ACS isoforms in unique subcellular locations.", "type": "CHEMICAL", "entities": [ "acyl-CoAs" ], "offsets": [ [ 38, 47 ] ] }, { "pmid": "11585753", "text": "The tyrosine kinase inhibitor ZD1839 (\"Iressa\") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells.\n", "type": "CHEMICAL", "entities": [ "ZD1839", "Iressa", "tyrosine" ], "offsets": [ [ 30, 36 ], [ 39, 45 ], [ 4, 12 ] ] }, { "pmid": "11585753", "text": "The epidermal growth factor receptor (EGFR) is commonly overexpressed in many human tumors and provides a new target for anticancer drug development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11585753", "text": "ZD1839 (\"Iressa\"), a quinazoline tyrosine kinase inhibitor selective for the EGFR, has shown good activity in preclinical studies and in the early phase of clinical trials.", "type": "CHEMICAL", "entities": [ "ZD1839", "Iressa", "quinazoline tyrosine" ], "offsets": [ [ 0, 6 ], [ 9, 15 ], [ 21, 41 ] ] }, { "pmid": "11585753", "text": "However, because it remains unclear which tumor types are the best targets for treatment with this agent, the molecular characteristics that correlate with tumor sensitivity to ZD1839 have been studied.", "type": "CHEMICAL", "entities": [ "ZD1839" ], "offsets": [ [ 177, 183 ] ] }, { "pmid": "11585753", "text": "In a panel of human breast cancer and other epithelial tumor cell lines, HER2-overexpressing tumors were particularly sensitive to ZD1839.", "type": "CHEMICAL", "entities": [ "ZD1839" ], "offsets": [ [ 131, 137 ] ] }, { "pmid": "11585753", "text": "Growth inhibition of these tumor cell lines was associated with the dephosphorylation of EGFR, HER2, and HER3, accompanied by the loss of association of HER3 with phosphatidylinositol 3-kinase, and down-regulation of Akt activity.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 163, 183 ] ] }, { "pmid": "11585753", "text": "These studies suggest that HER2-overexpressing tumors are particularly susceptible to the inhibition of HER family tyrosine kinase signaling and suggest novel strategies to treat these particularly aggressive tumors.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 115, 123 ] ] }, { "pmid": "23537582", "text": "Integrated chemical and biological analysis to explain estrogenic potency in bile extracts of red mullet (Mullus barbatus).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "A biological screening was performed to establish the total exposure to estrogenic compounds of red mullet (Mullus barbatus) collected at several sites along the Spanish Mediterranean coast by testing male fish bile extracts using the in vitro ER-LUC reporter gene assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "In addition, major metabolites were identified and measurements of OH-PAHs (1-naphthol, 9-phenantrol, 9-fluorenol, 1-pyrenol, 1OH-BaP and 3OH-BaP) and alkylphenols (4-n-nonylphenol (4-n-NP) and 4-tertoctylphenol (4-tert-OP))", "type": "CHEMICAL", "entities": [ "OH-PAHs", "1-naphthol", "9-phenantrol", "9-fluorenol", "1-pyrenol", "1OH-BaP", "3OH-BaP", "alkylphenols", "4-n-nonylphenol", "4-n-NP", "4-tertoctylphenol", "4-tert-OP" ], "offsets": [ [ 67, 74 ], [ 76, 86 ], [ 88, 100 ], [ 102, 113 ], [ 115, 124 ], [ 126, 133 ], [ 138, 145 ], [ 151, 163 ], [ 165, 180 ], [ 182, 188 ], [ 194, 211 ], [ 213, 222 ] ] }, { "pmid": "23537582", "text": "in the same fish bile extracts were taken by gas chromatography-mass spectrometry in electron ionization mode (GC-EI-MS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "Relative in vitro estrogenic potencies of the chemically quantified compounds were also tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "The highest biliary concentrations of 1-pyrenol, 9-fluorenol and 4-n-NP were found in fish from Barcelona and from the Mar Menor coastal lagoon.", "type": "CHEMICAL", "entities": [ "1-pyrenol", "9-fluorenol", "4-n-NP" ], "offsets": [ [ 38, 47 ], [ 49, 60 ], [ 65, 71 ] ] }, { "pmid": "23537582", "text": "However, these concentrations can be considered relatively low compared to values reported in red mullet from other polluted waters in the Mediterranean Sea.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "The contribution of 1-pyrenol, 4-n-NP and 4-tert-OP to the total estrogenic potency measured in male fish bile was found to be negligible, indicating the presence of other estrogenic compounds in red mullet bile.", "type": "CHEMICAL", "entities": [ "1-pyrenol", "4-n-NP", "4-tert-OP" ], "offsets": [ [ 20, 29 ], [ 31, 37 ], [ 42, 51 ] ] }, { "pmid": "23537582", "text": "Estrogenic potency in bile from male fish was markedly elevated in Mar Menor lagoon (234.8±5.7pgE2EQ/μl), and further research will be necessary to explain whether the presence of natural and synthetic-hormones in the lagoon contributed to this finding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537582", "text": "Values of approximately 15-16E2EQpg/mg bile can be regarded as preliminary baseline levels of bile estrogenicity in male red mullet from the western Mediterranean Sea.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19068776", "text": "[Pharmacological effects of a mu-opioid receptor antagonist naltrexone on alcohol dependence].\n", "type": "CHEMICAL", "entities": [ "naltrexone", "alcohol" ], "offsets": [ [ 60, 70 ], [ 74, 81 ] ] }, { "pmid": "19068776", "text": "Alcohol is one of the most commonly abused substances, and its chronic intake leads to the development of ethanol dependence in both humans and laboratory animals.", "type": "CHEMICAL", "entities": [ "Alcohol", "ethanol" ], "offsets": [ [ 0, 7 ], [ 106, 113 ] ] }, { "pmid": "19068776", "text": "In many countries, a mu-opioid receptor antagonist naltrexone has been used in the treatment of alcohol dependence.", "type": "CHEMICAL", "entities": [ "naltrexone", "alcohol" ], "offsets": [ [ 51, 61 ], [ 96, 103 ] ] }, { "pmid": "19068776", "text": "The introduction of naltrexone for the treatment of alcohol dependence has been mainly based on behavioral animal models that provide evidence of the involvement of the endogenous opioid system in alcohol drinking and dependence.", "type": "CHEMICAL", "entities": [ "naltrexone", "alcohol", "alcohol" ], "offsets": [ [ 20, 30 ], [ 52, 59 ], [ 197, 204 ] ] }, { "pmid": "19068776", "text": "It has been well known that alcohol leads to the activation of the endogenous opioid system.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "19068776", "text": "The endogenous opioid agonists, such as beta-endorphin, increase the activity of the mesolimbic dopaminergic system through the inhibition of the gamma-aminobutyric acid (GABA)-containing inhibitory interneurons in the ventral tegmental area, resulting in the expression of alcohol reinforcement and/or rewarding effect.", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid", "GABA", "alcohol" ], "offsets": [ [ 146, 169 ], [ 171, 175 ], [ 274, 281 ] ] }, { "pmid": "19068776", "text": "Therefore, naltrexone, which is useful for alcohol dependence therapy, may attenuate the rewarding effect of ethanol by interfering with the ethanol-induced stimulation of the mesolimbic dopaminergic system.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "naltrexone", "alcohol" ], "offsets": [ [ 109, 116 ], [ 141, 148 ], [ 11, 21 ], [ 43, 50 ] ] }, { "pmid": "19068776", "text": "The following review provides a summary of the interactions between endogenous opioid system and mesolimbic dopaminergic system in alcohol dependence.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 131, 138 ] ] }, { "pmid": "12373423", "text": "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats.\n", "type": "CHEMICAL", "entities": [ "lisuride", "5-hydroxytryptamine" ], "offsets": [ [ 17, 25 ], [ 40, 59 ] ] }, { "pmid": "12373423", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373423", "text": "There is substantial evidence that lisuride can produce effects linked to 5-HT(1A) receptor occupancy.", "type": "CHEMICAL", "entities": [ "lisuride" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "12373423", "text": "Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT(2A/2C) receptor activation in hallucinogenesis.", "type": "CHEMICAL", "entities": [ "lisuride", "dopamine" ], "offsets": [ [ 83, 91 ], [ 127, 135 ] ] }, { "pmid": "12373423", "text": "These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT(1A) receptors has been demonstrated in several different laboratories and that activation of 5-HT(1A) and 5-HT(1B) receptors can modulate dopaminergically mediated responses.", "type": "CHEMICAL", "entities": [ "lisuride" ], "offsets": [ [ 83, 91 ] ] }, { "pmid": "12373423", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373423", "text": "The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature.", "type": "CHEMICAL", "entities": [ "dopamine", "lisuride", "lysergic acid diethylamide", "LSD", "5-HT", "lisuride" ], "offsets": [ [ 383, 391 ], [ 33, 41 ], [ 46, 72 ], [ 74, 77 ], [ 144, 148 ], [ 306, 314 ] ] }, { "pmid": "12373423", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373423", "text": "In drug discrimination studies, lisuride fully mimicked the 5-HT(1A) agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine.", "type": "CHEMICAL", "entities": [ "lisuride", "LY 293284", "LSD", "DOI", "(+)-amphetamine" ], "offsets": [ [ 32, 40 ], [ 77, 86 ], [ 119, 122 ], [ 127, 130 ], [ 161, 176 ] ] }, { "pmid": "12373423", "text": "Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT(1A) receptors.", "type": "CHEMICAL", "entities": [ "Lisuride" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12373423", "text": "Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT(1A) antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD.", "type": "CHEMICAL", "entities": [ "4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride", "5-HT", "lisuride", "LSD" ], "offsets": [ [ 12, 101 ], [ 169, 173 ], [ 205, 213 ], [ 275, 278 ] ] }, { "pmid": "12373423", "text": "Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT(1A) agonist LY 293284.", "type": "CHEMICAL", "entities": [ "LY 293284" ], "offsets": [ [ 126, 135 ] ] }, { "pmid": "12373423", "text": "The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.", "type": "CHEMICAL", "entities": [ "lisuride", "ketanserin", "haloperidol" ], "offsets": [ [ 26, 34 ], [ 87, 97 ], [ 101, 112 ] ] }, { "pmid": "12373423", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373423", "text": "We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT(1A) receptors.", "type": "CHEMICAL", "entities": [ "lisuride" ], "offsets": [ [ 65, 73 ] ] }, { "pmid": "12183670", "text": "Bupropion inhibits nicotine-evoked", "type": "CHEMICAL", "entities": [ "Bupropion", "nicotine" ], "offsets": [ [ 0, 9 ], [ 19, 27 ] ] }, { "pmid": "12183670", "text": "[(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine.\nBupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively).", "type": "CHEMICAL", "entities": [ "Bupropion", "dopamine", "norepinephrine", "[(3)H]norepinephrine", "(3)H", "[(3)H]dopamine" ], "offsets": [ [ 139, 148 ], [ 218, 226 ], [ 231, 245 ], [ 117, 137 ], [ 1, 5 ], [ 55, 69 ] ] }, { "pmid": "12183670", "text": "Recently, bupropion has been reported to noncompetitively inhibit alpha3beta2, alpha3beta4, and alpha4beta2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines.", "type": "CHEMICAL", "entities": [ "bupropion", "nicotinic acetylcholine" ], "offsets": [ [ 10, 19 ], [ 108, 131 ] ] }, { "pmid": "12183670", "text": "The present study evaluated bupropion-induced inhibition of native alpha3beta2* and alpha3beta4* nAChRs using functional neurotransmitter release assays, nicotine-evoked [(3)H]overflow from superfused rat striatal slices preloaded with [(3)H]dopamine ([(3)H]DA), and nicotine-evoked [(3)H]overflow from hippocampal slices preloaded with [(3)H]norepinephrine ([(3)H]NE).", "type": "CHEMICAL", "entities": [ "bupropion", "nicotine", "(3)H", "[(3)H]dopamine", "[(3)H]DA", "nicotine", "(3)H", "[(3)H]norepinephrine", "[(3)H]NE" ], "offsets": [ [ 28, 37 ], [ 154, 162 ], [ 171, 175 ], [ 236, 250 ], [ 252, 260 ], [ 267, 275 ], [ 284, 288 ], [ 337, 357 ], [ 359, 367 ] ] }, { "pmid": "12183670", "text": "The mechanism of inhibition was evaluated using Schild analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12183670", "text": "To eliminate the interaction of bupropion with DAT or NET, nomifensine or desipramine, respectively, was included in the superfusion buffer.", "type": "CHEMICAL", "entities": [ "bupropion", "nomifensine", "desipramine" ], "offsets": [ [ 32, 41 ], [ 59, 70 ], [ 74, 85 ] ] }, { "pmid": "12183670", "text": "A high bupropion concentration (100 microM) elicited intrinsic activity in the [(3)H]DA release assay.", "type": "CHEMICAL", "entities": [ "[(3)H]DA", "bupropion" ], "offsets": [ [ 79, 87 ], [ 7, 16 ] ] }, { "pmid": "12183670", "text": "However, none of the concentrations (1 nM-100 microM) examined evoked [(3)H]NE overflow and, thus, were without intrinsic activity in this assay.", "type": "CHEMICAL", "entities": [ "[(3)H]NE" ], "offsets": [ [ 70, 78 ] ] }, { "pmid": "12183670", "text": "Moreover, bupropion inhibited both nicotine-evoked [(3)H]DA overflow (IC(50) = 1.27 microM) and nicotine-evoked [(3)H]NE overflow (IC(50) = 323 nM) at bupropion concentrations well below those eliciting intrinsic activity.", "type": "CHEMICAL", "entities": [ "bupropion", "nicotine", "[(3)H]DA", "nicotine", "[(3)H]NE", "bupropion" ], "offsets": [ [ 10, 19 ], [ 35, 43 ], [ 51, 59 ], [ 96, 104 ], [ 112, 120 ], [ 151, 160 ] ] }, { "pmid": "12183670", "text": "Results from Schild analyses suggest that bupropion competitively inhibits nicotine-evoked [(3)H]DA overflow, whereas evidence for receptor reserve was obtained upon assessment of bupropion inhibition of nicotine-evoked [(3)H]NE overflow.", "type": "CHEMICAL", "entities": [ "bupropion", "nicotine", "[(3)H]DA", "bupropion", "nicotine", "[(3)H]NE" ], "offsets": [ [ 42, 51 ], [ 75, 83 ], [ 91, 99 ], [ 180, 189 ], [ 204, 212 ], [ 220, 228 ] ] }, { "pmid": "12183670", "text": "Thus, bupropion acts as an antagonist at alpha3beta2* and alpha3beta4* nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 6, 15 ] ] }, { "pmid": "12183670", "text": "The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "23085435", "text": "Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway.\n", "type": "CHEMICAL", "entities": [ "Nitrogen", "bisphosphonates" ], "offsets": [ [ 0, 8 ], [ 20, 35 ] ] }, { "pmid": "23085435", "text": "Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins.", "type": "CHEMICAL", "entities": [ "Nitrogen", "bisphosphonates", "N", "BPs" ], "offsets": [ [ 0, 8 ], [ 20, 35 ], [ 37, 38 ], [ 39, 42 ] ] }, { "pmid": "23085435", "text": "However, the details of the apoptosis-inducing mechanism remain obscure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085435", "text": "The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis.", "type": "CHEMICAL", "entities": [ "N", "BPs", "geranylgeranyl pyrophosphate", "GGPP" ], "offsets": [ [ 60, 61 ], [ 62, 65 ], [ 196, 224 ], [ 226, 230 ] ] }, { "pmid": "23085435", "text": "Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression.", "type": "CHEMICAL", "entities": [ "N", "BPs" ], "offsets": [ [ 13, 14 ], [ 15, 18 ] ] }, { "pmid": "23085435", "text": "The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways.", "type": "CHEMICAL", "entities": [ "N", "BPs" ], "offsets": [ [ 35, 36 ], [ 37, 40 ] ] }, { "pmid": "23085435", "text": "The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors.", "type": "CHEMICAL", "entities": [ "N", "BPs" ], "offsets": [ [ 20, 21 ], [ 22, 25 ] ] }, { "pmid": "23085435", "text": "This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 72, 73 ] ] }, { "pmid": "23600800", "text": "CASK is a new intracellular modulator of P2X3 receptors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of painful stimuli and are modulated by extracellular algogenic substances, via changes in the receptor phosphorylation state.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23600800", "text": "The present study investigated the role of calcium/calmodulin-dependent serine protein kinase CASK in interacting and controlling P2X3 receptor expression and function in mouse trigeminal ganglia.", "type": "CHEMICAL", "entities": [ "calcium", "serine" ], "offsets": [ [ 43, 50 ], [ 72, 78 ] ] }, { "pmid": "23600800", "text": "Most ganglion neurons in situ or in culture co-expressed P2X3 and CASK.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "CASK was immunoprecipitated with P2X3 receptors from trigeminal ganglia and from P2X3/CASK-cotransfected HEK cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "Recombinant P2X3/CASK expression in HEK cells increased serine phosphorylation of P2X3 receptors, typically associated with receptor upregulation.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 56, 62 ] ] }, { "pmid": "23600800", "text": "CASK deletion mutants also enhanced P2X3 subunit expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "After silencing CASK, cell surface P2X3 receptor expression was decreased, which is consistent with depressed P2X3 currents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "The reduction of P2X3 expression levels was reversed by the proteasomal inhibitor MG-132.", "type": "CHEMICAL", "entities": [ "MG-132" ], "offsets": [ [ 82, 88 ] ] }, { "pmid": "23600800", "text": "Moreover, neuronal CASK/P2X3 interaction was upregulated by NGF signaling and downregulated by P2X3 agonist-induced desensitization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "These data suggest a novel interaction between CASK and P2X3 receptors with positive outcome for receptor stability and function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "As CASK-mediated control of P2X3 receptors was dependent on the receptor activation state, CASK represents an intracellular gateway to regulate purinergic nociceptive signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "This article is protected by copyright.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23600800", "text": "All rights reserved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20104269", "text": "Bile acids induce cdx2 expression through the farnesoid x receptor in gastric epithelial cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20104269", "text": "Clinical and experimental studies showed that the reflux of bile into the stomach contributes to the induction of intestinal metaplasia of the stomach and gastric carcinogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20104269", "text": "Caudal-type homeobox 2 (Cdx2) plays a key role in the exhibition of intestinal phenotypes by regulating the expression of intestine-specific genes such as goblet-specific gene mucin 2 (MUC2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20104269", "text": "We investigated the involvement of the farnesoid X receptor (FXR), a nuclear receptor for bile acids, in the chenodeoxycholic acid (CDCA)-induced expression of Cdx2 and MUC2 in normal rat gastric epithelial cells (RGM-1 cells).", "type": "CHEMICAL", "entities": [ "chenodeoxycholic acid", "CDCA" ], "offsets": [ [ 109, 130 ], [ 132, 136 ] ] }, { "pmid": "20104269", "text": "RGM-1 cells were treated with CDCA or GW4064, an FXR agonist, in the presence or absence of guggulsterone, an FXR antagonist.", "type": "CHEMICAL", "entities": [ "CDCA", "GW4064", "guggulsterone" ], "offsets": [ [ 30, 34 ], [ 38, 44 ], [ 92, 105 ] ] }, { "pmid": "20104269", "text": "CDCA induced dose-dependent expression of Cdx2 and MUC2 at both the mRNA and protein levels.", "type": "CHEMICAL", "entities": [ "CDCA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "20104269", "text": "The maximum stimulation of Cdx2 and MUC2 mRNA induced by CDCA was observed at 3 h and by 6 h, respectively.", "type": "CHEMICAL", "entities": [ "CDCA" ], "offsets": [ [ 57, 61 ] ] }, { "pmid": "20104269", "text": "GW4064 also induced expression of these molecules.", "type": "CHEMICAL", "entities": [ "GW4064" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "20104269", "text": "The effects of CDCA and GW4064 on expression of Cdx2 and MUC2 were abolished by guggulsterone.", "type": "CHEMICAL", "entities": [ "GW4064", "guggulsterone", "CDCA" ], "offsets": [ [ 24, 30 ], [ 80, 93 ], [ 15, 19 ] ] }, { "pmid": "20104269", "text": "These findings suggest that bile acids may induce gastric intestinal metaplasia and carcinogenesis through the FXR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12213053", "text": "Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.\n", "type": "CHEMICAL", "entities": [ "Mazindol", "cocaine", "dopamine" ], "offsets": [ [ 0, 8 ], [ 50, 57 ], [ 78, 86 ] ] }, { "pmid": "12213053", "text": "A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined.", "type": "CHEMICAL", "entities": [ "mazindol", "aryl", "benzo", "methoxy", "alkyl", "hydroxyl", "homomazindol", "dopamine" ], "offsets": [ [ 12, 20 ], [ 139, 143 ], [ 158, 163 ], [ 186, 193 ], [ 199, 204 ], [ 226, 234 ], [ 29, 41 ], [ 295, 303 ] ] }, { "pmid": "12213053", "text": "Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells.", "type": "CHEMICAL", "entities": [ "DA", "5-HT", "NE", "[(125)I] RTI-55" ], "offsets": [ [ 82, 84 ], [ 86, 90 ], [ 96, 98 ], [ 122, 137 ] ] }, { "pmid": "12213053", "text": "Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells.", "type": "CHEMICAL", "entities": [ "Mazindane", "5-H", "5-OH", "mazindol" ], "offsets": [ [ 0, 9 ], [ 54, 57 ], [ 62, 66 ], [ 71, 79 ] ] }, { "pmid": "12213053", "text": "The 4',7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K(i) = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38).", "type": "CHEMICAL", "entities": [ "4',7,8-trichloro", "mazindol" ], "offsets": [ [ 4, 20 ], [ 38, 46 ] ] }, { "pmid": "12213053", "text": "Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16547651", "text": "Herbicidal inhibitors of amino acid biosynthesis and herbicide-tolerant crops.\n", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 25, 35 ] ] }, { "pmid": "16547651", "text": "Acetohydroxyacid synthase (AHAS) inhibitors interfere with branched-chain amino acid biosynthesis by inhibiting AHAS.", "type": "CHEMICAL", "entities": [ "Acetohydroxyacid", "branched-chain amino acid" ], "offsets": [ [ 0, 16 ], [ 59, 84 ] ] }, { "pmid": "16547651", "text": "Glyphosate affects aromatic amino acid biosynthesis by inhibiting 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).", "type": "CHEMICAL", "entities": [ "Glyphosate", "aromatic amino acid", "5-enolpyruvylshikimate-3-phosphate" ], "offsets": [ [ 0, 10 ], [ 19, 38 ], [ 66, 100 ] ] }, { "pmid": "16547651", "text": "Glufosinate inhibits glutamine synthetase and blocks biosynthesis of glutamine.", "type": "CHEMICAL", "entities": [ "Glufosinate", "glutamine", "glutamine" ], "offsets": [ [ 0, 11 ], [ 21, 30 ], [ 69, 78 ] ] }, { "pmid": "16547651", "text": "AHAS gene variants that confer tolerance to AHAS inhibitors have been discovered in plants through selection or mutagenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16547651", "text": "Imidazolinone-tolerant crops have been commercialized based on these AHAS gene variants.", "type": "CHEMICAL", "entities": [ "Imidazolinone" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "16547651", "text": "A modified maize EPSPS gene and CP4-EPSPS gene from Agrobacterium sp. have been used to transform plants for target-based tolerance to glyphosate.", "type": "CHEMICAL", "entities": [ "glyphosate" ], "offsets": [ [ 135, 145 ] ] }, { "pmid": "16547651", "text": "A gox gene isolated from Ochrobactrum anthropi has also been employed to encode glyphosate oxidoreductase to detoxify glyphosate in plants.", "type": "CHEMICAL", "entities": [ "glyphosate", "glyphosate" ], "offsets": [ [ 80, 90 ], [ 118, 128 ] ] }, { "pmid": "16547651", "text": "Glyphosate-tolerant crops with EPSPS transgene alone or both EPSPS and gox transgenes have been commercialized.", "type": "CHEMICAL", "entities": [ "Glyphosate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16547651", "text": "Similarly, bar and pat genes isolated from Streptomyces hygroscopicus and S. viridochromogenes, respectively, have been inserted into plants to encode phosphinothricin N-acetyltransferase to detoxify glufosinate.", "type": "CHEMICAL", "entities": [ "phosphinothricin", "N", "glufosinate" ], "offsets": [ [ 151, 167 ], [ 168, 169 ], [ 200, 211 ] ] }, { "pmid": "16547651", "text": "Glufosinate-tolerant crops have been commercialized using one of these two transgenes.", "type": "CHEMICAL", "entities": [ "Glufosinate" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23579178", "text": "Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or With Metformin in Type 2 Diabetes: A double-tracer study.\n", "type": "CHEMICAL", "entities": [ "Metformin", "Glucose", "Sitagliptin" ], "offsets": [ [ 103, 112 ], [ 14, 21 ], [ 67, 78 ] ] }, { "pmid": "23579178", "text": "OBJECTIVETo assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).RESEARCH DESIGN AND METHODSWe randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [(14)C]glucose to calculate glucose kinetics.", "type": "CHEMICAL", "entities": [ "glucose", "MTT", "[(14)C]glucose", "glucose", "sitagliptin", "metformin" ], "offsets": [ [ 19, 26 ], [ 322, 325 ], [ 332, 346 ], [ 360, 367 ], [ 50, 61 ], [ 67, 76 ] ] }, { "pmid": "23579178", "text": "Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) was measured.", "type": "CHEMICAL", "entities": [ "glucose", "C" ], "offsets": [ [ 15, 22 ], [ 54, 55 ] ] }, { "pmid": "23579178", "text": "RESULTSFPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT PG decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01].", "type": "CHEMICAL", "entities": [ "MTT" ], "offsets": [ [ 98, 101 ] ] }, { "pmid": "23579178", "text": "The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (∼65-75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%.", "type": "CHEMICAL", "entities": [ "MTT" ], "offsets": [ [ 18, 21 ] ] }, { "pmid": "23579178", "text": "Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg ⋅ min, M", "type": "CHEMICAL", "entities": [ "MTT", "glucose" ], "offsets": [ [ 12, 15 ], [ 108, 115 ] ] }, { "pmid": "23579178", "text": "1.8 ± 0.2 mg/kg ⋅ min", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23579178", "text": "[both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg ⋅ min (P < 0.01 vs. P).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23579178", "text": "Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05).CONCLUSIONSM+S combined produce additive effects to 1) reduce FPG and postmeal PG, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23423713", "text": "Modulation of cytochrome P450 1 (Cyp1) by vanadium in hepatic tissue and isolated hepatocyte of C57BL/6 mice.\n", "type": "CHEMICAL", "entities": [ "vanadium" ], "offsets": [ [ 42, 50 ] ] }, { "pmid": "23423713", "text": "The objective of the current study was to investigate the effect of vanadium (V(5+)) on Cyp1 expression and activity in C57BL/6 mice liver and isolated hepatocytes.", "type": "CHEMICAL", "entities": [ "vanadium", "V(5+)" ], "offsets": [ [ 68, 76 ], [ 78, 83 ] ] }, { "pmid": "23423713", "text": "For this purpose, C57BL6 mice were injected intraperitoneally with V(5+) (5 mg/kg) in the absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 μg/kg) for 6 and 24 h.", "type": "CHEMICAL", "entities": [ "V(5+)", "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD" ], "offsets": [ [ 67, 72 ], [ 114, 149 ], [ 151, 155 ] ] }, { "pmid": "23423713", "text": "Furthermore, isolated hepatocytes from C57BL6 mice were treated with V(5+) (5, 10, and 20 μM) in the absence and presence of TCDD (1 nM) for 3, 6, 12, and 24 h.", "type": "CHEMICAL", "entities": [ "V(5+)", "TCDD" ], "offsets": [ [ 65, 70 ], [ 121, 125 ] ] }, { "pmid": "23423713", "text": "In vivo, V(5+) alone did not significantly alter Cyp1a1, Cyp1a2, or Cyp1b1 mRNA, protein, or catalytic activity levels.", "type": "CHEMICAL", "entities": [ "V(5+)" ], "offsets": [ [ 2, 7 ] ] }, { "pmid": "23423713", "text": "Upon co-exposure to V(5+) and TCDD, V(5+) significantly potentiated the TCDD-mediated induction of the Cyp1a1, Cyp1a2, and Cyp1b1 mRNA, protein, and catalytic activity levels at 24 h.", "type": "CHEMICAL", "entities": [ "V(5+)", "TCDD", "V(5+)", "TCDD" ], "offsets": [ [ 13, 18 ], [ 23, 27 ], [ 29, 34 ], [ 65, 69 ] ] }, { "pmid": "23423713", "text": "In vitro, V(5+) decreased the TCDD-mediated induction of Cyp1a1 mRNA, protein, and catalytic activity levels.", "type": "CHEMICAL", "entities": [ "V(5+)", "TCDD" ], "offsets": [ [ 2, 7 ], [ 22, 26 ] ] }, { "pmid": "23423713", "text": "Furthermore, V(5+) significantly inhibited the TCDD-induced AhR-dependent luciferase activity.", "type": "CHEMICAL", "entities": [ "V(5+)", "V(5+)", "TCDD" ], "offsets": [ [ 87, 92 ], [ 5, 10 ], [ 39, 43 ] ] }, { "pmid": "23423713", "text": "V(5+) also increased serum hemoglobin (Hb) levels in animals treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone or in the presence of TCDD, there was an increase in the AhR-dependent luciferase activity.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 146, 150 ] ] }, { "pmid": "23423713", "text": "When isolated hepatocytes were treated for 2 h with V(5+) in the presence of TCDD, followed by replacement of the medium with new medium containing Hb, there was further potentiation to the TCDD-mediated effect.", "type": "CHEMICAL", "entities": [ "V(5+)", "TCDD", "TCDD" ], "offsets": [ [ 43, 48 ], [ 68, 72 ], [ 181, 185 ] ] }, { "pmid": "23423713", "text": "The present study demonstrates that there is a differential modulation of Cyp1a1 by V(5+) in C57BL/6 mice livers and isolated hepatocytes and demonstrates Hb as an in vivo specific modulator.", "type": "CHEMICAL", "entities": [ "V(5+)" ], "offsets": [ [ 74, 79 ] ] }, { "pmid": "8600944", "text": "Glucocorticosteroids affect functions of airway- and blood-derived human T-cell clones, favoring the Th1 profile through two mechanisms.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8600944", "text": "Glucocorticosteroids (GCS) are beneficial in allergic asthma.", "type": "CHEMICAL", "entities": [ "GCS" ], "offsets": [ [ 22, 25 ] ] }, { "pmid": "8600944", "text": "GCS therapy results in reduced mRNA expression of interleukin-4 (IL-4) and IL-5 in cells from bronchoalveolar lavage (BAL) but not of IFN-gamma.", "type": "CHEMICAL", "entities": [ "GCS" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "8600944", "text": "In vitro studies with blood-derived T cells, however, show inhibition of all three cytokines by GCS.", "type": "CHEMICAL", "entities": [ "GCS" ], "offsets": [ [ 96, 99 ] ] }, { "pmid": "8600944", "text": "We studied the effects of GCS on T cells from BAL in vitro, namely Th0-, Th1, and Th2-like clones; and we compared BAL- with blood-derived clones.", "type": "CHEMICAL", "entities": [ "GCS" ], "offsets": [ [ 26, 29 ] ] }, { "pmid": "8600944", "text": "Dexamethasone (DEX) inhibited the anti-CD3-induced production of IL-4, IL-5 and IFN-gamma in all 20 clones tested.", "type": "CHEMICAL", "entities": [ "Dexamethasone", "DEX" ], "offsets": [ [ 0, 13 ], [ 15, 18 ] ] }, { "pmid": "8600944", "text": "IFN-gamma production was inhibited significantly less than IL-4 and IL-5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8600944", "text": "DEX enhanced the ratio IFN-gamma/IL-4 (mean +/- SEM: control, 28.7 +/- 17.6; with 10-7 M DEX, 55.0 +/- 27.5, P<0.005).", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "8600944", "text": "Interestingly, two categories of clones were distinguished based on the effects of GCS on IL-2 production and IL-2R alpha expression and proliferation; 1) In low IL-2 producers DEX blocked IL-2 production and decreased IL-2R alpha expression and proliferation; 2) In high IL-2 producers DEX inhibited IL-2 production partially and enhanced IL-2R alpha expression and proliferation.", "type": "CHEMICAL", "entities": [ "DEX", "GCS", "DEX" ], "offsets": [ [ 287, 290 ], [ 83, 86 ], [ 177, 180 ] ] }, { "pmid": "8600944", "text": "Anti-IL-2 and anti-IL2R alpha blocked the DEX-induced increase in proliferation.", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 42, 45 ] ] }, { "pmid": "8600944", "text": "High levels of added IL-2 induced the second type of response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8600944", "text": "In conclusion, the production of IL-4 and IL-5 by T-cell clones (derived either from BAL or blood) was more sensitive to inhibition by DEX than that of IFN-gamma, which may account for the therapeutic effects of glucocorticosteroids in patients with asthma.", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 135, 138 ] ] }, { "pmid": "8600944", "text": "The differential effects of DEX on the proliferation of high and low IL-2 producers in vitro may implicate a selective outgrowth of Th1-like T cells in vivo in patients treated with steroids.", "type": "CHEMICAL", "entities": [ "DEX", "steroids" ], "offsets": [ [ 28, 31 ], [ 182, 190 ] ] }, { "pmid": "23519392", "text": "Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mice.\n", "type": "CHEMICAL", "entities": [ "Pregnane", "Amprenavir" ], "offsets": [ [ 0, 8 ], [ 80, 90 ] ] }, { "pmid": "23519392", "text": "HIV protease inhibitors (PIs) have been used successfully in extending the lifespan of people infected with HIV.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23519392", "text": "The use of PIs has also been associated with dyslipidemia and an increased risk of cardiovascular disease but the underlying mechanisms remain elusive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23519392", "text": "Several PIs have been implicated to activate the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine.", "type": "CHEMICAL", "entities": [ "pregnane" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "23519392", "text": "Recent studies indicate that PXR may also play an important role in the regulation of lipid homeostasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23519392", "text": "In the present study, we identified amprenavir, a widely used HIV PI, as a potent PXR-selective agonist.", "type": "CHEMICAL", "entities": [ "amprenavir" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "23519392", "text": "Computational docking studies combined with site-direct mutagenesis identified several key residues within the ligand binding pocket of PXR that constitute points of interaction with amprenavir.", "type": "CHEMICAL", "entities": [ "amprenavir" ], "offsets": [ [ 183, 193 ] ] }, { "pmid": "23519392", "text": "Amprenavir efficiently activated PXR and induced PXR target gene expression in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Amprenavir" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23519392", "text": "Short-term exposure to amprenavir significantly increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "amprenavir" ], "offsets": [ [ 71, 82 ], [ 123, 134 ], [ 23, 33 ] ] }, { "pmid": "23519392", "text": "Amprenavir-mediated PXR activation stimulated the expression of several key intestinal genes involved in lipid homeostasis.", "type": "CHEMICAL", "entities": [ "Amprenavir" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23519392", "text": "These findings provide critical mechanistic insight for understanding the impact of PIs on cardiovascular disease and demonstrate a potential role of PXR in mediating adverse effects of HIV PIs in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "Charge screening between anionic and cationic surfactants in ionic liquids.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "The aggregation and interfacial behavior of mixtures of anionic (sodium dodecylsulfate, SDS) and cationic (dodecylammonium bromide, DTAB) surfactants were investigated.", "type": "CHEMICAL", "entities": [ "dodecylammonium bromide", "DTAB", "sodium dodecylsulfate", "SDS" ], "offsets": [ [ 107, 130 ], [ 132, 136 ], [ 65, 86 ], [ 88, 91 ] ] }, { "pmid": "23419036", "text": "A room-temperature ionic liquid (IL) was explored as a solvent for the SDS/DTAB system and compared to water.", "type": "CHEMICAL", "entities": [ "SDS", "DTAB" ], "offsets": [ [ 71, 74 ], [ 75, 79 ] ] }, { "pmid": "23419036", "text": "The critical micelle concentration (cmc) and composition in mixed micelles were determined for both solvents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "Our experiments showed nearly ideal mixing of SDS/DTAB over the entire composition range and suggest that charge screening is prominent in ILs.", "type": "CHEMICAL", "entities": [ "SDS", "DTAB" ], "offsets": [ [ 46, 49 ], [ 50, 54 ] ] }, { "pmid": "23419036", "text": "This behavior is in sharp contrast to the strong electrostatic attraction and a multiphase composition gap in water.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "Two models by Clint and Rubingh, which describe ideal and nonideal micellar behavior, respectively, are discussed on the basis of our results.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "According to Rubingh's model, the composition of mixed micelles is gradually changing with the bulk composition in ILs but tends to be a 1:1 ratio in water.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419036", "text": "The results here are further support of the strong charge screening in ionic liquids.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22718571", "text": "Anti-diabetic Activity of Swertiamarin is due to an Active Metabolite, Gentianine, that Upregulates PPAR-γ Gene Expression in 3T3-L1 cells.\n", "type": "CHEMICAL", "entities": [ "Swertiamarin", "Gentianine" ], "offsets": [ [ 26, 38 ], [ 71, 81 ] ] }, { "pmid": "22718571", "text": "We have previously shown the anti-diabetic effects of swertiamarin; however, pharmacokinetic analysis showed that swertiamarin had a plasma half-life of 1.3 h. Gentianine is an active metabolite of swertiamarin that possesses a pharmacophoric moiety.", "type": "CHEMICAL", "entities": [ "swertiamarin", "Gentianine", "swertiamarin", "swertiamarin" ], "offsets": [ [ 113, 125 ], [ 159, 169 ], [ 197, 209 ], [ 53, 65 ] ] }, { "pmid": "22718571", "text": "The aim of this study was to explore the possibility whether the anti-diabetic effect of swertiamarin is due to gentianine.", "type": "CHEMICAL", "entities": [ "swertiamarin", "gentianine" ], "offsets": [ [ 88, 100 ], [ 111, 121 ] ] }, { "pmid": "22718571", "text": "Swertiamarin treatment had no significant effect on adipogenesis, or the mRNA expression of PPAR-γ and GLUT-4; however, there was a significant increase in the mRNA expression of adiponectin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22718571", "text": "On the other hand, treatment with gentianine significantly increased adipogenesis, which was associated with a significant increase in the mRNA expression of PPAR-γ, GLUT-4 and adiponectin.", "type": "CHEMICAL", "entities": [ "gentianine" ], "offsets": [ [ 32, 42 ] ] }, { "pmid": "22718571", "text": "These findings suggest, for the first time, that the anti-diabetic effect of swertiamarin is due to gentianine, an active metabolite of swertiamarin.", "type": "CHEMICAL", "entities": [ "swertiamarin", "gentianine", "swertiamarin" ], "offsets": [ [ 74, 86 ], [ 97, 107 ], [ 133, 145 ] ] }, { "pmid": "22718571", "text": "Copyright © 2012 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "[Brugada syndrome].\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "In 1992 we described a new syndrome consisting of syncopal episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram displaying a pattern resembling right bundle branch block with an ST segment elevation in leads V1 to V3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "In 1998 it was described that the disease is genetically determined with an autosomal dominant pattern of transmission.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "Three different mutations have been identified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "All three mutations affect the structure and the function of the sodium channel SCN5A. Two mutations result in total loss of function of the sodium channel.", "type": "CHEMICAL", "entities": [ "sodium", "sodium" ], "offsets": [ [ 65, 71 ], [ 141, 147 ] ] }, { "pmid": "10443304", "text": "The other mutation results in acceleration of the recovery of the sodium channel from inactivation.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 66, 72 ] ] }, { "pmid": "10443304", "text": "The disease causes 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "Up to 50% of the yearly sudden deaths in patients with a normal heart might be caused by this syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "The diagnosis is easily made by means of the electrocardiogram (ECG).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "The presence of concealed and intermittent forms, however, makes the diagnosis difficult in some patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "The ECG can be modulated by changes in autonomic balance and the administration of antiarrhythmic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "Beta-adrenergic stimulation normalises the ECG, while i.v. ajmaline, flecainide or procainamide accentuate the ST segment elevation and are capable of unmasking concealed and intermittent forms of the disease.", "type": "CHEMICAL", "entities": [ "ajmaline", "flecainide", "procainamide" ], "offsets": [ [ 59, 67 ], [ 69, 79 ], [ 83, 95 ] ] }, { "pmid": "10443304", "text": "The prognosis is poor for patients who do not receive an implantable cardioverter-defibrillator.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10443304", "text": "Antiarrhythmic drugs like amiodarone or beta-blockers do not prevent sudden death in symptomatic or asymptomatic individuals.", "type": "CHEMICAL", "entities": [ "amiodarone" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "23261645", "text": "The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity.\n", "type": "CHEMICAL", "entities": [ "jaspamide" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "23261645", "text": "Jaspamide (jasplakinolide; NSC-613009) is a cyclodepsipeptide that has antitumor activity.", "type": "CHEMICAL", "entities": [ "Jaspamide", "jasplakinolide", "NSC-613009", "cyclodepsipeptide" ], "offsets": [ [ 0, 9 ], [ 11, 25 ], [ 27, 37 ], [ 44, 61 ] ] }, { "pmid": "23261645", "text": "A narrow margin of safety was observed between doses required for efficacy in mouse tumor models and doses that caused severe acute toxicity in rats and dogs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "We explored the hypothesis that the observed toxicity was due to cardiotoxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "Jaspamide was tested in a patch clamp assay to determine its effect on selected cardiac ion channels.", "type": "CHEMICAL", "entities": [ "Jaspamide" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23261645", "text": "Jaspamide (10 μM) inhibited Kv1.5 activity by 98.5%.", "type": "CHEMICAL", "entities": [ "Jaspamide" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23261645", "text": "Jaspamide also inhibited other channels including Cav1.2, Cav3.2, and HCN2; however, the Kv11.1 (hERG) channel was minimally affected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "Using spontaneously contracting human cardiomyocytes derived from induced pluripotent stem cells, effects on cardiomyocyte contraction and viability were also examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "Jaspamide (30 nM to 30 μM) decreased cardiomyocyte cell indices and beat amplitude, putative measurements of cell viability and cardiac contractility, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "Concentration-dependent increases in rhythmic beating rate were noted at ≤ 6 h of treatment, followed by dose-dependent decreases after 6 and 72 h exposure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261645", "text": "The toxic effects of jaspamide were compared with that of the known cardiotoxicant mitoxantrone, and confirmed by multiparameter fluorescence imaging analysis.", "type": "CHEMICAL", "entities": [ "jaspamide", "mitoxantrone" ], "offsets": [ [ 17, 26 ], [ 79, 91 ] ] }, { "pmid": "23261645", "text": "These results support the hypothesis that the toxicity observed in rats and dogs is due to toxic effects of jaspamide on cardiomyocytes.", "type": "CHEMICAL", "entities": [ "jaspamide" ], "offsets": [ [ 104, 113 ] ] }, { "pmid": "15732037", "text": "Carvedilol modulates the expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in a rat model of volume-overload heart failure.\n", "type": "CHEMICAL", "entities": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15732037", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "The use of beta-blockers has emerged as a beneficial treatment for congestive heart failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "However, the expression of HIF-1alpha in chronic heart failure resulting from volume overload and after treatment with beta-blocker is little known.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "METHODS AND RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "To test the hypothesis that HIF-1alpha plays a role in the failing myocardium because of volume overload, an aorta-caval shunt was created for 4 weeks in adult Sprague-Dawley rats to induce volume-overload heart failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Carvedilol at 50 mg/kg body weight per day after surgery was given.", "type": "CHEMICAL", "entities": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15732037", "text": "The heart weight and body weight ratio increased from 2.6 +/- 0.3 in the sham group to 3.9 +/- 0.7", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "(P < .001) in the shunt group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Left ventricular end-diastolic dimension increased from 6.5 +/- 0.5 mm to 8.7 +/- 0.6 mm (P < .001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Treatment with carvedilol in the shunt group reversed the heart weight and ventricular dimension to the baseline values.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "15732037", "text": "Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF), and brain natriuretic peptide (BNP) proteins were upregulated and nerve growth factor-beta (NGF-beta) downregulated in the shunt group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF, and BNP increased and mRNA of NGF-beta decreased in the shunt group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and NGF-beta to the baseline values.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "15732037", "text": "Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the shunt group and carvedilol again normalized the labeling.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 134, 144 ] ] }, { "pmid": "15732037", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "HIF-1alpha and VEGF mRNA and protein expression were upregulated in the rat model of volume-overload heart failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15732037", "text": "Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha and VEGF in the failing ventricular myocardium.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "17588737", "text": "Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds.\n", "type": "CHEMICAL", "entities": [ "phenolic" ], "offsets": [ [ 130, 138 ] ] }, { "pmid": "17588737", "text": "In this study, we investigated the alterations of the redox balance induced by the lipid fraction of oxLDL in Caco-2 intestinal cells, and the effects of tyrosol and protocatechuic acid, two dietary phenolic compounds.", "type": "CHEMICAL", "entities": [ "tyrosol", "protocatechuic acid", "phenolic" ], "offsets": [ [ 154, 161 ], [ 166, 185 ], [ 199, 207 ] ] }, { "pmid": "17588737", "text": "We found that oxidized lipids extracted from oxLDL (LipE) induced oxidative stress by determining, 6 h after treatment, ROS overproduction (about a 100% and a 43% increase of O*2 and H2O2 production, respectively, P<.05: LipE vs. control) and, 12 h after treatment, GSH depletion (about a 26% decrease, P<.05: LipE vs. control), and by impairing the activities of superoxide dismutase, catalase and glutathione peroxidase.", "type": "CHEMICAL", "entities": [ "O*2", "H2O2", "superoxide", "glutathione" ], "offsets": [ [ 175, 178 ], [ 183, 187 ], [ 364, 374 ], [ 399, 410 ] ] }, { "pmid": "17588737", "text": "In response to the induced oxidative stress, we observed significant overexpression of glutathione peroxidase (6 h after treatment: P<.05), glutathione reductase and gamma-glutamylcysteine synthetase (12 h after treatment: P<.05).", "type": "CHEMICAL", "entities": [ "glutathione", "glutathione", "gamma-glutamylcysteine" ], "offsets": [ [ 87, 98 ], [ 140, 151 ], [ 166, 188 ] ] }, { "pmid": "17588737", "text": "Notably, when GSH depletion occurred, p66Shc protein expression increased by about 300% with respect to control (P<.001; LipE vs. control).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588737", "text": "These effects were fully counteracted by dietary phenolics which inhibited ROS overproduction and GSH consumption, rendered the reactive transcription of glutathione-associated enzymes unnecessary and blocked the intracellular signals leading to the overexpression and rearrangement of p66Shc signalling molecule.", "type": "CHEMICAL", "entities": [ "phenolics", "glutathione" ], "offsets": [ [ 49, 58 ], [ 154, 165 ] ] }, { "pmid": "17588737", "text": "Altogether, these results suggest that the impairment of the antioxidant system hijacks intestinal cells towards an apoptotic-prone phenotype via the activation of p66Shc molecule.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588737", "text": "They also propose a reappraisal of dietary polyphenols as intestinal protecting agents, indicating the antiapoptotic effect as a further mechanism of action of these antioxidant compounds.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 43, 54 ] ] }, { "pmid": "17499824", "text": "Serine racemases from barley, Hordeum vulgare L., and other plant species represent a distinct eukaryotic group: gene cloning and recombinant protein characterization.\n", "type": "CHEMICAL", "entities": [ "Serine" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "17499824", "text": "Several d-amino acids have been identified in plants.", "type": "CHEMICAL", "entities": [ "d-amino acids" ], "offsets": [ [ 8, 21 ] ] }, { "pmid": "17499824", "text": "However, the biosynthetic pathway to them is unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17499824", "text": "In this study, we cloned and sequenced a cDNA encoding a serine racemase from barley which contained an open reading frame encoding 337 amino acid residues.", "type": "CHEMICAL", "entities": [ "serine", "amino acid" ], "offsets": [ [ 57, 63 ], [ 136, 146 ] ] }, { "pmid": "17499824", "text": "The deduced amino acid sequence showed significant identity to plant and mammalian serine racemases and contained conserved pyridoxal 5-phosphate (PLP)-binding lysine and PLP-interacting amino acid residues.", "type": "CHEMICAL", "entities": [ "amino acid", "serine", "pyridoxal 5-phosphate", "PLP", "lysine", "PLP", "amino acid" ], "offsets": [ [ 12, 22 ], [ 83, 89 ], [ 124, 145 ], [ 147, 150 ], [ 160, 166 ], [ 171, 174 ], [ 187, 197 ] ] }, { "pmid": "17499824", "text": "The purified gene product catalyzed not only racemization of serine but also dehydration of serine to pyruvate.", "type": "CHEMICAL", "entities": [ "serine", "serine", "pyruvate" ], "offsets": [ [ 61, 67 ], [ 92, 98 ], [ 102, 110 ] ] }, { "pmid": "17499824", "text": "The enzyme requires PLP and divalent cations such as Ca(2+), Mg(2+), or Mn(2+), but not ATP, whereas mammalian serine racemase activity is increased by ATP.", "type": "CHEMICAL", "entities": [ "PLP", "Ca(2+)", "Mg(2+)", "Mn(2+)", "ATP", "serine", "ATP" ], "offsets": [ [ 20, 23 ], [ 53, 59 ], [ 61, 67 ], [ 72, 78 ], [ 88, 91 ], [ 111, 117 ], [ 152, 155 ] ] }, { "pmid": "17499824", "text": "In addition to the results regarding the effect of ATP on enzyme activity and the phylogenetic analysis of eukaryotic serine racemases, the antiserum against Arabidopsis serine racemase did not form a precipitate with barley and rice serine racemases.", "type": "CHEMICAL", "entities": [ "ATP", "serine", "serine", "serine" ], "offsets": [ [ 51, 54 ], [ 118, 124 ], [ 170, 176 ], [ 234, 240 ] ] }, { "pmid": "17499824", "text": "This suggests that plant serine racemases represent a distinct group in the eukaryotic serine racemase family and can be clustered into monocot and dicot types.", "type": "CHEMICAL", "entities": [ "serine", "serine" ], "offsets": [ [ 25, 31 ], [ 87, 93 ] ] }, { "pmid": "17308037", "text": "Characterization of renal ecto-phosphodiesterase.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17308037", "text": "In kidneys, stimulation of adenylyl cyclase causes egress of cAMP, conversion of cAMP to AMP by ecto-phosphodiesterase, and metabolism of AMP to adenosine by ecto-5'-nucleotidase.", "type": "CHEMICAL", "entities": [ "AMP", "adenosine", "cAMP", "cAMP", "AMP" ], "offsets": [ [ 138, 141 ], [ 145, 154 ], [ 61, 65 ], [ 81, 85 ], [ 89, 92 ] ] }, { "pmid": "17308037", "text": "Although much is known about ecto-5'-nucleotidase, the renal ecto-phosphodiesterase remains uncharacterized.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17308037", "text": "We administered cAMP (10 microM in the perfusate) to 12 different groups of perfused kidneys.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 16, 20 ] ] }, { "pmid": "17308037", "text": "AMP was measured in perfusate using ion trap mass spectrometry.", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "17308037", "text": "In control kidneys (n=19), basal renal secretion rate of AMP was 0.49+/-0.08 and increased to 3.0+/-0.2 nmol AMP/g kidney weight/min during administration of cAMP.", "type": "CHEMICAL", "entities": [ "AMP", "AMP", "cAMP" ], "offsets": [ [ 57, 60 ], [ 109, 112 ], [ 158, 162 ] ] }, { "pmid": "17308037", "text": "A broad-spectrum phosphodiesterase (PDE) inhibitor (1,3-isobutyl-1-methylxanthine, 300 microM, n=6) and an ecto-phosphodiesterase inhibitor (1,3-dipropyl-8-p-sulfophenylxanthine, 1 mM, n=6) significantly attenuated cAMP-induced AMP secretion by 60 and 74%, respectively.", "type": "CHEMICAL", "entities": [ "1,3-isobutyl-1-methylxanthine", "1,3-dipropyl-8-p-sulfophenylxanthine", "cAMP", "AMP" ], "offsets": [ [ 52, 81 ], [ 141, 177 ], [ 215, 219 ], [ 228, 231 ] ] }, { "pmid": "17308037", "text": "Blockade of PDE1 (8-methoxymethyl-3-isobutyl-1-methylxanthine, 100 microM), PDE2 [erythro-9-(2-hydroxy-3-nonyl)adenine, 30 microM], PDE3 (milrinone, 10 microM; cGMP, 10 microM), PDE4 (Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one], 100 microM), PDE5 and PDE6 (zaprinast, 30 microM), and PDE7 [BRL-50481 (5-nitro-2,N,N-trimethylbenzenesulfonamide), 10 microM] did not alter renal ecto-phosphodiesterase activity.", "type": "CHEMICAL", "entities": [ "milrinone", "4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one", "zaprinast", "BRL-50481", "5-nitro-2,N,N-trimethylbenzenesulfonamide", "8-methoxymethyl-3-isobutyl-1-methylxanthine", "erythro-9-(2-hydroxy-3-nonyl)adenine" ], "offsets": [ [ 138, 147 ], [ 196, 242 ], [ 273, 282 ], [ 306, 315 ], [ 317, 358 ], [ 18, 61 ], [ 82, 118 ] ] }, { "pmid": "17308037", "text": "Administration of a concentration (100 microM) of dipyridamole that blocks PDE8 inhibited ecto-phosphodiesterase activity (by 44%).", "type": "CHEMICAL", "entities": [ "dipyridamole" ], "offsets": [ [ 50, 62 ] ] }, { "pmid": "17308037", "text": "However, a lower concentration of dipyridamole (3 microM) that blocks PDE9, PDE10, and PDE11, but not PDE8, did not inhibit ecto-phosphodiesterase activity.", "type": "CHEMICAL", "entities": [ "dipyridamole" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "17308037", "text": "These data support the conclusion that renal ecto-phosphodiesterase activity is not mediated by PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE9, PDE10, or PDE11 and is inhibited by high concentrations of dipyridamole.", "type": "CHEMICAL", "entities": [ "dipyridamole" ], "offsets": [ [ 203, 215 ] ] }, { "pmid": "17308037", "text": "Ecto-phosphodiesterase has some pharmacological characteristics similar to PDE8.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "Hyperglycemia slows embryonic growth and suppresses cell cycle via cyclin D1 and p21.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "In pregnant women, the diabetic condition results in a three- to fivefold increased risk for fetal cardiac malformations as a result of elevated glucose concentrations and the resultant osmotic stress in the developing embryo and fetus.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 145, 152 ] ] }, { "pmid": "23193186", "text": "Heart development before septation in the chick embryo was studied under two hyperglycemic conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "Pulsed hyperglycemia induced by daily administration of glucose during 3 days of development caused daily spikes in plasma glucose concentration.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 56, 63 ], [ 123, 130 ] ] }, { "pmid": "23193186", "text": "In a second model, sustained hyperglycemia was induced with a single injection of glucose into the yolk on day 0.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "23193186", "text": "The sustained model raised the average plasma glucose concentration from 70 mg/dL to 180 mg/dL and led to decreased gene expression of glucose transporter GLUT1.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 46, 53 ], [ 135, 142 ] ] }, { "pmid": "23193186", "text": "Both models of hyperglycemia reduced embryo size, increased mortality, and delayed development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "Within the heart outflow tract, reduced proliferation of myocardial and endocardial cells resulted from the sustained hyperglycemia and hyperosmolarity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "The cell cycle inhibitor p21 was significantly increased, whereas cyclin D1, a cell cycle promoter, decreased in sustained hyperglycemia compared with controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "The evidence suggests that hyperglycemia-induced developmental delays are associated with slowed cell cycle progression, leading to reduced cellular proliferation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23193186", "text": "The suppression of critical developmental steps may underlie the cardiac defects observed during late gestation under hyperglycemic conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19389876", "text": "Effect of ketoconazole on the pharmacokinetic profile of ambrisentan.\n", "type": "CHEMICAL", "entities": [ "ketoconazole", "ambrisentan" ], "offsets": [ [ 10, 22 ], [ 57, 68 ] ] }, { "pmid": "19389876", "text": "Ambrisentan is an endothelin type A (ET(A))-selective receptor antagonist that is metabolized primarily by glucuronidation but also undergoes oxidative metabolism by CYP3A4.", "type": "CHEMICAL", "entities": [ "Ambrisentan" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19389876", "text": "The potential for ketoconazole, the archetypal strong inhibitor of CYP3A4, to alter the pharmacokinetic profile of ambrisentan and its oxidative metabolite, 4-hydroxymethyl ambrisentan, was assessed in an open-label, nonrandomized, 2-period, single-sequence study in 16 healthy men.", "type": "CHEMICAL", "entities": [ "ketoconazole", "ambrisentan", "4-hydroxymethyl ambrisentan" ], "offsets": [ [ 18, 30 ], [ 115, 126 ], [ 157, 184 ] ] }, { "pmid": "19389876", "text": "Participants received a single dose of ambrisentan 10 mg alone and after 4 days of ketoconazole 400 mg administered once daily.", "type": "CHEMICAL", "entities": [ "ambrisentan", "ketoconazole" ], "offsets": [ [ 39, 50 ], [ 83, 95 ] ] }, { "pmid": "19389876", "text": "In the presence of multiple doses of ketoconazole, single-dose ambrisentan AUC(0-infinity) estimate was increased by 35.3%, whereas C(max) was increased by 20.0%.", "type": "CHEMICAL", "entities": [ "ketoconazole", "ambrisentan" ], "offsets": [ [ 37, 49 ], [ 63, 74 ] ] }, { "pmid": "19389876", "text": "For the 4-hydroxymethyl ambrisentan metabolite, AUC(0-infinity) estimate was decreased by 4.0%, whereas C(max) was decreased by 16.5%.", "type": "CHEMICAL", "entities": [ "4-hydroxymethyl ambrisentan" ], "offsets": [ [ 8, 35 ] ] }, { "pmid": "19389876", "text": "Concomitant administration of ambrisentan and ketoconazole was well tolerated.", "type": "CHEMICAL", "entities": [ "ambrisentan", "ketoconazole" ], "offsets": [ [ 30, 41 ], [ 46, 58 ] ] }, { "pmid": "19389876", "text": "In summary, ketoconazole had no clinically significant effect on the pharmacokinetics or safety profile of ambrisentan; therefore, no changes in ambrisentan dose should be necessary when the drug is administered concomitantly with known CYP3A4 inhibitors.", "type": "CHEMICAL", "entities": [ "ambrisentan", "ambrisentan", "ketoconazole" ], "offsets": [ [ 107, 118 ], [ 145, 156 ], [ 12, 24 ] ] }, { "pmid": "23606523", "text": "A Model-Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti-Diabetic Treatment.\n", "type": "CHEMICAL", "entities": [ "Glucose" ], "offsets": [ [ 72, 79 ] ] }, { "pmid": "23606523", "text": "Predicting late phase outcomes from early-phase findings can help inform decisions in drug development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "If the measurements in early-phase differ from those in late phase, forecasting is more challenging.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 116, 123 ] ] }, { "pmid": "23606523", "text": "Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av ).", "type": "CHEMICAL", "entities": [ "glucose", "glucose", "glucose" ], "offsets": [ [ 57, 64 ], [ 132, 139 ], [ 225, 232 ] ] }, { "pmid": "23606523", "text": "Output from the IGI model was used as input to the IGRH model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23606523", "text": "We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 147, 154 ] ] }, { "pmid": "23414340", "text": "Reduction of dimethylarsinic acid to the highly toxic dimethylarsinous acid by rats and rat liver cytosol.\n", "type": "CHEMICAL", "entities": [ "dimethylarsinic acid", "dimethylarsinous acid" ], "offsets": [ [ 13, 33 ], [ 54, 75 ] ] }, { "pmid": "23414340", "text": "Dimethylarsinic acid (DMAs(V)), the major urinary metabolite of inorganic arsenic, is weakly cytotoxic, whereas its reduced form, dimethylarsinous acid (DMAs(III)), is highly toxic.", "type": "CHEMICAL", "entities": [ "Dimethylarsinic acid", "dimethylarsinous acid", "DMAs(III)", "DMAs(V)", "arsenic" ], "offsets": [ [ 0, 20 ], [ 130, 151 ], [ 153, 162 ], [ 22, 29 ], [ 74, 81 ] ] }, { "pmid": "23414340", "text": "Although glutathione S-transferase omega 1 (GSTO1) and arsenic methyltransferase have been shown or thought to catalyze DMAs(V) reduction, their role in DMAs(V) reduction in vivo, or in cell extracts is uncertain.", "type": "CHEMICAL", "entities": [ "glutathione", "S", "arsenic", "DMAs(V)", "DMAs(V)" ], "offsets": [ [ 9, 20 ], [ 21, 22 ], [ 55, 62 ], [ 120, 127 ], [ 153, 160 ] ] }, { "pmid": "23414340", "text": "Therefore, the reduction of DMAs(V) to DMAs(III) in rats and in rat liver cytosol was studied to better understand its mechanism.", "type": "CHEMICAL", "entities": [ "DMAs(V)", "DMAs(III)" ], "offsets": [ [ 28, 35 ], [ 39, 48 ] ] }, { "pmid": "23414340", "text": "To assess DMAs(V) reduction in rats, a novel procedure was devised based on following the accumulation of red blood cell (RBC)-bound dimethylarsenic (DMAs), which represents DMAs(III), in the blood of DMAs(V)-injected anesthetized rats.", "type": "CHEMICAL", "entities": [ "DMAs(V)", "dimethylarsenic", "DMAs", "DMAs(III)", "DMAs(V)" ], "offsets": [ [ 10, 17 ], [ 133, 148 ], [ 150, 154 ], [ 174, 183 ], [ 201, 208 ] ] }, { "pmid": "23414340", "text": "These studies indicated that rats reduced DMAs(V) to DMAs(III) to a significant extent, as in 90 min 31% of the injected 50 μmol/kg DMAs(V) dose was converted to DMAs(III) that was sequestered by the circulating erythrocytes.", "type": "CHEMICAL", "entities": [ "DMAs(V)", "DMAs(III)", "DMAs(V)", "DMAs(III)" ], "offsets": [ [ 42, 49 ], [ 53, 62 ], [ 132, 139 ], [ 162, 171 ] ] }, { "pmid": "23414340", "text": "Pretreatment of rats with glutathione (GSH) depletors (phorone or BSO) delayed the elimination of DMAs(V) and the accumulation of RBC-bound DMAs, whereas the indirect methyltransferase inhibitor periodate-oxidized adenosine was without effect.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH", "phorone", "BSO", "DMAs(V)", "DMAs", "periodate", "adenosine" ], "offsets": [ [ 25, 36 ], [ 38, 41 ], [ 54, 61 ], [ 65, 68 ], [ 97, 104 ], [ 139, 143 ], [ 194, 203 ], [ 213, 222 ] ] }, { "pmid": "23414340", "text": "Assessment of DMAs(V)-reducing activity of rat liver cytosol revealed that reduction of DMAs(V) required cytosolic protein and GSH and was inhibited by thiol reagents, GSSG and dehydroascorbate.", "type": "CHEMICAL", "entities": [ "DMAs(V)", "DMAs(V)", "GSH", "thiol", "GSSG", "dehydroascorbate" ], "offsets": [ [ 13, 20 ], [ 87, 94 ], [ 126, 129 ], [ 151, 156 ], [ 167, 171 ], [ 176, 192 ] ] }, { "pmid": "23414340", "text": "Although thioredoxin reductase (TRR) inhibitors (aurothioglucose and Sb(III)) inhibited cytosolic DMAs(V) reduction, recombinant rat TRR plus NADPH, alone or when added to the cytosol, failed to support DMAs(V) reduction.", "type": "CHEMICAL", "entities": [ "aurothioglucose", "Sb(III)", "DMAs(V)", "NADPH", "DMAs(V)" ], "offsets": [ [ 48, 63 ], [ 68, 75 ], [ 97, 104 ], [ 141, 146 ], [ 202, 209 ] ] }, { "pmid": "23414340", "text": "On ultrafiltration of the cytosol through a 3 kDa filter, the reducing activity in the retentate was lost but was largely restored by NADPH.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 133, 138 ] ] }, { "pmid": "23414340", "text": "Such experiments also suggested that the reducing enzyme was larger than 100 kDa and was not GSTO1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23414340", "text": "In summary, reduction of DMAs(V) to the highly toxic DMAs(III) in rats and rat liver cytosol is a GSH-dependent enzymatic process, yet its mechanism remains uncertain.", "type": "CHEMICAL", "entities": [ "DMAs(V)", "DMAs(III)", "GSH" ], "offsets": [ [ 24, 31 ], [ 52, 61 ], [ 97, 100 ] ] }, { "pmid": "10480573", "text": "Effect of thiazinotrienomycin B, an ansamycin antibiotic, on the function of epidermal growth factor receptor in human stomach tumor cells.\n", "type": "CHEMICAL", "entities": [ "thiazinotrienomycin B", "ansamycin" ], "offsets": [ [ 10, 31 ], [ 36, 45 ] ] }, { "pmid": "10480573", "text": "Thiazinotrienomycin B (TT-B), an ansamycin isolated from fermentation broths of Streptomyces sp.", "type": "CHEMICAL", "entities": [ "Thiazinotrienomycin B", "TT-B", "ansamycin" ], "offsets": [ [ 0, 21 ], [ 23, 27 ], [ 33, 42 ] ] }, { "pmid": "10480573", "text": "MJ672-m3, inhibited the growth in vitro of human stomach tumor SC-6 cells over 10 times more strongly than the growth of other human tumor cells, such as HeLa (cervix), T24 (bladder) and LX-1 (lung).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10480573", "text": "The extent of growth inhibition by TT-B of SC-6, but not of LX-1 nor T24, was lowered in a competitive manner by raising serum concentrations in the culture medium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10480573", "text": "TT-B inhibited the cell cycle progression of SC-6 at an early stage of the progression from G0/G1 to S. The inhibition was again competitive with serum concentrations in the culture medium.", "type": "CHEMICAL", "entities": [ "TT-B" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "10480573", "text": "No direct inhibition of DNA synthesis was observed at the concentration range which caused the cell cycle arrest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10480573", "text": "TT-B and anti-epidermal growth factor receptor (anti-EGFR) were antagonistic to each other in inhibiting the cell cycle progression of SC-6 from G0/G1 to S, suggesting that the two compounds share the same target, EGFR.", "type": "CHEMICAL", "entities": [ "TT-B" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "10480573", "text": "The kinase activity of EGFR was little inhibited by TT-B in a cell-free system.", "type": "CHEMICAL", "entities": [ "TT-B" ], "offsets": [ [ 52, 56 ] ] }, { "pmid": "19708854", "text": "Vapreotide: a somatostatin analog for the treatment of acute variceal bleeding.\n", "type": "CHEMICAL", "entities": [ "Vapreotide", "somatostatin" ], "offsets": [ [ 0, 10 ], [ 14, 26 ] ] }, { "pmid": "19708854", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "Portal hypertension is a clinically important consequence of cirrhosis that can lead to morbidities such as variceal bleeding, hepatic encephalopathy and ascites.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "All of these outcomes carry high mortality rates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "There have been several drugs created to assist with endoscopic therapy for the treatment of acute variceal bleeding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "Recently, vapreotide has been studied in patients to evaluate its efficacy as treatment for acute variceal hemorrhage.", "type": "CHEMICAL", "entities": [ "vapreotide" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "19708854", "text": "Although no comparisons have been made between vapreotide and other somatostatin analogues, this drug has been shown to have efficacy in the control of acute variceal bleeding as well as reducing the risk of recurrent bleeding and death, especially when started prior to endoscopy.", "type": "CHEMICAL", "entities": [ "vapreotide", "somatostatin" ], "offsets": [ [ 47, 57 ], [ 68, 80 ] ] }, { "pmid": "19708854", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "This paper reviews the literature regarding the basic science and clinical efficacy of vapreotide in acute variceal bleeding.", "type": "CHEMICAL", "entities": [ "vapreotide" ], "offsets": [ [ 87, 97 ] ] }, { "pmid": "19708854", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "We used a PubMed/Medline search in order to review the literature regarding the drug, vapreotide.", "type": "CHEMICAL", "entities": [ "vapreotide" ], "offsets": [ [ 86, 96 ] ] }, { "pmid": "19708854", "text": "RESULTS/CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "Vapreotide appears to have benefit in the control of acute variceal bleeding.", "type": "CHEMICAL", "entities": [ "Vapreotide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "19708854", "text": "It is easy to administer and has few side effects, which are minor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19708854", "text": "These findings endorse the need for future trials to evaluate vapreotide and its use in acute variceal hemorrhage, a morbidity among patients with cirrhosis.", "type": "CHEMICAL", "entities": [ "vapreotide" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "16757355", "text": "Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature.\n", "type": "CHEMICAL", "entities": [ "Sorafenib", "tyrosine", "BAY 43-9006", "Nexavar" ], "offsets": [ [ 0, 9 ], [ 110, 118 ], [ 11, 22 ], [ 24, 31 ] ] }, { "pmid": "16757355", "text": "Activating mutations in Ras and B-RAF were identified in several human cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16757355", "text": "In addition, several receptor tyrosine kinases, acting upstream of Ras, were found either mutated or overexpressed in human tumors.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "16757355", "text": "Because oncogenic activation of the Ras/RAF pathway may lead to a sustained proliferative signal resulting in tumor growth and progression, inhibition of this pathway represents an attractive approach for cancer drug discovery.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16757355", "text": "A novel class of biaryl urea that inhibits C-RAF kinase was discovered using a combination of medicinal and combinatorial chemistry approaches.", "type": "CHEMICAL", "entities": [ "biaryl urea" ], "offsets": [ [ 17, 28 ] ] }, { "pmid": "16757355", "text": "This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials.", "type": "CHEMICAL", "entities": [ "BAY 43-9006", "Sorafenib", "Nexavar" ], "offsets": [ [ 71, 82 ], [ 84, 93 ], [ 95, 102 ] ] }, { "pmid": "16757355", "text": "Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant).", "type": "CHEMICAL", "entities": [ "Sorafenib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16757355", "text": "It inhibited MEK and ERK phosphorylation in various cancer cell lines and tumor xenografts and exhibited potent oral antitumor activity in a broad spectrum of human tumor xenograft models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16757355", "text": "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "16757355", "text": "Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling).", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 6, 15 ] ] }, { "pmid": "16757355", "text": "In phase I and phase II clinical trials, sorafenib showed limited side effects and, more importantly, disease stabilization.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "16757355", "text": "This agent is currently being evaluated in phase III clinical trials in renal cell and hepatocellular carcinomas.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17062721", "text": "Treatment-related osteoporosis in men with prostate cancer.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17062721", "text": "The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17062721", "text": "Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17062721", "text": "Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17062721", "text": "Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists.", "type": "CHEMICAL", "entities": [ "Estrogens", "estrogen", "testosterone" ], "offsets": [ [ 0, 9 ], [ 78, 86 ], [ 110, 122 ] ] }, { "pmid": "17062721", "text": "In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist-treated men.", "type": "CHEMICAL", "entities": [ "bisphosphonates", "pamidronate", "zoledronic acid", "estrogen", "raloxifene", "toremifene" ], "offsets": [ [ 33, 48 ], [ 50, 61 ], [ 66, 81 ], [ 97, 105 ], [ 127, 137 ], [ 142, 152 ] ] }, { "pmid": "17062721", "text": "Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.", "type": "CHEMICAL", "entities": [ "toremifene" ], "offsets": [ [ 198, 208 ] ] }, { "pmid": "23619386", "text": "Rapamycin allosterically inhibits the proteasome.\n", "type": "CHEMICAL", "entities": [ "Rapamycin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23619386", "text": "Rapamycin is a canonical allosteric inhibitor of the mTOR kinase with immunosuppressive and pro-apoptotic activities.", "type": "CHEMICAL", "entities": [ "Rapamycin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23619386", "text": "We found that in vitro rapamycin also regulates the proteasome, an essential intracellular protease of the ubiquitin-proteasome pathway.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "23619386", "text": "Rapamycin inhibits proteinase and selected peptidase activities of the catalytic core proteasome at low micromolar concentrations.", "type": "CHEMICAL", "entities": [ "Rapamycin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23619386", "text": "Moreover, the drug interferes with binding of the 19S cap essential for processing of polyubiquitinylated substrates, and the PA200 activator to the 20S catalytic core proteasome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23619386", "text": "These protein complexes are known to bind to specific grooves on the α face region of the 20S core.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23619386", "text": "A treatment with rapamycin affects conformational dynamics of the proteasomal gate, a centrally positioned within the α face and allosterically regulated element responsible for the intake of substrates.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "23619386", "text": "Interestingly, we showed that rapamycin shares all the proteasome targeting properties not only with other two-domain, closed-ring analogs (rapalogs), but also with its single domain mimics, and with seco-rapamycin.", "type": "CHEMICAL", "entities": [ "seco-rapamycin", "rapamycin" ], "offsets": [ [ 198, 212 ], [ 28, 37 ] ] }, { "pmid": "23619386", "text": "The latter is the first in vivo open-ring metabolite of rapamycin that does not affect mTOR.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "23619386", "text": "We hypothesize that the rapamycin and related compounds bind to the α face and allosterically impact the proteasome function.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "23619386", "text": "The implications of our finding for mechanism of in vivo actions of rapamycin and for design of novel allosteric drugs targeting the proteasome are discussed.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "16293341", "text": "Effect of MELANOTAN, [Nle(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles.\n", "type": "CHEMICAL", "entities": [ "MELANOTAN", "[Nle(4), D-Phe(7)]-alpha-MSH" ], "offsets": [ [ 10, 19 ], [ 21, 49 ] ] }, { "pmid": "16293341", "text": "MELANOTAN (NDP-MSH) binds the MC1 receptor to significantly increase the eumelanin content of human skin cells.", "type": "CHEMICAL", "entities": [ "MELANOTAN", "NDP-MSH" ], "offsets": [ [ 0, 9 ], [ 11, 18 ] ] }, { "pmid": "16293341", "text": "In this study of 77 Caucasian individuals, we investigated the effects of MELANOTAN in individuals with variant MC1R genotypes, as it has been suggested through in vitro studies that variant alleles decrease MELANOTAN binding efficacy, which would subsequently affect the synthesis of melanin.", "type": "CHEMICAL", "entities": [ "MELANOTAN", "MELANOTAN" ], "offsets": [ [ 74, 83 ], [ 208, 217 ] ] }, { "pmid": "16293341", "text": "Administration of MELANOTAN produced a significant (p<0.001) increase in melanin density in treated, compared to placebo, individuals.", "type": "CHEMICAL", "entities": [ "MELANOTAN" ], "offsets": [ [ 18, 27 ] ] }, { "pmid": "16293341", "text": "Importantly, MELANOTAN increased the melanin density to a greater extent in individuals carrying the variant alleles Val60Leu, Asp84Glu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp than in individuals with no variant alleles.", "type": "CHEMICAL", "entities": [ "MELANOTAN" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "16293341", "text": "This study demonstrates that MELANOTAN effectively increases the melanin content of skin in those individuals with MC1R variant alleles and therefore, those most in need of photoprotection.", "type": "CHEMICAL", "entities": [ "MELANOTAN" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "14507109", "text": "In vitro simulation of therapeutic plasmatic fibrinolysis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "One type of therapy for thromboembolism is plasmatic thrombolysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Several plasminogen activators (PA) are clinically available, including urokinase (u-PA), tissue plasminogen activator (t-PA), streptokinase (SK), plasminogen-streptokinase-activator-complex (PSAC), or mutants of t-PA such as reteplase (RP) or tenecteplase (TP).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Therapeutic plasmatic fibrinolysis was simulated, using the PA at relevant plasma concentrations, and plasmin (Pli) and PA activities were determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Normal citrated plasma was supplemented with 31 to 1,000 IU/mL u-PA, 0.31 to 20 microg/mL t-PA, 125 to 4,000 IU/mL SK, 12.5 to 400 U/mL PSAC, 125 to 4,000 U/mL RP, or 0.31 to 10 microg/mL TP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Ten IU/mL urokinase was also incubated with pooled plasma of stroke patients, that was previously oxidized with the singlet oxygen (1O2) donor chloramine T (CT), to destroy plasmatic PAI-1 and alpha2-antiplasmin.", "type": "CHEMICAL", "entities": [ "singlet oxygen", "1O2", "chloramine T", "CT" ], "offsets": [ [ 116, 130 ], [ 132, 135 ], [ 143, 155 ], [ 157, 159 ] ] }, { "pmid": "14507109", "text": "After 0 to 80 minutes (37 degrees C), 50-microL samples were withdrawn and added to 100 microL 1.5 M arginine, pH 8.7, and oxidized with 50 microL of 20 mM CT.", "type": "CHEMICAL", "entities": [ "CT", "arginine" ], "offsets": [ [ 156, 158 ], [ 101, 109 ] ] }, { "pmid": "14507109", "text": "For determination of plasmin activity, 10 microL thereof was incubated with 150 microL 1.5 M arginine, pH 8.7, and 100 microL 20 mM CT preoxidized (15 minutes 37 degrees C) pooled normal citrate buffered EDTA-plasma for 30 minutes (37 degrees C).", "type": "CHEMICAL", "entities": [ "arginine", "CT", "citrate", "EDTA" ], "offsets": [ [ 93, 101 ], [ 132, 134 ], [ 187, 194 ], [ 204, 208 ] ] }, { "pmid": "14507109", "text": "For determination of [PA+Pli]-activity, arginine was added after this incubation.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "14507109", "text": "25-microL 6 mM Val-Leu-Lys-pNA were added and deltaA/h at room temperature (RT) was monitored, using a microtiterplate reader.", "type": "CHEMICAL", "entities": [ "Val-Leu-Lys" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "14507109", "text": "[PA+Pli]-Pli = PA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "The PA concentration required to induce 25%", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "[ED25] of the maximally inducible Pli-activity in plasma (= 1 U/mL = 45 mg/L = 0.53 micromol/L active Pli; deltaA = 363 +/- 8 mA/h RT) after 10 minutes (37 degrees C) were 320 IU/mL u-PA, 8 microg/mL t-PA, 140 U/mL PSAC, 6,000 IU/mL SK, 720 U/mL RP, and approximately 150 microg/mL TP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "The approximate activity half-lives of the PA in plasma were 30 minutes for u-PA, 30 minutes for t-PA, greater than 80 minutes for SK, greater than 80 minutes for PSAC, 50 minutes for RP, and 80 minutes for TP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "The present study shows--for the first time--a combined kinetic in vitro simulation of the plasmatic activity of six different PAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "At clinically used concentrations, RP induces the highest plasmatic Pli activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Due to unselective generation of plasmin in plasma, all PA are of some danger in inducing severe hemorrhagias.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14507109", "text": "Clinical thrombolysis might be improved by usage of more physiologic activators of thrombolysis, such as activators of polymorphonuclear neutrophils.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "Novel assays for detection of urinary KIM-1 in mouse models of kidney injury.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "Kidney injury molecule-1 (KIM-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a urinary biomarker to monitor preclinical nephrotoxicity in rats and on a case-by-case basis for the translation of potentially nephrotoxic drugs into first-in human studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "Although mouse models are widely employed in preclinical studies, few urinary biomarker studies have been performed in mice due to limited urine availability and lack of sensitive assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "Here, we report the development and validation of two different assays for quantitative assessment of mouse urinary KIM-1 (uKIM-1) and compare the sensitivity of KIM-1 relative to other standard markers in ischemia reperfusion and aristolochic acid (AA)-induced kidney injury in mice.", "type": "CHEMICAL", "entities": [ "aristolochic acid" ], "offsets": [ [ 231, 248 ] ] }, { "pmid": "23019274", "text": "A sensitive, reproducible, and quantitative microbead-based KIM-1 ELISA was established, which requires only 10 μl urine for triplicate determination with an assay range of 12.21 pg/ml to 50 ng/ml.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "The second assay is a laminar flow dipstick assay, which has an assay range of 195 pg/ml to 50 ng/ml and provides quantitative assessment of KIM-1 in 15 min. uKIM-1 levels increased with increasing time of ischemia or time after AA administration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "After only 10-min ischemia followed by 24-h reperfusion, uKIM-1 was significantly elevated by 13-fold, whereas serum creatinine (sCr), blood urea nitrogen, N-acetyl-β-glucosaminidase (NAG), and proteinuria levels did not change.", "type": "CHEMICAL", "entities": [ "creatinine", "urea", "nitrogen", "N-acetyl" ], "offsets": [ [ 116, 126 ], [ 140, 144 ], [ 145, 153 ], [ 155, 163 ] ] }, { "pmid": "23019274", "text": "After AA administration, uKIM-1 levels were significantly upregulated by greater than threefold within 12 h, whereas sCr and NAG levels were unchanged.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23019274", "text": "Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at -80°C.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "Individuals with spinal cord injury (SCI) are highly susceptible to infection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "This post-traumatic immune suppression is thought to occur via alterations in sympathetic nervous system (SNS) or hypothalamic-pituitary-adrenal (HPA) axis function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "Normally, the HPA axis and SNS help coordinate proper immune function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "After SCI, the HPA axis becomes activated and descending input to sympathetic preganglionic neurons (SPNs) is impaired.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "Because lymphoid organs are innervated by SPNs distributed throughout the thoracolumbar spinal cord, we predicted level-dependent immune suppression after SCI due to activation of the HPA axis and loss of descending input to SPNs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "We tested this hypothesis by measuring indices of HPA (circulating corticosterone; CORT) and SNS function (norepinephrine (NE) in spleen) as well as antigen-specific antibody synthesis against an exogenous non-self protein following high- or low-level SCI.", "type": "CHEMICAL", "entities": [ "corticosterone", "CORT", "norepinephrine", "NE" ], "offsets": [ [ 67, 81 ], [ 83, 87 ], [ 107, 121 ], [ 123, 125 ] ] }, { "pmid": "17597612", "text": "Using a mid-thoracic (T9) spinal contusion injury model, we found that CORT was elevated after SCI with aberrant patterns of diurnal CORT synthesis evident through at least the first 24 h post-injury.", "type": "CHEMICAL", "entities": [ "CORT", "CORT" ], "offsets": [ [ 133, 137 ], [ 71, 75 ] ] }, { "pmid": "17597612", "text": "However, splenic NE and antibody synthesis were similar to uninjured controls.", "type": "CHEMICAL", "entities": [ "NE" ], "offsets": [ [ 17, 19 ] ] }, { "pmid": "17597612", "text": "Injury severity did not change these parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "Indeed, CORT, NE and antibody synthesis were similar after T9 contusion or transection SCI.", "type": "CHEMICAL", "entities": [ "CORT", "NE" ], "offsets": [ [ 8, 12 ], [ 14, 16 ] ] }, { "pmid": "17597612", "text": "In contrast, high-level SCI (T3) caused sustained increases in CORT and splenic NE along with impaired antibody synthesis and elevated splenocyte apoptosis.", "type": "CHEMICAL", "entities": [ "CORT", "NE" ], "offsets": [ [ 63, 67 ], [ 80, 82 ] ] }, { "pmid": "17597612", "text": "The immunosuppressive effects of T3 SCI were caused by NE acting at beta2-adrenergic receptors (beta2AR) and could be reversed using beta2AR blockers.", "type": "CHEMICAL", "entities": [ "NE" ], "offsets": [ [ 55, 57 ] ] }, { "pmid": "17597612", "text": "Interestingly, impaired antibody after T3 SCI could be mimicked after T9 SCI with a beta2AR agonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17597612", "text": "These data illustrate the immunosuppressive effects of the SNS after high-level SCI and indicate that immune deficits may be overcome using beta-blockers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12957216", "text": "Zuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.\n", "type": "CHEMICAL", "entities": [ "Zuclopenthixol" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "12957216", "text": "Although disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12957216", "text": "The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes.", "type": "CHEMICAL", "entities": [ "zuclopenthixol", "thioxanthene" ], "offsets": [ [ 30, 44 ], [ 48, 60 ] ] }, { "pmid": "12957216", "text": "In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats.", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 29, 43 ] ] }, { "pmid": "12957216", "text": "Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.)", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 24, 38 ] ] }, { "pmid": "12957216", "text": "before retrieval testing increased step-through latency during the test session.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12957216", "text": "The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties.", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 18, 32 ] ] }, { "pmid": "12957216", "text": "This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (AChE) activity, both of which are known to be important in control of cognitive function.", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 43, 57 ] ] }, { "pmid": "12957216", "text": "Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.)", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 18, 32 ] ] }, { "pmid": "12957216", "text": "neither affected dopamine (DA) level nor AChE activity in rat cortex and hippocampus.", "type": "CHEMICAL", "entities": [ "dopamine", "DA" ], "offsets": [ [ 17, 25 ], [ 27, 29 ] ] }, { "pmid": "12957216", "text": "On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level.", "type": "CHEMICAL", "entities": [ "zuclopenthixol", "norepinephrine", "NE", "NE", "serotonin", "5-HT" ], "offsets": [ [ 37, 51 ], [ 70, 84 ], [ 86, 88 ], [ 158, 160 ], [ 193, 202 ], [ 204, 208 ] ] }, { "pmid": "12957216", "text": "These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory.", "type": "CHEMICAL", "entities": [ "zuclopenthixol" ], "offsets": [ [ 114, 128 ] ] }, { "pmid": "12957216", "text": "Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.", "type": "CHEMICAL", "entities": [ "Zuclopenthixol" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "23616352", "text": "Selective Bisubstrate Inhibitors with Sub-nanomolar Affinity for Protein Kinase Pim-1.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23616352", "text": "Potent and selective: The unique nature of the ATP binding pocket structure of Pim family protein kinases (PKs) was used for the development of bisubstrate inhibitors and a fluorescent probe with sub-nanomolar affinity.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23616352", "text": "Conjugates of arginine-rich peptides with two ATP mimetic scaffolds were synthesized and tested as inhibitors of Pim-1.", "type": "CHEMICAL", "entities": [ "arginine", "ATP" ], "offsets": [ [ 14, 22 ], [ 46, 49 ] ] }, { "pmid": "23616352", "text": "Against a panel of 124 protein kinases, a novel ARC-PIM conjugate selectively inhibited PKs of the Pim family.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291559", "text": "Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia.\n", "type": "CHEMICAL", "entities": [ "phenobarbital", "K+" ], "offsets": [ [ 118, 131 ], [ 57, 59 ] ] }, { "pmid": "23291559", "text": "KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment.", "type": "CHEMICAL", "entities": [ "phenobarbital", "K(+)" ], "offsets": [ [ 118, 131 ], [ 42, 46 ] ] }, { "pmid": "23291559", "text": "Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 129, 142 ] ] }, { "pmid": "23291559", "text": "Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 19, 32 ] ] }, { "pmid": "23291559", "text": "This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291559", "text": "Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 121, 134 ] ] }, { "pmid": "23291559", "text": "Thus, KCNK1 suppresses phenobarbital-induced hyperplasia.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 23, 36 ] ] }, { "pmid": "23291559", "text": "These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 28, 41 ] ] }, { "pmid": "23291559", "text": "Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23294255", "text": "Development of new cyclic plasmin inhibitors with excellent potency and selectivity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23294255", "text": "The trypsin-like serine protease plasmin is a target for the development of antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce excessive blood loss.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 17, 23 ] ] }, { "pmid": "23294255", "text": "The optimization of our recently described substrate-analogue plasmin inhibitors, which were cyclized between their P3 and P2 side chains, provided a new series with improved efficacy and excellent selectivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23294255", "text": "The most potent inhibitor 8 binds to plasmin with an inhibition constant of 0.2 nM, whereas K(i) values >1", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23294255", "text": "μM were determined for nearly all other tested trypsin-like serine proteases, with the exception of trypsin, which is also inhibited in the nanomolar range.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 60, 66 ] ] }, { "pmid": "23294255", "text": "Docking studies revealed a potential binding mode in the widely open active site of plasmin that explains the strong potency and selectivity profile of these inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23294255", "text": "The dialkylated piperazine-linker segment contributes to an excellent solubility of all analogues.", "type": "CHEMICAL", "entities": [ "piperazine" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "23294255", "text": "Based on their overall profile the presented inhibitors are well suited for further development as injectable antifibrinolytic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "Different responses to dexamethasone and prednisolone in the same depressed patients.\n", "type": "CHEMICAL", "entities": [ "dexamethasone", "prednisolone" ], "offsets": [ [ 23, 36 ], [ 41, 53 ] ] }, { "pmid": "17016711", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "Patients with major depression show hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "We have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic-pituitary-adrenal (HPA) axis in depressed patients.", "type": "CHEMICAL", "entities": [ "dexamethasone", "prednisolone" ], "offsets": [ [ 46, 59 ], [ 64, 76 ] ] }, { "pmid": "17016711", "text": "Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function.", "type": "CHEMICAL", "entities": [ "Dexamethasone", "prednisolone" ], "offsets": [ [ 0, 13 ], [ 66, 78 ] ] }, { "pmid": "17016711", "text": "MATERIALS AND METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "We used a single-blind, repeated-measure design.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "We administered placebo, prednisolone (5 mg) or dexamethasone (0.5 mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers.", "type": "CHEMICAL", "entities": [ "prednisolone", "dexamethasone" ], "offsets": [ [ 25, 37 ], [ 48, 61 ] ] }, { "pmid": "17016711", "text": "On the following days, we collected salivary cortisol from 9:00 to 22:00.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 45, 53 ] ] }, { "pmid": "17016711", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "Depressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001).", "type": "CHEMICAL", "entities": [ "cortisol", "prednisolone", "dexamethasone" ], "offsets": [ [ 39, 47 ], [ 106, 118 ], [ 123, 136 ] ] }, { "pmid": "17016711", "text": "Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5 mg) was -85% in controls vs -46% in depressed patients (p=0.018).", "type": "CHEMICAL", "entities": [ "dexamethasone", "dexamethasone" ], "offsets": [ [ 86, 99 ], [ 175, 188 ] ] }, { "pmid": "17016711", "text": "However, the same depressed patients showed normal suppression by prednisolone (5 mg): suppression was -41% in controls and -36% in depressed patients (p=0.6).", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 66, 78 ] ] }, { "pmid": "17016711", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17016711", "text": "We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 42, 54 ] ] }, { "pmid": "23623751", "text": "Adolescence methylphenidate treatment in a rodent model of attention deficit/hyperactivity disorder: Dopamine transporter function and cellular distribution in adulthood.\n", "type": "CHEMICAL", "entities": [ "Dopamine", "methylphenidate" ], "offsets": [ [ 101, 109 ], [ 12, 27 ] ] }, { "pmid": "23623751", "text": "Attention deficit/hyperactivity disorder (ADHD) is attributed to dysfunction of the prefrontal cortex.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23623751", "text": "Methylphenidate, an inhibitor of dopamine and norepinephrine transporters (DAT and NET, respectively), is a standard treatment for ADHD.", "type": "CHEMICAL", "entities": [ "Methylphenidate", "dopamine", "norepinephrine" ], "offsets": [ [ 0, 15 ], [ 33, 41 ], [ 46, 60 ] ] }, { "pmid": "23623751", "text": "The Spontaneously Hypertensive Rat (SHR) is a well-established animal model of ADHD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23623751", "text": "Our previous results showed that methylphenidate treatment in adolescent SHR enhanced cocaine self-administration during adulthood, and alterations in DAT function in prefrontal cortex play a role in this response.", "type": "CHEMICAL", "entities": [ "methylphenidate", "cocaine" ], "offsets": [ [ 33, 48 ], [ 86, 93 ] ] }, { "pmid": "23623751", "text": "Importantly, prefrontal cortex subregions, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), have been shown to have distinct roles in ADHD and cocaine self-administration.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 158, 165 ] ] }, { "pmid": "23623751", "text": "In the current study, SHR, Wistar-Kyoto (WKY) and Wistar (WIS) rats received a therapeutically relevant dose of methylphenidate (1.5mg/kg, p.o.) or vehicle during adolescence and then OFC and mPFC DAT function and cellular expression were assessed during adulthood.", "type": "CHEMICAL", "entities": [ "methylphenidate" ], "offsets": [ [ 112, 127 ] ] }, { "pmid": "23623751", "text": "In both OFC and mPFC, no strain differences in Vmax or Km for dopamine uptake into synaptosomes were found between vehicle-treated SHR, WKY and WIS.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 62, 70 ] ] }, { "pmid": "23623751", "text": "Methylphenidate increased DAT Vmax in SHR mPFC and decreased DAT Vmax in WKY OFC.", "type": "CHEMICAL", "entities": [ "Methylphenidate" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "23623751", "text": "Also, methylphenidate decreased DAT Km in WIS OFC.", "type": "CHEMICAL", "entities": [ "methylphenidate" ], "offsets": [ [ 6, 21 ] ] }, { "pmid": "23623751", "text": "Further, methylphenidate did not alter DAT cellular localization, indicating that methylphenidate treatment during adolescence regulated DAT function in SHR mPFC in a trafficking-independent manner.", "type": "CHEMICAL", "entities": [ "methylphenidate", "methylphenidate" ], "offsets": [ [ 9, 24 ], [ 82, 97 ] ] }, { "pmid": "23623751", "text": "Thus, the increase in mPFC DAT function was an SHR-specific long term consequence of methylphenidate treatment during adolescence, which may be responsible for the treatment-induced alterations in behavior including the observed increases in cocaine self-administration.", "type": "CHEMICAL", "entities": [ "methylphenidate", "cocaine" ], "offsets": [ [ 85, 100 ], [ 242, 249 ] ] }, { "pmid": "22749842", "text": "Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit.", "type": "CHEMICAL", "entities": [ "amphetamine", "MK-801" ], "offsets": [ [ 57, 68 ], [ 78, 84 ] ] }, { "pmid": "22749842", "text": "The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 137, 148 ] ] }, { "pmid": "22749842", "text": "The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22749842", "text": "This article is part of a Special Issue entitled 'Cognitive Enhancers'.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10340919", "text": "Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state.\n", "type": "CHEMICAL", "entities": [ "meloxicam", "diclofenac", "thromboxane" ], "offsets": [ [ 36, 45 ], [ 50, 60 ], [ 70, 81 ] ] }, { "pmid": "10340919", "text": "OBJECTIVE: To evaluate the extent of human cyclooxygenase-1 (COX-1) inhibition by meloxicam, which has been reported to preferentially inhibit cyclooxygenase-2 (COX-2).", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "10340919", "text": "The effects of meloxicam were compared with those of diclofenac, a nonselective COX inhibitor.", "type": "CHEMICAL", "entities": [ "meloxicam", "diclofenac" ], "offsets": [ [ 15, 24 ], [ 53, 63 ] ] }, { "pmid": "10340919", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10340919", "text": "COX-1 inhibition was determined by measuring thromboxane B2 (TXB2)-generation from clotting whole blood ex vivo after single oral doses of 7.5 and 15 mg meloxicam and 75 mg diclofenac and at steady state (15 mg meloxicam daily and 150 mg diclofenac daily).", "type": "CHEMICAL", "entities": [ "thromboxane B2", "TXB2", "meloxicam", "diclofenac", "meloxicam", "diclofenac" ], "offsets": [ [ 45, 59 ], [ 61, 65 ], [ 153, 162 ], [ 173, 183 ], [ 211, 220 ], [ 238, 248 ] ] }, { "pmid": "10340919", "text": "The effect was expressed as percentage inhibition of serum TXB2 generation and was directly related to the serum drug concentration with use of a standard sigmoidal E(max) model.", "type": "CHEMICAL", "entities": [ "TXB2" ], "offsets": [ [ 59, 63 ] ] }, { "pmid": "10340919", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10340919", "text": "In terms of inhibition of TXB2 generation, diclofenac was about 1 order of magnitude more potent than meloxicam, indicated by a diclofenac EC50 (concentration of drug required to cause 50% of maximum effect) that was about 10 times lower than that of meloxicam (EC50 diclofenac single doses: 37.50+/-29.64; EC50 meloxicam single doses: 677.50+/-189.08).", "type": "CHEMICAL", "entities": [ "meloxicam", "TXB2", "diclofenac", "meloxicam", "diclofenac", "meloxicam", "diclofenac" ], "offsets": [ [ 312, 321 ], [ 26, 30 ], [ 43, 53 ], [ 102, 111 ], [ 128, 138 ], [ 251, 260 ], [ 267, 277 ] ] }, { "pmid": "10340919", "text": "However, serum concentrations of meloxicam after administration of 15 mg were approximately 10-fold higher than those of diclofenac.", "type": "CHEMICAL", "entities": [ "meloxicam", "diclofenac" ], "offsets": [ [ 33, 42 ], [ 121, 131 ] ] }, { "pmid": "10340919", "text": "Therefore there was no statistically significant difference in the area under the effect time curve (P = .115)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10340919", "text": "and the mean effect (P = .424) between meloxicam and diclofenac.", "type": "CHEMICAL", "entities": [ "meloxicam", "diclofenac" ], "offsets": [ [ 39, 48 ], [ 53, 63 ] ] }, { "pmid": "10340919", "text": "The EC50 of both drugs was significantly higher at steady state (diclofenac steady state: 87.07+/-55.24 ng/mL; meloxicam steady state: 1850.12+/-829.93 ng/mL) than after a single dose (P < .001).", "type": "CHEMICAL", "entities": [ "diclofenac", "meloxicam" ], "offsets": [ [ 65, 75 ], [ 111, 120 ] ] }, { "pmid": "10340919", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10340919", "text": "These data show that meloxicam inhibits TXB2 generation at clinically relevant doses, although less potently than diclofenac.", "type": "CHEMICAL", "entities": [ "meloxicam", "TXB2", "diclofenac" ], "offsets": [ [ 21, 30 ], [ 40, 44 ], [ 114, 124 ] ] }, { "pmid": "10340919", "text": "Thus our data suggest that the COX-2 preference of meloxicam observed in vitro may not result in clinical advantages when the higher dose of 15 mg is needed.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 51, 60 ] ] }, { "pmid": "10340919", "text": "Because of the increase in EC50 at steady state, COX-1 is relatively spared when the lower dose of 7.5 mg is administered.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "Interleukin 2 toxin: a step toward selective immunomodulation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "We have used protein engineering and recombinant DNA methodologies to genetically replace the eukaryotic cell receptor binding domain of diphtheria toxin with interleukin 2 (IL-2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "The toxin-related T cell growth factor fusion gene has been cloned in Escherichia coli K12.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "Recombinant strains of E coli produce a 68,086 K hybrid toxin, IL-2 toxin that retains immunologic properties intrinsic to both its diphtheria toxin and IL-2 components.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "IL-2 toxin has been found to selectively inhibit protein synthesis in both human and murine T cell lines that bear high affinity IL-2 receptors, whereas the hybrid toxin is not active against cells that do not bear this receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "The cytotoxic action of IL-2 toxin is specifically blocked by free IL-2 and monoclonal antibodies that bind to the p55 (Tac antigen) subunit of the high affinity IL-2 receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3124610", "text": "In addition, IL-2 toxin, like diphtheria toxin itself, must pass through an acidic compartment in order to deliver its adenosine diphosphate ribosyl transferase activity to the cytosol of target T cells.", "type": "CHEMICAL", "entities": [ "adenosine diphosphate", "ribosyl" ], "offsets": [ [ 119, 140 ], [ 141, 148 ] ] }, { "pmid": "3124610", "text": "In a murine delayed type hypersensitivity (DTH) model system, we have shown that IL-2 toxin treatment induces a marked immunosuppression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "3D Organotypic Cultures of Human HepaRG Cells: A Tool for In Vitro Toxicity Studies.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "Drug-induced human hepatotoxicity is difficult to predict using the current in vitro systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "In this study, long-term 3D organotypic cultures of the human hepatoma HepaRG cell line were prepared using a high-throughput hanging drop method.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "The organotypic cultures were maintained for 3 weeks and assessed for (1) liver specific functions, including phase I enzyme and transporter activities, (2) expression of liver-specific proteins, and (3) responses to three drugs (acetaminophen, troglitazone, and rosiglitazone).", "type": "CHEMICAL", "entities": [ "acetaminophen", "troglitazone", "rosiglitazone" ], "offsets": [ [ 230, 243 ], [ 245, 257 ], [ 263, 276 ] ] }, { "pmid": "23377618", "text": "Our results show that the organotypic cultures maintain high liver-specific functionality during 3 weeks of culture.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "The immunohistochemistry analyses illustrate that the organotypic cultures express liver-specific markers such as albumin, CYP3A4, CYP2E1, and MRP-2 throughout the cultivation period.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23377618", "text": "Accordingly, the production rates of albumin and glucose, as well as CYP2E1 activity, were significantly higher in the 3D versus the 2D cultures.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "23377618", "text": "Toxicity studies show that the organotypic cultures are more sensitive to acetaminophen- and rosiglitazone-induced toxicity but less sensitive to troglitazone-induced toxicity than the 2D cultures.", "type": "CHEMICAL", "entities": [ "acetaminophen", "rosiglitazone", "troglitazone" ], "offsets": [ [ 74, 87 ], [ 93, 106 ], [ 146, 158 ] ] }, { "pmid": "23377618", "text": "Furthermore, the EC50 value (2.7mM) for acetaminophen on the 3D cultures was similar to in vivo toxicity.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 40, 53 ] ] }, { "pmid": "23377618", "text": "In summary, the results from our study suggest that the 3D organotypic HepaRG culture is a promising in vitro tool for more accurate assessment of acute and also possibly for chronic drug-induced hepatotoxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454149", "text": "Inhibition of angiogenesis and invasion by DMBT is mediated by downregulation of VEGF and MMP-9 through Akt pathway in MDA-MB-231 breast cancer cells.\n", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 43, 47 ] ] }, { "pmid": "23454149", "text": "Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23454149", "text": "In order to obtain more potent inhibitors, a series of brartemicin analogs were synthesized and evaluated for their inhibitory activity against invasion.", "type": "CHEMICAL", "entities": [ "brartemicin" ], "offsets": [ [ 55, 66 ] ] }, { "pmid": "23454149", "text": "Among the synthetic analogs tested, DMBT, 6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose, was found to be the most potent anti-invasive agent.", "type": "CHEMICAL", "entities": [ "DMBT", "6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose" ], "offsets": [ [ 36, 40 ], [ 42, 89 ] ] }, { "pmid": "23454149", "text": "But the effects of DMBT on breast cancer cells were not known.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 19, 23 ] ] }, { "pmid": "23454149", "text": "In this study, the effects of DMBT on invasion and metastasis in MDA-MB-231 cells were investigated.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 30, 34 ] ] }, { "pmid": "23454149", "text": "MTT assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found.", "type": "CHEMICAL", "entities": [ "MTT", "DMBT" ], "offsets": [ [ 0, 3 ], [ 67, 71 ] ] }, { "pmid": "23454149", "text": "DMBT could inhibit invasion, migration and tube formation of HUVECs.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23454149", "text": "Gelatin zymography showed that DMBT inhibited secretion and activity of MMP-9.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 31, 35 ] ] }, { "pmid": "23454149", "text": "Western blotting demonstrated that DMBT effectively suppressed the expression of VEGF, p-VEGFR-2, p-EGFR, and p-Akt.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 35, 39 ] ] }, { "pmid": "23454149", "text": "These results suggested that DMBT could inhibit invasion and angiogenesis by downregulation of VEGFand MMP-9, resulting from the inhibition of Akt pathway.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 29, 33 ] ] }, { "pmid": "23454149", "text": "DMBT might be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit breast cancer cell invasion and metastasis.", "type": "CHEMICAL", "entities": [ "DMBT" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23122096", "text": "Quantitative determination of fatty acid chain composition in pork meat products by high resolution 1H NMR spectroscopy.\n", "type": "CHEMICAL", "entities": [ "1H", "fatty acid" ], "offsets": [ [ 100, 102 ], [ 30, 40 ] ] }, { "pmid": "23122096", "text": "High resolution (1)H NMR spectroscopy was proposed for the determination of the fatty acid chain profile of lipids in pork meat products during ripening.", "type": "CHEMICAL", "entities": [ "(1)H", "fatty acid" ], "offsets": [ [ 16, 20 ], [ 80, 90 ] ] }, { "pmid": "23122096", "text": "Two typical Mediterranean PDO salami produced in Calabria, a region in the Southern Italy, were chosen as a case of study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122096", "text": "Quantitative NMR analysis provided the fatty acid chain profiles of total lipid extracts.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "23122096", "text": "The transesterification of total lipid extracts furnished FAME mixtures that enabled quantitation of fatty acid acyl chains in the acylglycerol and FFA portions.", "type": "CHEMICAL", "entities": [ "FAME", "fatty acid acyl", "acylglycerol" ], "offsets": [ [ 58, 62 ], [ 101, 116 ], [ 131, 143 ] ] }, { "pmid": "23122096", "text": "In all cases, oleyl chains were predominant, and high amounts of polyunsaturated fatty acid chains were observed.", "type": "CHEMICAL", "entities": [ "oleyl", "polyunsaturated fatty acid" ], "offsets": [ [ 14, 19 ], [ 65, 91 ] ] }, { "pmid": "23122096", "text": "The proposed spectroscopic method allowed also the estimation of the most important nutritional parameters of dry fermented meat products.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "Identification of the regulatory region of the L-type pyruvate kinase gene in mouse liver by hydrodynamics-based gene transfection.\n", "type": "CHEMICAL", "entities": [ "pyruvate" ], "offsets": [ [ 54, 62 ] ] }, { "pmid": "16365052", "text": "Expression of L-type pyruvate kinase (L-PK) is upregulated in the liver by dietary carbohydrate.", "type": "CHEMICAL", "entities": [ "pyruvate", "carbohydrate" ], "offsets": [ [ 21, 29 ], [ 83, 95 ] ] }, { "pmid": "16365052", "text": "Previously, 3 carbohydrate/insulin response elements were identified in the 5'-flanking region of the L-PK gene up to bp -170.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "16365052", "text": "Studies of the 5'-flanking region beyond bp -183 in transgenic mice suggested that other regulatory elements may be present upstream of bp -183, but the positions of these elements were uncertain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "In the present study, the existence of regulatory regions of the L-PK gene responding to stimulation by feeding was examined using in vivo hydrodynamics-based gene transfection (HT) in mouse liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "The firefly-luciferase (FL) gene, fused with various lengths of the 5'-flanking region of the L-PK gene, was introduced into mouse liver by HT.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "The mice had free access to a high-carbohydrate diet.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "16365052", "text": "In liver homogenate, luciferase activity of pL-PK(-1467)-FL (which included the 5'-flanking region from bp -1467 to +17), was markedly stimulated by feeding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "5'-Deletion up to bp -1065 caused only minor changes in luciferase activity, but further deletion up to bp -690 and bp -203 caused significant, gradual decreases in activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "Further analyses utilizing 5'-deletion mutants indicated the existence of positive regulatory regions that respond to stimulation by feeding between bp -1065 and -945, and between -300 and -203 on the L-PK gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16365052", "text": "These results suggest that unidentified cis-acting DNA elements exist in the upstream region of the L-PK gene, and that HT is a useful approach for detecting regulatory regions of genes expressed in the liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "The Ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "The severe defects in growth plate development caused by chondrocyte extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) gain or loss-of-function suggest that tight spatial and temporal regulation of mitogen-activated protein kinase signaling is necessary to achieve harmonious growth plate elongation and structure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "We provide here evidence that neurofibromin, via its Ras guanosine triphosphatase -activating activity, controls ERK1/2-dependent fibroblast growth factor receptor (FGFR) signaling in chondrocytes.", "type": "CHEMICAL", "entities": [ "guanosine" ], "offsets": [ [ 57, 66 ] ] }, { "pmid": "23571107", "text": "We show first that neurofibromin is expressed in FGFR-positive prehypertrophic and hypertrophic chondrocytes during growth plate endochondral ossification.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "Using mice lacking neurofibromin 1 (Nf1) in type II collagen-expressing cells, (Nf1col2(-/-) mutant mice), we then show that lack of neurofibromin in post-mitotic chondrocytes triggers a number of phenotypes reminiscent of the ones observed in mice characterized by FGFR gain-of-function mutations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "Those include dwarfism, constitutive ERK1/2 activation, strongly reduced Ihh expression and decreased chondrocyte proliferation and maturation, increased chondrocytic expression of Rankl, matrix metalloproteinase 9 (Mmp9) and Mmp13 and enhanced growth plate osteoclastogenesis, as well as increased sensitivity to caspase-9 mediated apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "Using wildtype (WT) and Nf1(-/-) chondrocyte cultures in vitro, we show that FGF2 pulse-stimulation triggers rapid ERK1/2 phosphorylation in both genotypes, but that return to the basal level is delayed in Nf1(-/-) chondrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "Importantly, in vivo ERK1/2 inhibition by daily injection of a recombinant form of C-type natriuretic peptide to post-natal pups for 18 days was able to correct the short stature of Nf1col2(-/-) mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23571107", "text": "Together, these results underscore the requirement of neurofibromin and ERK1/2 for normal endochondral bone formation and support the notion that neurofibromin, by restraining RAS-ERK1/2 signaling, is a negative regulator of FGFR signaling in differentiating chondrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10690753", "text": "Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit.\n", "type": "CHEMICAL", "entities": [ "Felbamate", "N-methyl-D-aspartate" ], "offsets": [ [ 0, 9 ], [ 31, 51 ] ] }, { "pmid": "10690753", "text": "The anticonvulsant felbamate blocks N-methyl-D-asparate (NMDA) receptors but fails to exhibit the neurobehavioral toxicity characteristic of other NMDA receptor antagonists.", "type": "CHEMICAL", "entities": [ "NMDA", "felbamate", "N-methyl-D-asparate", "NMDA" ], "offsets": [ [ 147, 151 ], [ 19, 28 ], [ 36, 55 ], [ 57, 61 ] ] }, { "pmid": "10690753", "text": "To investigate the possibility that felbamate's favorable toxicity profile could be related to NMDA receptor subtype selectivity, we examined the specificity of felbamate block of recombinant NMDA receptors composed of the NR1a subunit and various NR2 subunits.", "type": "CHEMICAL", "entities": [ "NMDA", "felbamate", "NMDA" ], "offsets": [ [ 95, 99 ], [ 161, 170 ], [ 192, 196 ] ] }, { "pmid": "10690753", "text": "Felbamate produced a rapid, concentration-dependent block of currents evoked by 50 microM NMDA and 10 microM glycine in human embryonic kidney 293 cells expressing the rat NR1a subunit, and either the NR2A, NR2B or NR2C subunits; the IC50 values for block were 2.6, 0.52 and 2.4 mM, respectively (holding potential, - 60 mV).", "type": "CHEMICAL", "entities": [ "Felbamate", "NMDA", "glycine" ], "offsets": [ [ 0, 9 ], [ 90, 94 ], [ 109, 116 ] ] }, { "pmid": "10690753", "text": "The Hill coefficient values were < 1 and, in kinetic analyses, onset and recovery from block were well fit by double exponential functions, indicating binding to more than one blocking site on the NMDA receptor channel complex.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 197, 201 ] ] }, { "pmid": "10690753", "text": "The higher affinity of felbamate block of NMDA receptors containing the NR2B subunit could be accounted for by more rapid association and slower dissociation from these sites.", "type": "CHEMICAL", "entities": [ "felbamate", "NMDA" ], "offsets": [ [ 23, 32 ], [ 42, 46 ] ] }, { "pmid": "10690753", "text": "We conclude that felbamate exhibits modest selectivity for NMDA receptors composed of NR1a/NR2B subunits.", "type": "CHEMICAL", "entities": [ "felbamate", "NMDA" ], "offsets": [ [ 17, 26 ], [ 59, 63 ] ] }, { "pmid": "10690753", "text": "This selectivity could, in part, account for the more favorable clinical profile of felbamate in comparison with NMDA receptor antagonists that do not show subunit selectivity.", "type": "CHEMICAL", "entities": [ "felbamate", "NMDA" ], "offsets": [ [ 84, 93 ], [ 113, 117 ] ] }, { "pmid": "23532634", "text": "Adrenocortical reserves in hyperthyroidism.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "Explicit data regarding the changes in adrenocortical reserves during hyperthyroidism do not exist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "We aimed to document the capability (response) of adrenal gland to secrete cortisol and DHEA-S during hyperthyroidism compared to euthyroidism, and to describe factors associated with these responses.", "type": "CHEMICAL", "entities": [ "cortisol", "DHEA" ], "offsets": [ [ 75, 83 ], [ 88, 92 ] ] }, { "pmid": "23532634", "text": "A standard-dose (0.25 mg/i.v.)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "ACTH stimulation test was performed to the same patients before hyperthyroidism treatment, and after attainment of euthyroidism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "Baseline cortisol (Cor0), DHEA-S (DHEA-S0), cortisol binding globulin (CBG), ACTH, calculated free cortisol (by Coolen's equation = CFC), free cortisol index (FCI), 60-min cortisol (Cor60), and DHEA-S (DHEA-S60), delta cortisol (ΔCor), delta DHEA-S (ΔDHEA-S) responses were evaluated.", "type": "CHEMICAL", "entities": [ "cortisol", "DHEA", "DHEA", "cortisol", "cortisol", "cortisol", "cortisol", "DHEA", "DHEA", "delta cortisol", "ΔCor", "delta DHEA", "ΔDHEA" ], "offsets": [ [ 8, 16 ], [ 25, 29 ], [ 33, 37 ], [ 43, 51 ], [ 98, 106 ], [ 142, 150 ], [ 171, 179 ], [ 193, 197 ], [ 201, 205 ], [ 212, 226 ], [ 228, 232 ], [ 235, 245 ], [ 249, 254 ] ] }, { "pmid": "23532634", "text": "Forty-one patients [22 females, 49.5 ± 15.2 years old, 32 Graves disease, nine toxic nodular goiter] had similar Cor0, DHEA-S0, CFC, FCI, and DHEA-S60 in hyperthyroid and euthyroid states.", "type": "CHEMICAL", "entities": [ "DHEA", "DHEA" ], "offsets": [ [ 114, 118 ], [ 137, 141 ] ] }, { "pmid": "23532634", "text": "Cor60, ΔCor, and ΔDHEA-S were lower in hyperthyroidism.", "type": "CHEMICAL", "entities": [ "ΔDHEA" ], "offsets": [ [ 8, 13 ] ] }, { "pmid": "23532634", "text": "In four (10 %)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "patients the peak ACTH-stimulated cortisol values were lower than 18 μg/dL. When the test repeated after attainment of euthyroidism, all of the patients had normal cortisol response.", "type": "CHEMICAL", "entities": [ "cortisol", "cortisol" ], "offsets": [ [ 22, 30 ], [ 152, 160 ] ] }, { "pmid": "23532634", "text": "Regression analysis demonstrated an independent association of Cor60 with free T3 in hyperthyroidism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532634", "text": "However, the predictors of CFC, FCI, and DHEA-S levels were serum creatinine levels in hyperthyroidism, and both creatinine and transaminase levels in euthyroidism.", "type": "CHEMICAL", "entities": [ "DHEA", "creatinine", "creatinine" ], "offsets": [ [ 27, 31 ], [ 52, 62 ], [ 99, 109 ] ] }, { "pmid": "23532634", "text": "ACTH-stimulated peak cortisol, delta cortisol, and delta DHEA-S levels are decreased during hyperthyroidism, probably due to increased turnover.", "type": "CHEMICAL", "entities": [ "cortisol", "delta cortisol", "delta DHEA" ], "offsets": [ [ 7, 15 ], [ 17, 31 ], [ 37, 47 ] ] }, { "pmid": "23532634", "text": "Since about 10 % of the subjects with hyperthyroidism are at risk for adrenal insufficiency, clinicians dealing with Graves' disease should be alert to the possibility of adrenal insufficiency during hyperthyroid stage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "Mechanisms of agonist-induced down-regulation of the human kappa-opioid receptor: internalization is required for down-regulation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "Previously, we showed that the human kappa-opioid receptor (hkor) stably expressed in Chinese hamster ovary (CHO) cells underwent down-regulation after prolonged U50,488H treatment.", "type": "CHEMICAL", "entities": [ "U50,488H" ], "offsets": [ [ 162, 170 ] ] }, { "pmid": "10999950", "text": "In the present study, we determined the mechanisms underlying this process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "U50, 488H caused a significant down-regulation of the hkor, although etorphine did not.", "type": "CHEMICAL", "entities": [ "U50, 488H", "etorphine" ], "offsets": [ [ 0, 9 ], [ 69, 78 ] ] }, { "pmid": "10999950", "text": "Neither U50,488H nor etorphine caused down-regulation of the rat kappa-opioid receptor.", "type": "CHEMICAL", "entities": [ "U50,488H", "etorphine" ], "offsets": [ [ 8, 16 ], [ 21, 30 ] ] }, { "pmid": "10999950", "text": "Thus, similar to internalization, there are agonist and species differences in down-regulation of kappa-opioid receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "Expression of the dominant negative mutants arrestin-2(319-418) or dynamin I-K44A significantly reduced U50,488H-induced down-regulation of the hkor.", "type": "CHEMICAL", "entities": [ "U50,488H" ], "offsets": [ [ 104, 112 ] ] }, { "pmid": "10999950", "text": "Coexpression of GRK2 or GRK2 and arrestin-2 permitted etorphine to induce down-regulation of the hkor, although expression of arrestin-2 or dynamin", "type": "CHEMICAL", "entities": [ "etorphine" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "10999950", "text": "I alone did not.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "Expression of the dominant negative mutants rab5A-N133I or rab7-N125I blunted U50,488H-induced down-regulation.", "type": "CHEMICAL", "entities": [ "U50,488H" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "10999950", "text": "Pretreatment with lysosomal enzyme inhibitors [(2S, 3S)trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester or chloroquine] or proteasome inhibitors (proteasome inhibitor I, MG-132, or lactacystin) decreased the extent of U50,488H-induced down-regulation.", "type": "CHEMICAL", "entities": [ "[(2S, 3S)trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester or chloroquine]", "MG-132", "lactacystin", "U50,488H" ], "offsets": [ [ 46, 131 ], [ 182, 188 ], [ 193, 204 ], [ 230, 238 ] ] }, { "pmid": "10999950", "text": "A combination of chloroquine and proteasome inhibitor I abolished U50,488H-induced down-regulation.", "type": "CHEMICAL", "entities": [ "chloroquine", "U50,488H" ], "offsets": [ [ 17, 28 ], [ 66, 74 ] ] }, { "pmid": "10999950", "text": "These results indicate that U50,488H-induced down-regulation of the hkor involves GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms and receptors seem to be trafficked to lysosomes and proteasomes for degradation.", "type": "CHEMICAL", "entities": [ "U50,488H" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "10999950", "text": "Thus, U50,488H-induced internalization and down-regulation of the hkor share initial common mechanisms.", "type": "CHEMICAL", "entities": [ "U50,488H" ], "offsets": [ [ 6, 14 ] ] }, { "pmid": "10999950", "text": "To the best of our knowledge, these results represent the first report on the involvement of both rab5 and rab7 in agonist-induced down-regulation of a G protein-coupled receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10999950", "text": "In addition, this study is among the first to show the involvement of proteasomes in agonist-induced down-regulation of a G protein-coupled receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "Dose-dependent release of endogenous tissue factor pathway inhibitor by different low molecular weight heparins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "Tissue factor pathway inhibitor (TFPI) is released to circulating blood after intravenous and subcutaneous injections of heparins, and may thus contribute to the antithrombotic effect of heparins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "A previous study suggested different abilities of various low molecular weight heparins (LMWH) to release endogenous TFPI, but the dose-response relationship was not determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "In the present study, the dose-response relationship for escalating doses of two LMWHs, dalteparin and enoxaparin, on the release of endogenous TFPI was investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "Six healthy male participants were given 50, 100 and 200 U/kg dalteparin and 0.5, 1.0 and 2.0 mg/kg enoxaparin as a single subcutaneous injection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "The study was a randomized, cross-over design with a 1-week wash-out period between each injection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10847421", "text": "Peak free TFPI antigen and TFPI activity were detected after only 1 h, whereas anti-activated factor X (anti-FXa) and anti-activated factor II (anti-FIIa) activities were detected after 2-6 h. Putative therapeutic equivalent doses of dalteparin and enoxaparin gave similar release of endogenous TFPI, but dissimilar effects on anti-FXa and anti-FIIa activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "Life-threatening hypoglycemia associated with intentional insulin ingestion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "There are reports of insulin overdose by injection, yet little is known regarding the potential harms of intentional oral ingestion of insulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "In this report, we describe a case of massive insulin ingestion and ensuing hypoglycemia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "To our knowledge, there are no previously published cases of hypoglycemia caused by intentional insulin ingestion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "A 51-year-old man intentionally ingested three 10-ml vials (total of 3000 units) of various insulins: one vial each of insulin aspart, lispro, and glargine.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "Four symptomatic hypoglycemic episodes, with blood glucose levels of 48, 25, 34, and 40 mg/dl, occurred approximately 1, 3, 4, and 5 hours, respectively, after ingestion.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 51, 58 ] ] }, { "pmid": "23456735", "text": "The hypoglycemia could not be explained other than the ingestion of the insulins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "The patient was admitted for observation, and euglycemia occurred within 24 hours without any additional hypoglycemic episodes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "Hypoglycemia treatment is reviewed in this case report, and factors that may affect systemic response of orally ingested insulin, including gastrointestinal absorption and insulin sensitivity, are discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "In addition, the findings of our case report may provide useful insight into the development of novel oral insulin products that are currently in research.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "Despite poor bioavailability (1%) when taken orally, insulin may produce symptomatic hypoglycemia with a massive ingestion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23456735", "text": "Vigilant blood glucose monitoring, supportive care with glucose replacement therapy, and admission to the hospital for observation may be required.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 12, 19 ], [ 53, 60 ] ] }, { "pmid": "22532499", "text": "Effect of water extracts from edible myrtaceae plants on uptake of 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-α-treated FL83B mouse hepatocytes.\n", "type": "CHEMICAL", "entities": [ "2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose" ], "offsets": [ [ 67, 128 ] ] }, { "pmid": "22532499", "text": "This study investigated the glucose uptake activity of the water extracts from the leaves and fruit of edible Myrtaceae plants, including guava (Psidium guajava Linn.), wax apples [Syzygium samarangense (Blume) Merr.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 27, 34 ] ] }, { "pmid": "22532499", "text": "and L.M. Perry], Pu-Tau [Syzygium jambo (L.) Alston], and Kan-Shi Pu-Tau (Syzygium cumini Linn.)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532499", "text": "in FL83B mouse hepatocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532499", "text": "The fluorescent dye 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose was used to estimate the uptake ability of the cells.", "type": "CHEMICAL", "entities": [ "2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose" ], "offsets": [ [ 19, 80 ] ] }, { "pmid": "22532499", "text": "Glucose uptake test showed that pink wax apple fruit extract (PWFE) exhibits the highest glucose uptake activity, at an increment of 21% in the insulin-resistant FL83B mouse hepatocytes as compared with the TNF-α-treated control group.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 88, 95 ] ] }, { "pmid": "22532499", "text": "Vescalagin was isolated using column chromatography of PWFE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532499", "text": "This compound, at the concentration of 6.25 µg/mL, exhibits the same glucose uptake improvement in insulin-resistant cells as PWFE at a 100-µg/mL dose.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "22532499", "text": "We postulate that vescalagin is an active component in PWFE that may alleviate the insulin resistance in mouse hepatocytes.", "type": "CHEMICAL", "entities": [ "vescalagin" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "23313557", "text": "FXR-dependent and -independent interaction of glucocorticoids with the regulatory pathways involved in the control of bile acid handling by the liver.\n", "type": "CHEMICAL", "entities": [ "bile acid" ], "offsets": [ [ 118, 127 ] ] }, { "pmid": "23313557", "text": "Treatment with glucocorticoids (GCs) may cause adverse effects, including cholestasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313557", "text": "The ability of dexamethasone, prednisolone and budesonide to affect the liver handling of bile acids (BAs) has been investigated.", "type": "CHEMICAL", "entities": [ "dexamethasone", "prednisolone", "budesonide", "bile acids" ], "offsets": [ [ 15, 28 ], [ 30, 42 ], [ 47, 57 ], [ 90, 100 ] ] }, { "pmid": "23313557", "text": "In rats treated with GCs for 4 days, altered serum and bile BA levels, changed conjugation pattern, and delayed and decreased ability to conjugate/secrete exogenously administered deoxycholate, were found using HPLC-MS/MS. RT-QPCR analyses revealed that GC treatment also induced a down-regulation of liver nuclear receptors (Fxr, Gr and Shp), transporters (Ntcp, Mrp4 and Bcrp) and enzymes (Cyp7a1 and Baat), whereas Bsep, Mrp2 and Cyp27a1 were up-regulated.", "type": "CHEMICAL", "entities": [ "deoxycholate" ], "offsets": [ [ 180, 192 ] ] }, { "pmid": "23313557", "text": "Human HepG2 and Alexander cell lines were used as in vitro models of liver cells with and without constitutive FXR expression, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313557", "text": "In HepG2 cells, GCs induced a decreased expression of FXR and SHP, and inhibited the regulatory effect of GW4064 on FXR-target genes.", "type": "CHEMICAL", "entities": [ "GW4064" ], "offsets": [ [ 106, 112 ] ] }, { "pmid": "23313557", "text": "In Alexander cells, only when they were transfected with FXR+RXR, GW4064 caused up-regulation of SHP and OSTβ, and a down-regulation of CYP27A1.", "type": "CHEMICAL", "entities": [ "GW4064" ], "offsets": [ [ 66, 72 ] ] }, { "pmid": "23313557", "text": "GCs had the opposite effect on these genes, both in the absence and in the presence of FXR expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313557", "text": "Co-transfection of Alexander cells with IR-1-Luc and FXR+RXR revealed that GCs did not inhibit but moderately enhanced FXR activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313557", "text": "Moreover, GCs have a synergistic effect on GW4064-induced FXR activation, whereas chenodeoxycholate and GW4064 have an additive effect.", "type": "CHEMICAL", "entities": [ "GW4064", "chenodeoxycholate", "GW4064" ], "offsets": [ [ 42, 48 ], [ 81, 98 ], [ 103, 109 ] ] }, { "pmid": "23313557", "text": "In conclusion, GCs are able to directly or indirectly activate FXR but they also antagonize, through FXR-independent mechanisms, the expression of FXR and FXR target genes involved in the hepatic handling of BAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "Ethanol extract of Adiantum capillus-veneris L. suppresses the production of inflammatory mediators by inhibiting NF-κB activation.\n", "type": "CHEMICAL", "entities": [ "Ethanol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23542147", "text": "ETHNOPHARMACOLOGICAL RELEVANCE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "Adiantum capillus-veneris L. is a wildly distributed plant species and has been extensively used in south of China as traditional folk medicine for the treatment of inflammatory diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "AIM OF THE STUDY: To investigate the anti-inflammatory effect of ethanolic extracts of Adiantum capillus-veneris L. and the involvement of NF-κB signaling in the regulation of inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "MATERIALS AND METHODS: The plant ethanolic extracts were initially tested against lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in RAW264.7 mouse macrophages, and interleukin 6 (IL-6) and tumor necrosis factor (TNF) production in human U937 monocytes.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2" ], "offsets": [ [ 113, 129 ], [ 131, 135 ] ] }, { "pmid": "23542147", "text": "The effect of the plant extracts on the transcription factor nuclear factor kappa B (NF-κB) pathway was evaluated in TNF-α stimulated HepG2 cells by luciferase gene reporter assay and Western blotting at the transcriptional and translational levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "Subsequently, the inhibition of NF-κB downstream gene expression (IL-8 and ICAM-1) by the plant extracts was assessed via quantitative real time polymerase chain reaction (qPCR).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "Lastly, the anti-inflammatory activities of the plant extracts in vivo were evaluated by testing spleen index and NF-κB related protein expression in LPS-stimulated CD1 mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "The plant ethanolic extracts effectively suppressed PGE2, IL-6 and TNF release with an IC50 less than 50μg/ml.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "23542147", "text": "Moreover, luciferase expression could be specifically blocked in HepG2 cells, not in HEK293 cells, showing that the plant extracts displayed a cell-specific pattern on NF-κB gene transcription.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "The assayed biological activity also depended on the order of adding TNF-α and the plant extracts because the plant extracts could only block the NF-κB activation if added earlier but were unable to stop the signal when added after TNF-α.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "However, the plant extracts did not exert any effect on ubiquitination which regulates several steps in the NF-κB pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "Additionally, the plant extracts down-regulated phosphorylation of IKKα/β at S176/180, p38 at T180/Y182 and p65 at S536, but not p65 at S276.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "This was confirmed by their ability to selectively abrogate the induction of IL-8 transcription, whereas the ICAM-1 gene, which is not transcribed selectively by an NF-κB complex containing a form of p65 phosphorylated on Ser536, did not change.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 208, 211 ] ] }, { "pmid": "23542147", "text": "Finally, the plant extracts at 200μg/mg could normalize the LPS-induced elevation of spleen index as well as NF-κB and p38 activations in CD1 mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23542147", "text": "The present studies presents the potential utilization of this plant extracts, as a natural resources for the development of an anti-inflammatory medicine.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis associated cationic trypsinogen mutants.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "Mutations in human cationic trypsinogen cause hereditary pancreatitis by altering its proteolytic regulation of activation and degradation by chymotrypsin C (CTRC).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "CTRC stimulates trypsinogen autoactivation by processing the activation peptide to a shorter form but also promotes degradation by cleaving the calcium binding loop in trypsinogen.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 144, 151 ] ] }, { "pmid": "23601753", "text": "Mutations render trypsinogen resistant to CTRC-mediated degradation and/or increase processing of the activation peptide by CTRC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "Here we demonstrate that activation peptide mutations D19A, D22G, K23R and K23_I24insIDK robustly increased the rate of trypsinogen autoactivation, both in the presence and absence of CTRC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "Degradation of the mutants by CTRC was unchanged and processing of the activation peptide was increased only in the D19A mutant by 4-fold.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "Surprisingly, however, this increased processing had only a minimal effect on autoactivation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "The tetra-aspartate motif in the trypsinogen activation peptide binds calcium (KD ~1.6 mM), which stimulates autoactivation.", "type": "CHEMICAL", "entities": [ "aspartate", "calcium" ], "offsets": [ [ 10, 19 ], [ 70, 77 ] ] }, { "pmid": "23601753", "text": "Unexpectedly, calcium binding was not compromised by any of the activation peptide mutations.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 14, 21 ] ] }, { "pmid": "23601753", "text": "Despite normal binding, autoactivation of mutants D22G and K23_I24insIDK was not stimulated by calcium.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 95, 102 ] ] }, { "pmid": "23601753", "text": "Finally, the activation peptide mutants exhibited reduced secretion from transfected cells, and secreted trypsinogen levels were inversely proportional with autoactivation rates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "We conclude that D19A, D22G, K23R and K23_I24insIDK form a mechanistically distinct subset of hereditary pancreatitis associated mutations, which exert their effect primarily through direct stimulation of autoactivation, independently of CTRC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype indistinguishable from typical hereditary pancreatitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "This article is protected by copyright.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601753", "text": "All rights reserved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "Small molecule mediated proliferation of primary retinal pigment epithelial cells.\n", "type": "CHEMICAL", "entities": [ "retinal" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "23621521", "text": "Retinal pigment epithelial (RPE) cells form a monolayer adjacent to the retina and play a critical role in the visual light cycle.", "type": "CHEMICAL", "entities": [ "Retinal" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23621521", "text": "Degeneration of this layer results in vision loss, causing retinal disorders such as age-related macular degeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "Cell transplant therapies exist to restore vision loss; however, risks associated with and an inadequate supply of donor cells have limited their therapeutic success.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "The identification of factors that proliferate RPE cells ex vivo could provide a renewable source of cells for the treatment of such disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "We show that a small molecule (WS3) can reversibly proliferate primary RPE cells isolated from fetal and adult human donors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "Following withdrawal of WS3, RPE cells differentiate into a functional monolayer, as exhibited by their expression of mature RPE genes and phagocytosis of photoreceptor outer segments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23621521", "text": "Furthermore, chemically expanded RPE cells preserve vision when transplanted into dystrophic Royal College of Surgeons (RCS) rats, a well-established model of retinal degeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7959748", "text": "Murine chromosomal location of the mu and kappa opioid receptor genes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7959748", "text": "Opioid receptors are the membrane proteins that mediate the pain-relieving effect of opioid drugs, such as morphine and fentanyl as well as endogenous opioid peptides enkephalins and endorphins.", "type": "CHEMICAL", "entities": [ "morphine", "fentanyl", "enkephalins" ], "offsets": [ [ 107, 115 ], [ 120, 128 ], [ 167, 178 ] ] }, { "pmid": "7959748", "text": "Using cDNAs for the mu and the kappa opioid receptors, we mapped the chromosomal locations of their genes in mouse.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7959748", "text": "Multilocus cross analysis located the mu receptor gene Oprm on Chr 10 and the kappa receptor gene Oprk1 on Chr 1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7959748", "text": "Both genes are near centromere, with no markers more centromeric.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7959748", "text": "These data indicate that the two opioid receptors are different gene products, ruling out the possibility that they may be differential splicing products from the same gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone.\n", "type": "CHEMICAL", "entities": [ "buspirone", "aconitine" ], "offsets": [ [ 242, 251 ], [ 29, 38 ] ] }, { "pmid": "23085095", "text": "Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "The herbs are always used with drugs such as paclitaxel.", "type": "CHEMICAL", "entities": [ "paclitaxel" ], "offsets": [ [ 45, 55 ] ] }, { "pmid": "23085095", "text": "Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots.", "type": "CHEMICAL", "entities": [ "Aconitine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23085095", "text": "AC is metabolized by cytochrome P450 (CYP)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "3A.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "However, whether AC inhibits/induces CYP3A, which causes drug-drug interaction (DDI) is unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats.", "type": "CHEMICAL", "entities": [ "buspirone" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "23085095", "text": "The effects of oral AC on pharmacokinetics of buspirone were evaluated.", "type": "CHEMICAL", "entities": [ "buspirone" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "23085095", "text": "CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot.", "type": "CHEMICAL", "entities": [ "buspirone" ], "offsets": [ [ 116, 125 ] ] }, { "pmid": "23085095", "text": "Buspirone and its major metabolites 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone were determined using a newly validated UPLC-MS/MS method.", "type": "CHEMICAL", "entities": [ "Buspirone", "1-(2-pyrimidinyl)piperazine", "6'-hydroxybuspirone" ], "offsets": [ [ 0, 9 ], [ 36, 63 ], [ 68, 87 ] ] }, { "pmid": "23085095", "text": "Single dose and 7-day AC administration at 0.125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone.", "type": "CHEMICAL", "entities": [ "1-(2-pyrimidinyl)piperazine", "6'-hydroxybuspirone" ], "offsets": [ [ 122, 149 ], [ 154, 173 ] ] }, { "pmid": "23085095", "text": "CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0.125mg/kg.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085095", "text": "Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "The yeast cap binding complex modulates transcription factor recruitment and establishes proper histone H3K36 trimethylation during active transcription.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "Recent studies have revealed a close relationship between transcription, histone modification, and RNA processing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "In fact, genome-wide analyses that correlate histone marks with RNA processing signals raise the possibility that specific RNA processing factors may modulate transcription and help to \"write\" chromatin marks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "Here we show that the nuclear cap binding complex (CBC) directs recruitment of transcription elongation factors and establishes proper histone marks during active transcription.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "A directed genetic screen revealed that deletion of either subunit of the CBC confers a synthetic growth defect when combined with deletion of genes encoding either Ctk2 or Bur2, a component of the Saccharomyces cerevisiae ortholog of P-TEFb.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "The CBC physically associates with these complexes to recruit them during transcription and mediates phosphorylation at Ser-2 of the C-terminal domain (CTD) of RNA polymerase II.", "type": "CHEMICAL", "entities": [ "Ser", "C" ], "offsets": [ [ 120, 123 ], [ 133, 134 ] ] }, { "pmid": "23230273", "text": "To understand how these interactions influence downstream events, histone H3K36me3 was examined, and we demonstrate that CBCΔ affects proper Set2-dependent H3K36me3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "Consistent with this, the CBC and Set2 have similar effects on the ability to rapidly induce and sustain activated gene expression, and these effects are distinct from other histone methyltransferases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23230273", "text": "This work provides evidence for an emerging model that RNA processing factors can modulate the recruitment of transcription factors and influence histone modification during elongation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10947967", "text": "Kinetic and stereochemical studies on novel inactivators of C-terminal amidation.\n", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 60, 61 ] ] }, { "pmid": "10947967", "text": "C-terminal amidation, a required post-translational modification for the bioactivation of many neuropeptides, entails sequential enzymic action by peptidylglycine alpha-mono-oxygenase (PAM, EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5).", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 0, 1 ] ] }, { "pmid": "10947967", "text": "Here we introduce novel compounds in which an olefinic functionality is incorporated into peptide analogues as the most potent turnover-dependent inactivators of PAM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10947967", "text": "Kinetic parameters for PAM inactivation by 4-oxo-5-acetamido-6-phenyl-hex-2-enoic acid and 4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid were obtained by using both the conventional dilution assay method and the more complex progress curve method.", "type": "CHEMICAL", "entities": [ "4-oxo-5-acetamido-6-phenyl-hex-2-enoic acid and 4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid" ], "offsets": [ [ 43, 139 ] ] }, { "pmid": "10947967", "text": "The results obtained from the progress curve method establish that these compounds exhibit the kinetic characteristics of pure competitive inactivators (i.e. no ESI complex forms during inactivation).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10947967", "text": "On the basis of k(inact)/K(i) values, 4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid is almost two orders of magnitude more potent than benzoylacrylate, a chemically analogous olefinic inactivator that lacks the peptide moiety.", "type": "CHEMICAL", "entities": [ "benzoylacrylate", "4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid" ], "offsets": [ [ 138, 153 ], [ 38, 86 ] ] }, { "pmid": "10947967", "text": "Stereochemical studies established that PAM inactivation by 4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid is stereospecific with respect to the moiety at the P(2) position, which is consistent with previous results with substrates and reversible inhibitors.", "type": "CHEMICAL", "entities": [ "4-oxo-5-acetamido-6-(2-thienyl)-hex-2-enoic acid" ], "offsets": [ [ 60, 108 ] ] }, { "pmid": "10947967", "text": "In contrast, 2, 4-dioxo-5-acetamido-6-phenylhexanoic acid, which is a competitive inhibitor with respect to ascorbate, exhibits a low degree of stereospecificity in binding to the ascorbate sites of both PAM and dopamine-beta-hydroxylase.", "type": "CHEMICAL", "entities": [ "2, 4-dioxo-5-acetamido-6-phenylhexanoic acid", "ascorbate", "ascorbate", "dopamine" ], "offsets": [ [ 13, 57 ], [ 108, 117 ], [ 180, 189 ], [ 212, 220 ] ] }, { "pmid": "23530018", "text": "Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by MRP1, MRP2 and MRP4.\n", "type": "CHEMICAL", "entities": [ "Chalcogenopyrylium" ], "offsets": [ [ 0, 18 ] ] }, { "pmid": "23530018", "text": "Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiological organic anions.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 49, 52 ] ] }, { "pmid": "23530018", "text": "Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [(3)H]estradiol glucuronide (E217βG) (a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles.", "type": "CHEMICAL", "entities": [ "chalcogenopyrylium", "CGPs", "[(3)H]estradiol glucuronide", "E217βG" ], "offsets": [ [ 16, 34 ], [ 41, 45 ], [ 104, 131 ], [ 133, 139 ] ] }, { "pmid": "23530018", "text": "Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay.", "type": "CHEMICAL", "entities": [ "CGPs", "calcein" ], "offsets": [ [ 18, 22 ], [ 71, 78 ] ] }, { "pmid": "23530018", "text": "Sixteen of 34 CGPs inhibited MRP1-mediated E217βG uptake by >50% (IC50's 0.7-7.6 μM).", "type": "CHEMICAL", "entities": [ "CGPs", "E217βG" ], "offsets": [ [ 13, 17 ], [ 42, 48 ] ] }, { "pmid": "23530018", "text": "Of 9 CGPs with IC50's ≤2 μM, two belonged to Class I, two to Class III and five to Class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 μM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, -4, -6) while a fifth (I-5) inhibited efflux by just 23%.", "type": "CHEMICAL", "entities": [ "CGPs", "CGPs", "calcein" ], "offsets": [ [ 2, 6 ], [ 135, 139 ], [ 175, 182 ] ] }, { "pmid": "23530018", "text": "These five CGPs also inhibited [(3)H]E217βG uptake by MRP4.", "type": "CHEMICAL", "entities": [ "CGPs", "[(3)H]E217βG" ], "offsets": [ [ 4, 8 ], [ 24, 36 ] ] }, { "pmid": "23530018", "text": "In contrast, their effects on MRP2 varied with two (V-4, V-6) inhibiting E217βG transport (IC50's 2.0, 9.2 μM), two (V-3, III-1) stimulating transport (>2-fold), while CGP I-5 had no effect.", "type": "CHEMICAL", "entities": [ "CGP", "E217βG" ], "offsets": [ [ 160, 163 ], [ 65, 71 ] ] }, { "pmid": "23530018", "text": "Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te).", "type": "CHEMICAL", "entities": [ "chalcogen", "Se", "Te" ], "offsets": [ [ 111, 120 ], [ 127, 129 ], [ 137, 139 ] ] }, { "pmid": "23530018", "text": "This study is the first to identify Class V CGPs with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties as a particularly potent class of MRP modulators and also show that within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2.", "type": "CHEMICAL", "entities": [ "methine", "trimethine", "pyrylium", "chalcogen" ], "offsets": [ [ 62, 69 ], [ 73, 83 ], [ 118, 126 ], [ 287, 296 ] ] }, { "pmid": "23290724", "text": "Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface.\n", "type": "CHEMICAL", "entities": [ "Zinc" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23290724", "text": "The cellular prion protein PrP(C) consists of two domains--a flexible N-terminal domain, which participates in copper and zinc regulation, and a largely helical C-terminal domain that converts to β sheet in the course of prion disease.", "type": "CHEMICAL", "entities": [ "copper", "zinc", "C", "N" ], "offsets": [ [ 111, 117 ], [ 122, 126 ], [ 161, 162 ], [ 70, 71 ] ] }, { "pmid": "23290724", "text": "These two domains are thought to be fully independent and noninteracting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290724", "text": "Compelling cellular and biophysical studies, however, suggest a higher order structure that is relevant to both PrP(C) function and misfolding in disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290724", "text": "Here, we identify a Zn²⁺-driven N-terminal to C-terminal tertiary interaction in PrP(C).", "type": "CHEMICAL", "entities": [ "Zn²⁺", "N", "C" ], "offsets": [ [ 19, 23 ], [ 31, 32 ], [ 45, 46 ] ] }, { "pmid": "23290724", "text": "The C-terminal surface participating in this interaction carries the majority of the point mutations that confer familial prion disease.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 0, 1 ] ] }, { "pmid": "23290724", "text": "Investigation of mutant PrPs finds a systematic relationship between the type of mutation and the apparent strength of this domain structure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23290724", "text": "The structural features identified here suggest mechanisms by which physiologic metal ions trigger PrP(C) trafficking and control prion disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "IFNα converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "Besides their antiviral activity, type I Interferons (IFN) display context-specific immunomodulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "In contrast to long-known IFNα/β, Interleukin (IL)-22 is an anti-bacterial, largely tissue protective cytokine that recently gained attention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "Herein, cellular IFNα/IL-22 interactions are investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "We report that pre-conditioning of epithelial cells with IFNα initiated dramatic changes in IL-22 signaling normally dominated by signal transducer and activator of transcription (STAT)-3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "Specifically, by using human DLD1 colon epithelial/carcinoma cells we demonstrate that, upon IFNα, IL-22 converts into a cytokine robustly activating STAT1 and its downstream pro-inflammatory targets CXCL9, CXCL10, and inducible nitric oxide synthase (iNOS).", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 224, 236 ] ] }, { "pmid": "23153456", "text": "Accordingly, only after IFNα pre-incubation was IL-22-induced STAT1 binding to the CXCL10 promoter detectable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "Using the viral mimic polyinosinic:polycytidylic acid and the IFNα/β antagonist B18R we furthermore demonstrate the capability of endogenous IFN to promote IL-22-induced STAT1 activation and expression of CXCL10.", "type": "CHEMICAL", "entities": [ "polyinosinic:polycytidylic acid" ], "offsets": [ [ 15, 46 ] ] }, { "pmid": "23153456", "text": "IL-22-induced STAT1 activation subsequent to IFNα priming became likewise apparent in human Caco2 colon epithelial/carcinoma cells, HepG2 hepatoma cells, and primary keratinocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23153456", "text": "Current observations may relate to characteristics of IFNα/β in clinical therapy and expose margins of tissue protection by IL-22 application.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12244038", "text": "Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes.\n", "type": "CHEMICAL", "entities": [ "Gemfibrozil", "nitric-oxide" ], "offsets": [ [ 0, 11 ], [ 62, 74 ] ] }, { "pmid": "12244038", "text": "Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes.", "type": "CHEMICAL", "entities": [ "Gemfibrozil", "nitric-oxide", "NO" ], "offsets": [ [ 0, 11 ], [ 112, 124 ], [ 77, 79 ] ] }, { "pmid": "12244038", "text": "Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS.", "type": "CHEMICAL", "entities": [ "gemfibrozil", "clofibrate", "fibrate" ], "offsets": [ [ 11, 22 ], [ 24, 34 ], [ 44, 51 ] ] }, { "pmid": "12244038", "text": "Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS.", "type": "CHEMICAL", "entities": [ "gemfibrozil" ], "offsets": [ [ 64, 75 ] ] }, { "pmid": "12244038", "text": "Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha), we investigated the role of PPAR-alpha in gemfibrozil-mediated inhibition of iNOS.", "type": "CHEMICAL", "entities": [ "gemfibrozil", "gemfibrozil" ], "offsets": [ [ 6, 17 ], [ 144, 155 ] ] }, { "pmid": "12244038", "text": "Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of DeltahPPAR-alpha, the dominant-negative mutant of human PPAR-alpha.", "type": "CHEMICAL", "entities": [ "Gemfibrozil" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12244038", "text": "However, DeltahPPAR-alpha was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-alpha.", "type": "CHEMICAL", "entities": [ "gemfibrozil", "gemfibrozil" ], "offsets": [ [ 49, 60 ], [ 105, 116 ] ] }, { "pmid": "12244038", "text": "The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-gamma (IFN-gamma) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to gamma-activation site (GAS), nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein beta (C/EBPbeta); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors.", "type": "CHEMICAL", "entities": [ "gemfibrozil" ], "offsets": [ [ 475, 486 ] ] }, { "pmid": "12244038", "text": "The combination of interleukin (IL)-1beta and IFN-gamma induced the activation of NF-kappaB, AP-1, C/EBPbeta, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12244038", "text": "Interestingly, gemfibrozil strongly inhibited the activation of NF-kappaB, AP-1, and C/EBPbeta but not that of GAS in cytokine-stimulated astroglial cells.", "type": "CHEMICAL", "entities": [ "gemfibrozil" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "12244038", "text": "These results suggest that gemfibrozil inhibits the induction of iNOS probably by inhibiting the activation of NF-kappaB, AP-1, and C/EBPbeta and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.", "type": "CHEMICAL", "entities": [ "gemfibrozil", "gemfibrozil" ], "offsets": [ [ 27, 38 ], [ 151, 162 ] ] }, { "pmid": "17692748", "text": "Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans.\n", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 52, 59 ] ] }, { "pmid": "17692748", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 adrenergic receptor (AR) agonist (dexmedetomidine).", "type": "CHEMICAL", "entities": [ "dexmedetomidine" ], "offsets": [ [ 167, 182 ] ] }, { "pmid": "17692748", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "We recently showed that cocaine stimulates the human cardiovascular system primarily by acting in the brain to increase sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release.", "type": "CHEMICAL", "entities": [ "cocaine", "norepinephrine" ], "offsets": [ [ 24, 31 ], [ 177, 191 ] ] }, { "pmid": "17692748", "text": "Thus, SNA constitutes a putative new drug target to block cocaine's adverse cardiovascular effects at their origin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "In 22 healthy cocaine-naive humans, we measured skin SNA (microneurography) and skin blood flow (laser Doppler velocimetry) as well as heart rate and blood pressure before and after intranasal cocaine (2 mg/kg) alone and in combination with dexmedetomidine or saline.", "type": "CHEMICAL", "entities": [ "cocaine", "cocaine", "dexmedetomidine" ], "offsets": [ [ 14, 21 ], [ 193, 200 ], [ 241, 256 ] ] }, { "pmid": "17692748", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "During intranasal cocaine alone, SNA increased by 2-fold and skin vascular resistance increased from 13.2 +/- 2.3 to 20.1 +/- 2.2 resistance units while mean arterial pressure increased by 14 +/- 3 mm Hg and heart rate by 18 +/- 3 beats/min (p < 0.01).", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "17692748", "text": "Dexmedetomidine abolished these increases, whereas intravenous saline was without effect.", "type": "CHEMICAL", "entities": [ "Dexmedetomidine" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "17692748", "text": "Dexmedetomidine was effective in blocking these sympathomimetic actions of cocaine even in all 7 subjects who were homozygous for the Del322-325 polymorphism in the alpha2C AR, a loss-of-function mutation that is highly enriched in blacks.", "type": "CHEMICAL", "entities": [ "Dexmedetomidine", "cocaine" ], "offsets": [ [ 0, 15 ], [ 75, 82 ] ] }, { "pmid": "17692748", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17692748", "text": "The data advance the novel hypothesis that central sympatholysis with dexmedetomidine constitutes a highly effective countermeasure for cocaine's sympathomimetic actions on the human cardiovascular system, even in individuals carrying the alpha2CDel322-325 polymorphism.", "type": "CHEMICAL", "entities": [ "dexmedetomidine" ], "offsets": [ [ 70, 85 ] ] }, { "pmid": "17692748", "text": "(Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).", "type": "CHEMICAL", "entities": [ "Cocaine" ], "offsets": [ [ 76, 83 ] ] }, { "pmid": "15465035", "text": "The inhibitory effect of sodium nitroprusside on HIF-1 activation is not dependent on nitric oxide-soluble guanylyl cyclase pathway.\n", "type": "CHEMICAL", "entities": [ "guanylyl", "sodium nitroprusside", "nitric oxide" ], "offsets": [ [ 107, 115 ], [ 25, 45 ], [ 86, 98 ] ] }, { "pmid": "15465035", "text": "Adaptation to hypoxia and maintenance of O(2) homeostasis involve a wide range of responses that occur at different organizational levels in the body.", "type": "CHEMICAL", "entities": [ "O(2)" ], "offsets": [ [ 41, 45 ] ] }, { "pmid": "15465035", "text": "One of the most important transcription factors that activate the expression of O(2)-regulated genes is hypoxia-inducible factor 1 (HIF-1).", "type": "CHEMICAL", "entities": [ "O(2)" ], "offsets": [ [ 80, 84 ] ] }, { "pmid": "15465035", "text": "Nitric oxide (NO) mediates a variety of biological effects including relaxation of blood vessels and cytotoxicity of activated macrophages.", "type": "CHEMICAL", "entities": [ "Nitric oxide", "NO" ], "offsets": [ [ 0, 12 ], [ 14, 16 ] ] }, { "pmid": "15465035", "text": "We investigated the effect of the clinically used nitrates nitroglycerin (NTG), isosorbide dinitrate (ISDN), and sodium nitroprusside (SNP) on HIF-1-mediated transcriptional responses to hypoxia.", "type": "CHEMICAL", "entities": [ "nitroglycerin", "NTG", "isosorbide dinitrate", "ISDN", "sodium nitroprusside", "SNP" ], "offsets": [ [ 59, 72 ], [ 74, 77 ], [ 80, 100 ], [ 102, 106 ], [ 113, 133 ], [ 135, 138 ] ] }, { "pmid": "15465035", "text": "We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia.", "type": "CHEMICAL", "entities": [ "SNP" ], "offsets": [ [ 51, 54 ] ] }, { "pmid": "15465035", "text": "In contrast, NTG or ISDN does not affect HIF-1 activity.", "type": "CHEMICAL", "entities": [ "NTG", "ISDN" ], "offsets": [ [ 13, 16 ], [ 20, 24 ] ] }, { "pmid": "15465035", "text": "SNP inhibits the accumulation of HIF-1alpha, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1alpha via a mechanism that is not dependent on either NO or soluble guanylate cyclase.", "type": "CHEMICAL", "entities": [ "SNP", "NO", "guanylate" ], "offsets": [ [ 0, 3 ], [ 175, 177 ], [ 189, 198 ] ] }, { "pmid": "11430635", "text": "Indomethacin activates carbonic anhydrase and antagonizes the effect of the specific carbonic anhydrase inhibitor acetazolamide, by a direct mechanism of action.\n", "type": "CHEMICAL", "entities": [ "Indomethacin", "acetazolamide", "carbonic", "carbonic" ], "offsets": [ [ 0, 12 ], [ 114, 127 ], [ 23, 31 ], [ 85, 93 ] ] }, { "pmid": "11430635", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "In this paper we investigated the effect of indomethacin, acetazolamide and their combination in vitro and in vivo on carbonic anhydrase (CA) isozymes.", "type": "CHEMICAL", "entities": [ "carbonic", "indomethacin", "acetazolamide" ], "offsets": [ [ 118, 126 ], [ 44, 56 ], [ 58, 71 ] ] }, { "pmid": "11430635", "text": "METHOD:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "In vitro experiments followed the effect of the two substances at concentrations between 10(-8)-10(-4) M on purified human red cell CA I and II as well as on human gastric mucosa CA IV using dose-response relationships.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "Kinetic studies were also performed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "The effects of single and combined administration of indomethacin and acetazolamide on red cell CA and on gastric acid secretion were studied in vivo.", "type": "CHEMICAL", "entities": [ "indomethacin", "acetazolamide" ], "offsets": [ [ 53, 65 ], [ 70, 83 ] ] }, { "pmid": "11430635", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "Indomethacin, in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Indomethacin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "11430635", "text": "induces an increase in erythorcyte CA I and CA II activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "Acetazolamide, a specific inhibitor of CA, reduces the activity of CA I and CA II from red cells.", "type": "CHEMICAL", "entities": [ "Acetazolamide" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "11430635", "text": "Indomethacin completely antagonizes CA activity, i.e. abolishes the inhibitory effect of acetazolamide on CA.", "type": "CHEMICAL", "entities": [ "Indomethacin", "acetazolamide" ], "offsets": [ [ 0, 12 ], [ 89, 102 ] ] }, { "pmid": "11430635", "text": "In humans, an increase or decrease in erythrocyte CA II activity is correlated with an increase or decrease in gastric acid secretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11430635", "text": "Our results show that indomethacin, a known cyclooxygenase (COX) inhibitor, is also an activator of CA.", "type": "CHEMICAL", "entities": [ "indomethacin" ], "offsets": [ [ 22, 34 ] ] }, { "pmid": "11430635", "text": "Our data also prove that indomethacin is not only an activator of CA but also antagonizes the effect of acetazolamide, a specific inhibitor of this enzyme.", "type": "CHEMICAL", "entities": [ "indomethacin", "acetazolamide" ], "offsets": [ [ 25, 37 ], [ 104, 117 ] ] }, { "pmid": "11430635", "text": "In view of the role of CA in acid-base balance as well as the fact that an increase or decrease in its activity is accompanied by an increase or decrease in intra- and extracellular pH, our results suggest that: firstly, CA activation induced by indomethacin might cause changes in COX activity; secondly, PGs are synthetized as a consequence of the changes in COX activity, a hypothesis that requires further study.", "type": "CHEMICAL", "entities": [ "indomethacin" ], "offsets": [ [ 246, 258 ] ] }, { "pmid": "12871155", "text": "Recent developments in the synthesis of acetylcholinesterase inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12871155", "text": "The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described.", "type": "CHEMICAL", "entities": [ "pyrano[2,3-b]quinolines", "[1,8]naphthyridines", "4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines", "4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine", "4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline", "4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine" ], "offsets": [ [ 103, 126 ], [ 135, 154 ], [ 163, 221 ], [ 231, 306 ], [ 313, 374 ], [ 381, 458 ] ] }, { "pmid": "12871155", "text": "These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl", "type": "CHEMICAL", "entities": [ "tacrine" ], "offsets": [ [ 20, 27 ] ] }, { "pmid": "12871155", "text": "[6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12871155", "text": "[6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedlander condensation with selected ketones.", "type": "CHEMICAL", "entities": [ "2-amino-3-cyano-4,5-diarylfurans", "2-amino-3-cyano-4,5-diphenylthiophene", "ketones" ], "offsets": [ [ 49, 81 ], [ 94, 131 ], [ 180, 187 ] ] }, { "pmid": "12871155", "text": "These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine.", "type": "CHEMICAL", "entities": [ "tacrine" ], "offsets": [ [ 162, 169 ] ] }, { "pmid": "12871155", "text": "The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine.", "type": "CHEMICAL", "entities": [ "tacrine" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "12871155", "text": "Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23594301", "text": "Development and validation of NIR-chemometric methods for chemical and pharmaceutical characterization of meloxicam tablets.\n", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 106, 115 ] ] }, { "pmid": "23594301", "text": "Abstract Context: Near-Infrared (NIR) spectroscopy is an important component of a Process Analytical Technology (PAT) toolbox and is a key technology for enabling the rapid analysis of pharmaceutical tablets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23594301", "text": "Objective: The aim of this research work was to develop and validate NIR-chemometric methods not only for the determination of active pharmaceutical ingredients content but also pharmaceutical properties (crushing strength, disintegration time) of meloxicam tablets.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 248, 257 ] ] }, { "pmid": "23594301", "text": "Materials and methods: The development of the method for active content assay was performed on samples corresponding to 80%, 90%, 100%, 110% and 120% of meloxicam content and the development of the methods for pharmaceutical characterization was performed on samples prepared at seven different compression forces (ranging from 7 to 45 kN) using NIR transmission spectra of intact tablets and PLS as a regression method.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 153, 162 ] ] }, { "pmid": "23594301", "text": "Results:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23594301", "text": "The results show that the developed methods have good trueness, precision and accuracy and are appropriate for direct active content assay in tablets (ranging from 12 to 18 mg/tablet) and also for predicting crushing strength and disintegration time of intact meloxicam tablets.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 258, 267 ] ] }, { "pmid": "23594301", "text": "Discussion:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23594301", "text": "The comparative data show that the proposed methods are in good agreement with the reference methods currently used for the characterization of meloxicam tablets (HPLC-UV methods for the assay and European Pharmacopeia methods for determining the crushing strength and disintegration time).", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 142, 151 ] ] }, { "pmid": "23594301", "text": "Conclusion: The results show the possibility to predict both chemical properties (active content) and physical/pharmaceutical properties (crushing strength and disintegration time) directly, without any sample preparation, from the same NIR transmission spectrum of meloxicam tablets.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 264, 273 ] ] }, { "pmid": "23643730", "text": "Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells.\n", "type": "CHEMICAL", "entities": [ "Juglone" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23643730", "text": "Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim.", "type": "CHEMICAL", "entities": [ "Juglone" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23643730", "text": "Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer.", "type": "CHEMICAL", "entities": [ "juglone" ], "offsets": [ [ 31, 38 ] ] }, { "pmid": "23643730", "text": "However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643730", "text": "Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells.", "type": "CHEMICAL", "entities": [ "juglone", "androgen" ], "offsets": [ [ 98, 105 ], [ 109, 117 ] ] }, { "pmid": "23643730", "text": "MTT assay was performed to examine the anti-proliferative effect of juglone.", "type": "CHEMICAL", "entities": [ "MTT", "juglone" ], "offsets": [ [ 0, 3 ], [ 68, 75 ] ] }, { "pmid": "23643730", "text": "Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h.", "type": "CHEMICAL", "entities": [ "Hoechst 33342", "juglone" ], "offsets": [ [ 40, 53 ], [ 110, 117 ] ] }, { "pmid": "23643730", "text": "The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "juglone" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "23643730", "text": "Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining.", "type": "CHEMICAL", "entities": [ "juglone", "Hoechst 33342" ], "offsets": [ [ 56, 63 ], [ 91, 104 ] ] }, { "pmid": "23643730", "text": "This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643730", "text": "Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT).", "type": "CHEMICAL", "entities": [ "juglone", "androgen", "dihydrotestosterone", "DHT" ], "offsets": [ [ 24, 31 ], [ 81, 89 ], [ 243, 262 ], [ 264, 267 ] ] }, { "pmid": "23643730", "text": "Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression.", "type": "CHEMICAL", "entities": [ "juglone" ], "offsets": [ [ 45, 52 ] ] }, { "pmid": "23643730", "text": "Therefore, our results indicated that juglone may be a potential candidate of drug for androgen-sensitive prostate cancer.", "type": "CHEMICAL", "entities": [ "juglone", "androgen" ], "offsets": [ [ 38, 45 ], [ 87, 95 ] ] }, { "pmid": "23537942", "text": "Anticancer activity of novel hybrid molecules containing 5-benzylidene thiazolidine-2,4-dione.\n", "type": "CHEMICAL", "entities": [ "5-benzylidene thiazolidine-2,4-dione" ], "offsets": [ [ 57, 93 ] ] }, { "pmid": "23537942", "text": "Hybridization of two different bioactive molecules with different mechanism of action is one of the methods that are being adopted to treat cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537942", "text": "Molecules bearing a thiazolidine-2,4-dione scaffold have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines.", "type": "CHEMICAL", "entities": [ "thiazolidine-2,4-dione" ], "offsets": [ [ 20, 42 ] ] }, { "pmid": "23537942", "text": "In this manuscript we have described the synthesis and biological evaluation of two series of N-3-substituted-5-arylidene thiazolidine-2,4-diones, bearing the α-bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion.", "type": "CHEMICAL", "entities": [ "N-3-substituted-5-arylidene thiazolidine-2,4-diones", "α-bromoacryloylamido", "phenyl", "arylidene" ], "offsets": [ [ 94, 145 ], [ 159, 179 ], [ 224, 230 ], [ 238, 247 ] ] }, { "pmid": "23537942", "text": "We have observed that selected compounds 5a, 5c and 5g suppress proliferation of human myeloid leukaemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537942", "text": "Finally, our results indicated that the investigated compounds induced apoptotic cell death through a mechanism that involved activation of multiple caspases and was also associated with the release of cytochrome c from the mitochondria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "Methylation damage to RNA induced in vivo in Escherichia coli is repaired by endogenous AlkB as part of the adaptive response.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "Cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions induced in DNA and RNA in vitro and in pre-damaged DNA and RNA bacteriophages in vivo are repaired by the Escherichia coli (E. coli) protein AlkB and a human homolog, ALKBH3.", "type": "CHEMICAL", "entities": [ "1-methyladenine", "1-meA", "3-methylcytosine", "3-meC" ], "offsets": [ [ 10, 25 ], [ 27, 32 ], [ 38, 54 ], [ 56, 61 ] ] }, { "pmid": "23276627", "text": "However, it is not known whether endogenous RNA is repaired in vivo by repair proteins present at physiological concentrations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "The concept of RNA repair as a biologically relevant process has therefore remained elusive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "Here, we demonstrate AlkB-mediated repair of endogenous RNA in vivo by measuring differences in lesion-accumulation in two independent AlkB-proficient and deficient E. coli strains during exposure to methyl methanesulfonate (MMS).", "type": "CHEMICAL", "entities": [ "methyl methanesulfonate", "MMS" ], "offsets": [ [ 200, 223 ], [ 225, 228 ] ] }, { "pmid": "23276627", "text": "Repair was observed both in AlkB-overproducing strains and in the wild-type strains after AlkB induction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "RNA repair appeared to be highest in RNA species below 200 nucleotides in size, mainly comprising tRNAs.", "type": "CHEMICAL", "entities": [ "nucleotides" ], "offsets": [ [ 59, 70 ] ] }, { "pmid": "23276627", "text": "Strikingly, at least 10-fold more lesions were repaired in RNA than in DNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "This may be a consequence of some 30-fold higher levels of aberrant methylation in RNA than in DNA after exposure to MMS.", "type": "CHEMICAL", "entities": [ "MMS" ], "offsets": [ [ 117, 120 ] ] }, { "pmid": "23276627", "text": "A high primary kinetic isotope effect (>10) was measured using a deuterated methylated RNA substrate, D3-1me(rA), demonstrating that it is the catalytic step, and not the search step that is rate-limiting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276627", "text": "Our results demonstrate that RNA repair by AlkB takes place in endogenous RNA as part of an adaptive response in wild-type E. coli cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "OBJECTIVE: The clinical significance of the measurement of serum PCSK9 (proprotein subtilisin kexin type 9) is not well defined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "This study investigated the association between serum PCSK9 levels and atherosclerosis assessed by carotid intima media thickness (IMT) in hypertensive patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "A total of 126 hypertensive patients over the age of 45 were enrolled.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at the time of enrollment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "Clinical and laboratory parameters including serum PCSK9 were analyzed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "Patients were divided into tertiles based on serum PCSK9 levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "After adjusting for age, sex, total cholesterol, HDL-cholesterol and triglyceride, max-IMT was significantly increased in the highest tertile of serum PCSK9 (0.969±0.033 vs 0.959±0.033 vs 1.077±0.033mm, respectively; P=0.026).", "type": "CHEMICAL", "entities": [ "cholesterol", "triglyceride" ], "offsets": [ [ 36, 47 ], [ 69, 81 ] ] }, { "pmid": "23380568", "text": "Mean-IMT showed a tendency to increase across the tertile groups (0.773±0.025 vs 0.790±0.026 vs 0.856±0.025mm, respectively; P=0.059).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "Multivariate regression analysis revealed that serum PCSK9 was independently associated with carotid IMT (max-IMT: β=0.212, P=0.016; mean-IMT: β=0.184, P=0.04).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "The present study is the first to report the association between serum PCSK9 levels and carotid IMT in hypertensive patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380568", "text": "These results suggest that serum PCSK9 may have a certain role in early pathogenesis of atherosclerosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6146346", "text": "Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels.\n", "type": "CHEMICAL", "entities": [ "Astemizole", "histamine", "histamine" ], "offsets": [ [ 0, 10 ], [ 110, 119 ], [ 21, 30 ] ] }, { "pmid": "6146346", "text": "The efficacy of astemizole, a new, long acting, oral histamine H1-receptor antagonist was compared to placebo for the treatment of allergic rhinitis and conjunctivitis during the grass pollen season of 1982.", "type": "CHEMICAL", "entities": [ "astemizole", "histamine" ], "offsets": [ [ 16, 26 ], [ 53, 62 ] ] }, { "pmid": "6146346", "text": "Sixty-three patients with a positive skin prick test to grass pollen and current symptoms participated in an 8 week, double-blind, randomized study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6146346", "text": "Astemizole, 10 mg, was significantly better than placebo in alleviating both nose (P less than 0.05) and eye (P less than 0.01) symptoms despite significantly greater use of the reserve medication, clemastine, by the placebo group (P less than 0.003).", "type": "CHEMICAL", "entities": [ "Astemizole", "clemastine" ], "offsets": [ [ 0, 10 ], [ 198, 208 ] ] }, { "pmid": "6146346", "text": "There was a lag period of 5 days after initiation of therapy before treatment benefit became manifest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6146346", "text": "Subdivision of nasal symptoms indicated significant improvement compared to placebo over the 8 weeks for sneezing (P less than 0.05) and runny nose (P less than 0.05) but not blocked nose.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6146346", "text": "The absence of effect on nasal blockage was confirmed by parallel measurement of nasal calibre by body plethysmography.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6146346", "text": "The antihistaminic potency of astemizole was indicated by an 80% inhibition of the histamine induced skin weal response after 8 weeks therapy.", "type": "CHEMICAL", "entities": [ "astemizole", "histamine" ], "offsets": [ [ 30, 40 ], [ 83, 92 ] ] }, { "pmid": "6146346", "text": "A positive correlation was found between serum drug levels and % inhibition of histamine skin weal (r = 0.64, P less than 0.001).", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 79, 88 ] ] }, { "pmid": "6146346", "text": "Astemizole was free from adverse sedative or anticholinergic effects but did cause a mean increase in weight of 1.3 kg (P less than 0.01) after 8 weeks therapy, not found with placebo.", "type": "CHEMICAL", "entities": [ "Astemizole" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "19370562", "text": "Rivastigmine for Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19370562", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "Alzheimer's disease (AD) is the commonest cause of dementia affecting older people.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 248, 261 ] ] }, { "pmid": "19370562", "text": "Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity.", "type": "CHEMICAL", "entities": [ "Tacrine" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "19370562", "text": "Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 43, 55 ] ] }, { "pmid": "19370562", "text": "Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19370562", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 49, 61 ] ] }, { "pmid": "19370562", "text": "SEARCH STRATEGY:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR exelon OR ENA OR \"SDZ ENA 713\" .", "type": "CHEMICAL", "entities": [ "Rivastigmine", "exelon", "ENA", "SDZ ENA 713" ], "offsets": [ [ 206, 218 ], [ 222, 228 ], [ 232, 235 ], [ 240, 251 ] ] }, { "pmid": "19370562", "text": "The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 94, 106 ] ] }, { "pmid": "19370562", "text": "DATA COLLECTION AND ANALYSIS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "MAIN RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "Nine trials, involving 4775 participants, were included in the analyses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "Use of rivastigmine in high doses was associated with statistically significant benefits on several measures.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 7, 19 ] ] }, { "pmid": "19370562", "text": "High-dose rivastigmine (6 to 12 mg daily) was associated with a two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 10, 22 ] ] }, { "pmid": "19370562", "text": "At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 186, 198 ] ] }, { "pmid": "19370562", "text": "There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 102, 114 ] ] }, { "pmid": "19370562", "text": "The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 58, 70 ] ] }, { "pmid": "19370562", "text": "The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "AUTHORS' CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19370562", "text": "In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "Adverse events were consistent with the cholinergic actions of the drug.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19370562", "text": "This review has not examined economic data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12881227", "text": "NHE3 inhibition activates duodenal bicarbonate secretion in the rat.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12881227", "text": "We examined the effect of inhibition of Na+/H+ exchange (NHE) on duodenal bicarbonate secretion (DBS) in rats to further understand DBS regulation.", "type": "CHEMICAL", "entities": [ "Na+", "H+" ], "offsets": [ [ 40, 43 ], [ 44, 46 ] ] }, { "pmid": "12881227", "text": "DBS was measured by using the pH-stat method and by using CO2-sensitive electrodes.", "type": "CHEMICAL", "entities": [ "CO2" ], "offsets": [ [ 58, 61 ] ] }, { "pmid": "12881227", "text": "5-(N,N-dimethyl)-amiloride (50 microM; DMA), a concentration that selectively inhibits the NHE isoforms NHE1 and NHE2, but not NHE3, did not affect DBS.", "type": "CHEMICAL", "entities": [ "5-(N,N-dimethyl)-amiloride", "DMA" ], "offsets": [ [ 0, 26 ], [ 39, 42 ] ] }, { "pmid": "12881227", "text": "Nevertheless, 3 mM DMA, a higher concentration that inhibits NHE1, NHE2, and NHE3, significantly increased DBS.", "type": "CHEMICAL", "entities": [ "DMA" ], "offsets": [ [ 19, 22 ] ] }, { "pmid": "12881227", "text": "Moreover, S1611 and S3226, both specific inhibitors of NHE3 only, or perfusion with Na+-free solutions, dose dependently increased DBS, as measured by pH-stat and CO2-sensitive electrode, without affecting intracellular pH. Coperfusion with 0.1 microM indomethacin, 0.5 mM DIDS, or 1 mM methazolamide did not affect S3226-induced DBS.", "type": "CHEMICAL", "entities": [ "S1611", "S3226", "Na+", "CO2", "indomethacin", "methazolamide", "S3226" ], "offsets": [ [ 10, 15 ], [ 20, 25 ], [ 84, 87 ], [ 163, 166 ], [ 252, 264 ], [ 287, 300 ], [ 316, 321 ] ] }, { "pmid": "12881227", "text": "Nevertheless, coperfusion with 0.1 and 0.3 mM 5-nitro-2-(3-phenylpropylamino) benzoic acid, which inhibits the cystic fibrosis transmembrane conductor regulator (CFTR), dose dependently inhibited S3226-induced DBS.", "type": "CHEMICAL", "entities": [ "S3226", "5-nitro-2-(3-phenylpropylamino) benzoic acid" ], "offsets": [ [ 196, 201 ], [ 46, 90 ] ] }, { "pmid": "12881227", "text": "In conclusion, only specific apical NHE3 inhibition increased DBS, whereas prostaglandin synthesis, Na+-HCO3- cotransporter activation, or intracellular HCO3- formation by carbonic anhydrase was not involved.", "type": "CHEMICAL", "entities": [ "prostaglandin", "Na+", "HCO3", "HCO3", "carbonic" ], "offsets": [ [ 75, 88 ], [ 100, 103 ], [ 104, 108 ], [ 153, 157 ], [ 172, 180 ] ] }, { "pmid": "12881227", "text": "Because NHE3 inhibition-increased DBS was inhibited by an anion channel inhibitor and because reciprocal CFTR regulation has been previously shown between NHE3 and apical membrane anion transporters, we speculate that NHE3 inhibition increased DBS by altering anion transporter function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988-2010.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "OBJECTIVETo determine the prevalence of people with diabetes who meet hemoglobin A(1c) (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations, and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010.RESEARCH AND DESIGN METHODSData were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988-1994, 1999-2002, 2003-2006, and 2007-2010.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 123, 134 ] ] }, { "pmid": "23418368", "text": "Participants were 4,926 adults aged ≥20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination (n = 1,558 for valid LDL levels).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "23418368", "text": "RESULTSIn 2007-2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "These levels of control were significant improvements from 1988 to 1994 (all P < 0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Statin use significantly increased between 1988-1994 (4.2%) and 2007-2010 (51.4%, P < 0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals (P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals (P < 0.02).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals (P < 0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Younger individuals were less likely to meet A1C and LDL goals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "CONCLUSIONSDespite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418368", "text": "Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "EphB1 null mice exhibit neuronal loss in substantia nigra pars reticulata and spontaneous locomotor hyperactivity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "The molecular mechanisms that regulate basal ganglia development are largely unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "Eph receptor tyrosine kinases are potential participants in this process as they regulate development of other CNS regions and are expressed in basal ganglia nuclei, such as the substantia nigra (SN) and striatum.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "17561836", "text": "To address the role of Eph receptors in the development of these nuclei, we analysed anatomical changes in the SN and striatum of mice with null mutations for EphB1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "These mice express beta-galactosidase as a marker for cells normally expressing EphB1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "In situ hybridization data and a direct comparison of SN neurons expressing tyrosine hydroxylase (TH) and/or the beta-gal marker for EphB1 revealed that EphB1 is not expressed in TH+ neurons of pars compacta (SNc), but is restricted to neurons in pars reticulata (SNr).", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 76, 84 ] ] }, { "pmid": "17561836", "text": "Consistent with this, we find that EphB1 null mice exhibit a significant decrease in the volume and number of neurons (40% decrease) in SNr, whereas the volume and number of TH+ neurons in SNc is not significantly affected nor are there changes in the distribution of nigrostriatal dopamine neurons.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 282, 290 ] ] }, { "pmid": "17561836", "text": "Although EphB1 is expressed in the striatum, EphB1-/- mice exhibit no significant changes in striatal volume and TH fiber density, and have no obvious alterations in striatal patch/matrix organization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "Behavioral evaluation of EphB1 null mice in an open-field environment revealed that these mice exhibited spontaneous locomotor hyperactivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17561836", "text": "These results suggest that EphB1 is necessary for the proper formation of SNr, and that neuronal loss in SNr is associated with altered locomotor functions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207322", "text": "pH-responsive composite microspheres based on magnetic mesoporous silica nanoparticle for drug delivery.\n", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 66, 72 ] ] }, { "pmid": "23207322", "text": "pH-responsive composite microspheres, consisting of a core of Fe3O4 nanoparticle, a sandwiched layer of mesoporous silica and a shell of crosslinked poly (methacrylic acid) (PMAA), were successfully synthesized via distillation precipitation polymerization.", "type": "CHEMICAL", "entities": [ "silica", "poly (methacrylic acid)", "PMAA", "Fe3O4" ], "offsets": [ [ 115, 121 ], [ 149, 172 ], [ 174, 178 ], [ 62, 67 ] ] }, { "pmid": "23207322", "text": "The pKa of the composite microsphere increased with the increase in the crosslinking density.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23207322", "text": "Doxorubicin hydrochloride (DOX) was applied as a model drug, and the behavior of drug storage/release was investigated.", "type": "CHEMICAL", "entities": [ "Doxorubicin hydrochloride", "DOX" ], "offsets": [ [ 0, 25 ], [ 27, 30 ] ] }, { "pmid": "23207322", "text": "The cumulative release of DOX-loaded composite microsphere in vitro showed that the drug release rate was much faster below its pKa than that of above its pKa.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 26, 29 ] ] }, { "pmid": "23207322", "text": "Because pH of most tumor tissues was lower than that of normal tissues, the pH-responsive composite microspheres are promising drug delivery system especially for cancer therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "Novel therapeutic targets in non-small cell lung cancer.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively.", "type": "CHEMICAL", "entities": [ "crizotinib" ], "offsets": [ [ 204, 214 ] ] }, { "pmid": "23608109", "text": "Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "However, efforts to target some mutated genes like K-RAS have been unsuccessful.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23608109", "text": "In this review recent data on novel molecular targets and their future prospects are discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249624", "text": "Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases.\n", "type": "CHEMICAL", "entities": [ "threonine", "dabrafenib" ], "offsets": [ [ 40, 49 ], [ 88, 98 ] ] }, { "pmid": "23249624", "text": "Brain metastases are a common cause of death in stage IV metastatic melanoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249624", "text": "Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAF(V600E)), which is commonly found in metastatic melanoma.", "type": "CHEMICAL", "entities": [ "serine", "threonine", "valine", "glutamic acid" ], "offsets": [ [ 36, 42 ], [ 43, 52 ], [ 135, 141 ], [ 149, 162 ] ] }, { "pmid": "23249624", "text": "Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown.", "type": "CHEMICAL", "entities": [ "dabrafenib", "dabrafenib" ], "offsets": [ [ 21, 31 ], [ 116, 126 ] ] }, { "pmid": "23249624", "text": "Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB).", "type": "CHEMICAL", "entities": [ "dabrafenib" ], "offsets": [ [ 83, 93 ] ] }, { "pmid": "23249624", "text": "In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP.", "type": "CHEMICAL", "entities": [ "dabrafenib" ], "offsets": [ [ 92, 102 ] ] }, { "pmid": "23249624", "text": "Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249624", "text": "In vivo, the ratio of area under the concentration-time curve (AUC)(brain) to AUC(plasma) (K(p)) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b(-/-)Bcrp1(-/-) mice to 0.42.", "type": "CHEMICAL", "entities": [ "dabrafenib" ], "offsets": [ [ 100, 110 ] ] }, { "pmid": "23249624", "text": "Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b(-/-)Bcrp1(-/-) mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting K(p) of 0.25.", "type": "CHEMICAL", "entities": [ "Dabrafenib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23249624", "text": "Further, compared with vemurafenib, another BRAF(V600E) inhibitor, dabrafenib showed greater brain penetration with a similar dose.", "type": "CHEMICAL", "entities": [ "vemurafenib", "dabrafenib" ], "offsets": [ [ 21, 32 ], [ 65, 75 ] ] }, { "pmid": "23249624", "text": "In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.", "type": "CHEMICAL", "entities": [ "dabrafenib" ], "offsets": [ [ 17, 27 ] ] }, { "pmid": "23330542", "text": "PXR antagonists and implication in drug metabolism.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism.", "type": "CHEMICAL", "entities": [ "pregnane" ], "offsets": [ [ 38, 46 ] ] }, { "pmid": "23330542", "text": "Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "However, more recently, it is clear that PXR is also an important mediator of adverse xeno-", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "(e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis)", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 16, 29 ] ] }, { "pmid": "23330542", "text": "metabolic phenotypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "Thus, in these instances, there may be a role for PXR antagonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "The mode of action of these antagonists (e.g., sulforaphane) remains less clear.", "type": "CHEMICAL", "entities": [ "sulforaphane" ], "offsets": [ [ 47, 59 ] ] }, { "pmid": "23330542", "text": "Our laboratory efforts have focused on this question.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330542", "text": "Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists.", "type": "CHEMICAL", "entities": [ "azoles" ], "offsets": [ [ 32, 38 ] ] }, { "pmid": "23330542", "text": "In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold.", "type": "CHEMICAL", "entities": [ "azole" ], "offsets": [ [ 118, 123 ] ] }, { "pmid": "23330542", "text": "Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "Biophysical properties, pharmacology, and modulation of human, neuronal L-type (alpha(1D), Ca(V)1.3) voltage-dependent calcium currents.\n", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 119, 126 ] ] }, { "pmid": "11160515", "text": "Voltage-dependent calcium channels (VDCCs) are multimeric complexes composed of a pore-forming alpha(1) subunit together with several accessory subunits, including alpha(2)delta, beta, and, in some cases, gamma subunits.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "11160515", "text": "A family of VDCCs known as the L-type channels are formed specifically from alpha(1S) (skeletal muscle), alpha(1C) (in heart and brain), alpha(1D) (mainly in brain, heart, and endocrine tissue), and alpha(1F) (retina).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "Neuroendocrine L-type currents have a significant role in the control of neurosecretion and can be inhibited by GTP-binding (G-) proteins.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 112, 115 ] ] }, { "pmid": "11160515", "text": "However, the subunit composition of the VDCCs underlying these G-protein-regulated neuroendocrine L-type currents is unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "To investigate the biophysical and pharmacological properties and role of G-protein modulation of alpha(1D) calcium channels, we have examined calcium channel currents formed by the human neuronal L-type alpha(1D) subunit, co-expressed with alpha(2)delta-1 and beta(3a), stably expressed in a human embryonic kidney (HEK) 293 cell line, using whole cell and perforated patch-clamp techniques.", "type": "CHEMICAL", "entities": [ "calcium", "calcium" ], "offsets": [ [ 108, 115 ], [ 143, 150 ] ] }, { "pmid": "11160515", "text": "The alpha(1D)-expressing cell line exhibited L-type currents with typical characteristics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "The currents were high-voltage activated (peak at +20 mV in 20 mM Ba2+) and showed little inactivation in external Ba2+, while displaying rapid inactivation kinetics in external Ca2+.", "type": "CHEMICAL", "entities": [ "Ba2+", "Ba2+", "Ca2+" ], "offsets": [ [ 66, 70 ], [ 115, 119 ], [ 178, 182 ] ] }, { "pmid": "11160515", "text": "The L-type currents were inhibited by the 1,4 dihydropyridine (DHP) antagonists nifedipine and nicardipine and were enhanced by the DHP agonist BayK S-(-)8644.", "type": "CHEMICAL", "entities": [ "1,4 dihydropyridine", "DHP", "nifedipine", "nicardipine", "DHP", "BayK S-(-)8644" ], "offsets": [ [ 42, 61 ], [ 63, 66 ], [ 80, 90 ], [ 95, 106 ], [ 132, 135 ], [ 144, 158 ] ] }, { "pmid": "11160515", "text": "However, alpha(1D) L-type currents were not modulated by activation of a number of G-protein pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "Activation of endogenous somatostatin receptor subtype 2 (sst2) by somatostatin-14 or activation of transiently transfected rat D2 dopamine receptors (rD2(long))", "type": "CHEMICAL", "entities": [ "somatostatin", "somatostatin-14", "dopamine" ], "offsets": [ [ 25, 37 ], [ 67, 82 ], [ 131, 139 ] ] }, { "pmid": "11160515", "text": "by quinpirole had no effect.", "type": "CHEMICAL", "entities": [ "quinpirole" ], "offsets": [ [ 3, 13 ] ] }, { "pmid": "11160515", "text": "Direct activation of G-proteins by the nonhydrolyzable GTP analogue, guanosine 5'-0-(3-thiotriphospate) also had no effect on the alpha(1D) currents.", "type": "CHEMICAL", "entities": [ "GTP", "guanosine 5'-0-(3-thiotriphospate)" ], "offsets": [ [ 55, 58 ], [ 69, 103 ] ] }, { "pmid": "11160515", "text": "In contrast, in the same system, N-type currents, formed from transiently transfected alpha(1B)/alpha(2)delta-1/beta(3), showed strong G-protein-mediated inhibition.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 33, 34 ] ] }, { "pmid": "11160515", "text": "Furthermore, the I-II loop from the alpha(1D) clone, expressed as a glutathione-S-transferase (GST) fusion protein, did not bind Gbetagamma, unlike the alpha(1B)", "type": "CHEMICAL", "entities": [ "glutathione", "S" ], "offsets": [ [ 68, 79 ], [ 80, 81 ] ] }, { "pmid": "11160515", "text": "I-II loop fusion protein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11160515", "text": "These data show that the biophysical and pharmacological properties of recombinant human alpha(1D) L-type currents are similar to alpha(1C) currents, and these currents are also resistant to modulation by G(i/o)-linked G-protein-coupled receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23403203", "text": "Antofine-induced connexin43 gap junction disassembly in rat astrocytes involves protein kinase Cβ.\nAntofine, a phenanthroindolizidine alkaloid derived from Cryptocaryachinensis and Ficusseptica in the Asclepiadaceae milkweed family, is cytotoxic for various cancer cell lines.", "type": "CHEMICAL", "entities": [ "Antofine", "phenanthroindolizidine alkaloid", "Antofine" ], "offsets": [ [ 99, 107 ], [ 111, 142 ], [ 0, 8 ] ] }, { "pmid": "23403203", "text": "In this study, we demonstrated that treatment of rat primary astrocytes with antofine induced dose-dependent inhibition of gap junction intercellular communication (GJIC), as assessed by scrape-loading 6-carboxyfluorescein dye transfer.", "type": "CHEMICAL", "entities": [ "antofine", "6-carboxyfluorescein" ], "offsets": [ [ 76, 84 ], [ 201, 221 ] ] }, { "pmid": "23403203", "text": "Levels of Cx43 protein were also decreased in a dose- and time-dependent manner following antofine treatment.", "type": "CHEMICAL", "entities": [ "antofine" ], "offsets": [ [ 89, 97 ] ] }, { "pmid": "23403203", "text": "Double-labeling immunofluorescence microscopy showed that antofine (10ng/ml) induced endocytosis of surface gap junctions into the cytoplasm, where Cx43 was co-localized with the early endosome marker EEA1.", "type": "CHEMICAL", "entities": [ "antofine" ], "offsets": [ [ 57, 65 ] ] }, { "pmid": "23403203", "text": "Inhibition of lysosomes or proteasomes by co-treatment with antofine and their respective specific inhibitors, NH4Cl or MG132, partially inhibited the antofine-induced decrease in Cx43 protein levels, but did not inhibit the antofine-induced inhibition of GJIC.", "type": "CHEMICAL", "entities": [ "antofine", "NH4Cl", "MG132" ], "offsets": [ [ 59, 67 ], [ 110, 115 ], [ 119, 124 ] ] }, { "pmid": "23403203", "text": "After 30min of treatment, antofine induced a rapid increase in the intracellular Ca(2+) concentration and activation of protein kinase C (PKC)α/βII, which was maintained for at least 6h.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 80, 86 ] ] }, { "pmid": "23403203", "text": "Co-treatment of astrocytes with antofine and the intracellular Ca(2+) chelator BAPTA-AM prevented downregulation of Cx43 and inhibition of GJIC.", "type": "CHEMICAL", "entities": [ "antofine", "Ca(2+)", "BAPTA-AM" ], "offsets": [ [ 29, 37 ], [ 60, 66 ], [ 76, 84 ] ] }, { "pmid": "23403203", "text": "Moreover, co-treatment with antofine and a specific PKCβ inhibitor prevented endocytosis of gap junctions, downregulation of Cx43, and inhibition of GJIC.", "type": "CHEMICAL", "entities": [ "antofine" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "23403203", "text": "Taken together, these findings indicate that antofine induces Cx43 gap junction disassembly by the PKCβ signaling pathway.", "type": "CHEMICAL", "entities": [ "antofine" ], "offsets": [ [ 41, 49 ] ] }, { "pmid": "23403203", "text": "Inhibition of GJIC by antofine may undermine the neuroprotective effect of astrocytes in CNS.", "type": "CHEMICAL", "entities": [ "antofine" ], "offsets": [ [ 17, 25 ] ] }, { "pmid": "10406837", "text": "Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats.\n", "type": "CHEMICAL", "entities": [ "Torasemide", "calcium" ], "offsets": [ [ 0, 10 ], [ 78, 85 ] ] }, { "pmid": "10406837", "text": "Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension.", "type": "CHEMICAL", "entities": [ "Torasemide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10406837", "text": "Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10406837", "text": "In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats.", "type": "CHEMICAL", "entities": [ "torasemide" ], "offsets": [ [ 65, 75 ] ] }, { "pmid": "10406837", "text": "Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats.", "type": "CHEMICAL", "entities": [ "calcium", "Ca(2+)" ], "offsets": [ [ 47, 54 ], [ 71, 77 ] ] }, { "pmid": "10406837", "text": "A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10406837", "text": "Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L).", "type": "CHEMICAL", "entities": [ "torasemide" ], "offsets": [ [ 124, 134 ] ] }, { "pmid": "10406837", "text": "Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3).", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 129, 135 ] ] }, { "pmid": "10406837", "text": "The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L).", "type": "CHEMICAL", "entities": [ "Ca(2+)", "torasemide" ], "offsets": [ [ 27, 33 ], [ 116, 126 ] ] }, { "pmid": "10406837", "text": "Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro.", "type": "CHEMICAL", "entities": [ "torasemide" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "10406837", "text": "This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs.", "type": "CHEMICAL", "entities": [ "torasemide", "Ca(2+)" ], "offsets": [ [ 45, 55 ], [ 82, 88 ] ] }, { "pmid": "10406837", "text": "It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo.", "type": "CHEMICAL", "entities": [ "torasemide" ], "offsets": [ [ 86, 96 ] ] }, { "pmid": "23262271", "text": "Characterization of tyrosinase inhibitors in the twigs of Cudrania tricuspidata and their structure-activity relationship study.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262271", "text": "The twigs of Cudrania tricuspidata were found to show strong tyrosinase inhibitory activity, and further detailed component analysis resulted in the isolation of a new flavanol glucoside, (2S,3S)-2,3-trans-dihydromorin-7-O-β-d-glucoside (1), plus twenty-seven known compounds (2-28).", "type": "CHEMICAL", "entities": [ "flavanol glucoside", "(2S,3S)-2,3-trans-dihydromorin-7-O-β-d-glucoside" ], "offsets": [ [ 168, 186 ], [ 188, 236 ] ] }, { "pmid": "23262271", "text": "Their structures were elucidated on the basis of ESI-MS and NMR spectral data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262271", "text": "Among the isolated compounds, trans-dihydromorin (8), oxyresveratrol (9), and steppogenin (12) were found to exhibit significant tyrosinase inhibition activities.", "type": "CHEMICAL", "entities": [ "trans-dihydromorin", "oxyresveratrol", "steppogenin" ], "offsets": [ [ 29, 47 ], [ 53, 67 ], [ 77, 88 ] ] }, { "pmid": "23262271", "text": "Moreover, the structure-activity relationship of these isolated compounds was also discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17216302", "text": "Pyridoxal 5'-phosphate may be curative in early-onset epileptic encephalopathy.\n", "type": "CHEMICAL", "entities": [ "Pyridoxal 5'-phosphate" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "17216302", "text": "Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17216302", "text": "These conditions are often unresponsive to treatment with conventional antiepileptic drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17216302", "text": "Six children with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy.", "type": "CHEMICAL", "entities": [ "pyridox(am)ine-5'-phosphate" ], "offsets": [ [ 18, 45 ] ] }, { "pmid": "17216302", "text": "Two were treated with pyridoxal 5'-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter.", "type": "CHEMICAL", "entities": [ "pyridoxal 5'-phosphate", "PLP" ], "offsets": [ [ 22, 44 ], [ 46, 49 ] ] }, { "pmid": "17216302", "text": "Four children with late or no treatment died or showed severe mental handicap.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17216302", "text": "All of the children showed atypical biochemical findings.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17216302", "text": "Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 22, 25 ] ] }, { "pmid": "10670413", "text": "The prostaglandin E series modulates high-voltage-activated calcium channels probably through the EP3 receptor in rat paratracheal ganglia.\n", "type": "CHEMICAL", "entities": [ "prostaglandin E", "calcium" ], "offsets": [ [ 4, 19 ], [ 60, 67 ] ] }, { "pmid": "10670413", "text": "The modulation of high-voltage-activated (HVA) Ca2+ channels by the prostaglandin E series (PGE1 and PGE2) was studied in the paratracheal ganglion cells.", "type": "CHEMICAL", "entities": [ "PGE2", "Ca2+", "prostaglandin E", "PGE1" ], "offsets": [ [ 101, 105 ], [ 47, 51 ], [ 68, 83 ], [ 92, 96 ] ] }, { "pmid": "10670413", "text": "Prostaglandin E1, E2, STA2 (a stable analogue of thromboxane A2), 17-phenyl-trinor-PGE2 (an EP1-selective agonist) and sulprostone (an EP3-selective agonist) inhibited the HVA Ca2+ current (HVA ICa) dose-dependently, and the rank order of potency to inhibit HVA Ca2+ channels was sulprostone>PGE2, PGE1>STA2>>17-phenyl-trinor-PGE2. SC-51089 (10(-5) M), a selective EP1-receptor antagonist, showed no effect on the PGE1- or PGE2-induced inhibition of the HVA ICa, thereby indicating that PGE1- and PGE2-induced inhibition of the HVA Ca2+ channels is possibly mediated by the EP3 receptor.", "type": "CHEMICAL", "entities": [ "Prostaglandin E1, E2,", "STA2", "thromboxane A2", "17-phenyl-trinor-PGE2", "sulprostone", "Ca2+", "Ca2+", "sulprostone", "PGE2", "PGE1", "STA2", "17-phenyl-trinor-PGE2", "SC-51089", "PGE1", "PGE2", "PGE1", "PGE2", "Ca2+" ], "offsets": [ [ 0, 21 ], [ 22, 26 ], [ 49, 63 ], [ 66, 87 ], [ 119, 130 ], [ 176, 180 ], [ 262, 266 ], [ 280, 291 ], [ 292, 296 ], [ 298, 302 ], [ 303, 307 ], [ 309, 330 ], [ 332, 340 ], [ 414, 418 ], [ 423, 427 ], [ 487, 491 ], [ 497, 501 ], [ 532, 536 ] ] }, { "pmid": "10670413", "text": "The PGE1-sensitive component of the current was markedly reduced in the presence of omega-conotoxin-GVIA (3x10(-6) M), but not with nifedipine (3x10(-6) M).", "type": "CHEMICAL", "entities": [ "PGE1", "nifedipine" ], "offsets": [ [ 4, 8 ], [ 132, 142 ] ] }, { "pmid": "10670413", "text": "PGE1 and PGE2 also inhibited the remaining ICa in a saturating concentration of nifedipine, omega-conotoxin-GVIA and omega-conotoxin-MVIIC, suggesting that R-type Ca2+ channels are involved.", "type": "CHEMICAL", "entities": [ "Ca2+", "PGE1", "PGE2", "nifedipine" ], "offsets": [ [ 163, 167 ], [ 0, 4 ], [ 9, 13 ], [ 80, 90 ] ] }, { "pmid": "10670413", "text": "The inhibitory effect of PGE1 or sulprostone was prevented by pretreatment with pertussis toxin [islet activating protein (IAP)] or phorbol-12-myristate-13-acetate (PMA), and the protein kinase C (PKC) inhibitor chelerythrine blocked the action of PMA.", "type": "CHEMICAL", "entities": [ "PGE1", "sulprostone", "phorbol-12-myristate-13-acetate", "PMA", "chelerythrine", "PMA" ], "offsets": [ [ 25, 29 ], [ 33, 44 ], [ 132, 163 ], [ 165, 168 ], [ 212, 225 ], [ 248, 251 ] ] }, { "pmid": "10670413", "text": "It was concluded that PGE1 selectively reduces both N- and R-type Ca2+ currents by activating a G-protein probably through the EP3 receptor in paratracheal ganglion cells.", "type": "CHEMICAL", "entities": [ "PGE1", "Ca2+" ], "offsets": [ [ 22, 26 ], [ 66, 70 ] ] }, { "pmid": "11936838", "text": "Inhibition of MCP-1 and MIP-2 transcription and translation by mimosine in muscle tissue infected with the parasite Trichinella spiralis.\n", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 63, 71 ] ] }, { "pmid": "11936838", "text": "Mimosine is a non-toxic plant aminoacid which is an effective inhibitor of DNA replication by acting at the S-phase.", "type": "CHEMICAL", "entities": [ "Mimosine", "aminoacid" ], "offsets": [ [ 0, 8 ], [ 30, 39 ] ] }, { "pmid": "11936838", "text": "In this study we infected mice with T. spiralis, a nematode parasite, and studied the inflammatory response through the determination of MIP-2, a C-X-C chemokine and MCP-1, a C-C chemokine in the inflamed area around the parasitic cyst.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11936838", "text": "The animals were infected and their diaphragms were tested for inflammatory response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11936838", "text": "MCP-1 and MIP-2 was tested after 1, 10, 20, 30, and 40 days post inoculation, before and after mimosine treatment.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "11936838", "text": "The inflammatory index was calculated by counting the white blood cells around the nematode cysts, while expression of MIP-2 and MCP-1 was calculated by ELISA method and transcription by Northern blot and RT-PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11936838", "text": "Here we found that mimosine strongly inhibited the inflammatory index in the diaphragmatic tissue at 10, 20, 30 and 40 days post-treatment.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 19, 27 ] ] }, { "pmid": "11936838", "text": "In these experiments, mimosine had no effect on the number of cysts produced.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 22, 30 ] ] }, { "pmid": "11936838", "text": "In addition, we found that MCP-1 transcription and translation was completely inhibited by mimosine, while MIP-2 transcription and translation was partially inhibited at 30 and 40 days; yet it was totally inhibited after 10 and 20 days in encysted diaphragm tissue infected by T. spiralis.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 91, 99 ] ] }, { "pmid": "11936838", "text": "Our studies suggest that mimosine has an inhibitory effect through the inhibition of cytoplasmatic serine hydroxymethyltransferase altering the cell cycle of white blood cells.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "11936838", "text": "This study suggests for the first time the premise that mimosine acts as an anti-inflammatory compound.", "type": "CHEMICAL", "entities": [ "mimosine" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "23422872", "text": "Balancing societal needs and regulatory certainty: the case study of peramivir in Japan.\n", "type": "CHEMICAL", "entities": [ "peramivir" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "23422872", "text": "Regulators must balance societal and medical requirements against the need for certainty about benefit and risk for new medicines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23422872", "text": "This is described in a case study of the expedited review and approval of peramivir, a novel neuraminidase inhibitor, in Japan in the context of the emergence of new strain of influenza in 2009.", "type": "CHEMICAL", "entities": [ "peramivir" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "23422872", "text": "The case illustrates the importance of regulatory science and transparency in supporting such decision making.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "The influence of sex, ethnicity, and CYP2B6 genotype on bupropion metabolism as an index of hepatic CYP2B6 activity in humans.\n", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 56, 65 ] ] }, { "pmid": "23238783", "text": "The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate.", "type": "CHEMICAL", "entities": [ "bupropion", "Wellbutrin SR" ], "offsets": [ [ 158, 167 ], [ 169, 182 ] ] }, { "pmid": "23238783", "text": "A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "23238783", "text": "Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations.", "type": "CHEMICAL", "entities": [ "bupropion", "hydroxybupropion" ], "offsets": [ [ 83, 92 ], [ 102, 118 ] ] }, { "pmid": "23238783", "text": "Whole blood was obtained at baseline for CYP2B6 genotyping.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "Several CYP2B6 polymorphisms were associated with CYP2B6 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238783", "text": "These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 171, 180 ] ] }, { "pmid": "23238783", "text": "The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "23238783", "text": "Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.", "type": "CHEMICAL", "entities": [ "bupropion" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "8819507", "text": "Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats.\n", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 37, 49 ] ] }, { "pmid": "8819507", "text": "The alpha-2 adrenoceptor subtype and its signal transduction pathway mediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8819507", "text": "Removal of endothelium or incubation with NG-nitro-L-arginine completely blocked relaxant responses to UK14,304, suggesting endothelium-derived nitric oxide mediates relaxation.", "type": "CHEMICAL", "entities": [ "NG-nitro-L-arginine", "UK14,304", "nitric oxide" ], "offsets": [ [ 42, 61 ], [ 103, 111 ], [ 144, 156 ] ] }, { "pmid": "8819507", "text": "The order of potency for full (F) or partial (P) agonists causing relaxation was guanabenz (P) >", "type": "CHEMICAL", "entities": [ "guanabenz" ], "offsets": [ [ 81, 90 ] ] }, { "pmid": "8819507", "text": "UK14,304 (F) > clonidine (P) > epinephrine (F) > norepinephrine (F).", "type": "CHEMICAL", "entities": [ "UK14,304", "clonidine", "epinephrine", "norepinephrine" ], "offsets": [ [ 0, 8 ], [ 15, 24 ], [ 31, 42 ], [ 49, 63 ] ] }, { "pmid": "8819507", "text": "Affinities (Ka) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side-by-side experiments comparing rat mesenteric arteries with pig coronary arteries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8819507", "text": "Relaxation of pig coronary arteries is known to be mediated by the alpha-2A adrenoceptor subtype.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8819507", "text": "Ka values in nM for rauwolscine (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and prazosin (1531) for blocking relaxation in rat arteries were consistent with their affinities for binding at the alpha-2D adrenoceptor subtype.", "type": "CHEMICAL", "entities": [ "rauwolscine", "WB-4101", "SKF-104078", "spiroxatrine", "prazosin" ], "offsets": [ [ 20, 31 ], [ 38, 45 ], [ 53, 63 ], [ 71, 83 ], [ 95, 103 ] ] }, { "pmid": "8819507", "text": "Ka values for rauwolscine and WB-4101, drugs distinguishing the alpha-2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, suggesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxation in rat arteries.", "type": "CHEMICAL", "entities": [ "rauwolscine", "WB-4101", "NO" ], "offsets": [ [ 14, 25 ], [ 30, 37 ], [ 260, 262 ] ] }, { "pmid": "8819507", "text": "We used forskolin to oppose alpha-2 adrenoceptor-mediated inhibition of cAMP formation by directly stimulating cAMP formation in endothelium.", "type": "CHEMICAL", "entities": [ "forskolin", "cAMP", "cAMP" ], "offsets": [ [ 8, 17 ], [ 72, 76 ], [ 111, 115 ] ] }, { "pmid": "8819507", "text": "Forskolin did not affect the relaxant response to UK14,304, suggesting that cAMP is not involved in the coupling of alpha-2 adrenoceptors to nitric oxide-induced vascular relaxation.", "type": "CHEMICAL", "entities": [ "Forskolin", "UK14,304", "cAMP", "nitric oxide" ], "offsets": [ [ 0, 9 ], [ 50, 58 ], [ 76, 80 ], [ 141, 153 ] ] }, { "pmid": "23199998", "text": "Determination of paralytic shellfish poisoning toxins by HILIC-MS/MS coupled with dispersive solid phase extraction.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199998", "text": "This paper describes the use of QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) for the extraction, cleanup and detection of 10 paralytic shellfish toxins (PSP) in sea food by HILIC-MS/MS with positive ESI.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199998", "text": "Matrix matched calibration standards were used to compensate for matrix effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199998", "text": "The toxins were extracted with acetonitrile/water (90:10, v/v) containing 0.1% formic acid and cleaned by HLB and GCB sorbents.", "type": "CHEMICAL", "entities": [ "acetonitrile", "formic acid", "GCB" ], "offsets": [ [ 31, 43 ], [ 79, 90 ], [ 114, 117 ] ] }, { "pmid": "23199998", "text": "Qualitative and quantitative detection for the analytes were carried out under the multiple reaction monitoring (MRM) in positive ionization mode after chromatography separation on a TSK-gel Amide-80® column (150 mm×2.0 mm×3 μm).", "type": "CHEMICAL", "entities": [ "Amide" ], "offsets": [ [ 191, 196 ] ] }, { "pmid": "23199998", "text": "Studies at three fortification levels for the toxins in the range of 8.1-225.5 μg/kg gave mean recoveries from 71.3% to 104.6% with relative standard deviation (RSD) ≤ 15.8%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23199998", "text": "The limit of detection (LOD) was below the recommended regulatory limit of 170 μgSTX(equ.)/kg and the proposed method fully meets the needs of daily monitoring.", "type": "CHEMICAL", "entities": [ "STX" ], "offsets": [ [ 74, 77 ] ] }, { "pmid": "17192395", "text": "Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17192395", "text": "The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.", "type": "CHEMICAL", "entities": [ "succinate", "succinate" ], "offsets": [ [ 26, 35 ], [ 143, 152 ] ] }, { "pmid": "10826417", "text": "Neostigmine: safe and effective treatment for acute colonic pseudo-obstruction.\n", "type": "CHEMICAL", "entities": [ "Neostigmine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "10826417", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "Ogilvie's syndrome, or acute colonic pseudo-obstruction, is a common and relatively dangerous condition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "If left untreated, it may cause ischemic necrosis and colonic perforation, with a mortality rate as high as 50 percent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "Neostigmine enhances excitatory parasympathetic activity by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission and enhancing cholinergic action.", "type": "CHEMICAL", "entities": [ "Neostigmine", "acetylcholine" ], "offsets": [ [ 0, 11 ], [ 75, 88 ] ] }, { "pmid": "10826417", "text": "We hypothesized that neostigmine would restore peristalsis in patients with acute colonic pseudo-obstruction.", "type": "CHEMICAL", "entities": [ "neostigmine" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "10826417", "text": "METHODS: Twenty-eight patients at Fletcher Allen Health Care and The Cleveland Clinic Foundation were treated for acute colonic pseudo-obstruction with neostigmine 2.5 mg IV over 3 minutes while being monitored with telemetry.", "type": "CHEMICAL", "entities": [ "neostigmine" ], "offsets": [ [ 152, 163 ] ] }, { "pmid": "10826417", "text": "Mechanical obstruction had been excluded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "Complete clinical resolution of large bowel distention occurred in 26 of the 28 patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "Time to pass flatus varied from 30 seconds to 10 minutes after administration of neostigmine.", "type": "CHEMICAL", "entities": [ "neostigmine" ], "offsets": [ [ 81, 92 ] ] }, { "pmid": "10826417", "text": "No adverse effects or complications were noted.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "Of the two patients who did not resolve, one had a sigmoid cancer that required resection and one patient died from multiorgan failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "This study supports the theory that acute colonic pseudo-obstruction is the result of excessive parasympathetic suppression rather than sympathetic overactivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10826417", "text": "We have shown that neostigmine is a safe and effective treatment for acute colonic pseudo-obstruction.", "type": "CHEMICAL", "entities": [ "neostigmine" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23100158", "text": "Apoptosis initiation of β-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway.\nβ-ionone has been shown to hold potent anti-proliferative and apoptosis induction properties in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "β-ionone", "β-ionone" ], "offsets": [ [ 100, 108 ], [ 24, 32 ] ] }, { "pmid": "23100158", "text": "To investigate the effects of β-ionone on apoptosis initiation and its possible mechanisms of action, we qualified cell apoptosis, proteins related to apoptosis and a phosphatidylinositol 3-kinase (PI3K)-AKT pathway in human gastric adenocarcinoma cancer SGC-7901 cells.", "type": "CHEMICAL", "entities": [ "β-ionone", "phosphatidylinositol" ], "offsets": [ [ 28, 36 ], [ 165, 185 ] ] }, { "pmid": "23100158", "text": "The results demonstrated that β-ionone-induced apoptosis in a dose-dependent manner in SGC-7901 cells treated with β-ionone", "type": "CHEMICAL", "entities": [ "β-ionone", "β-ionone" ], "offsets": [ [ 27, 35 ], [ 112, 120 ] ] }, { "pmid": "23100158", "text": "(25, 50, 100 and 200 μmol/L) for 24 h. β-ionone was also shown to induce the expression of cleaved-caspase-3 and inhibit bcl-2 expression in SGC-7901 cells in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "β-ionone" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "23100158", "text": "The significantly decreased levels of p-PI3K and p-AKT expression were observed in SGC-7901 cells after β-ionone treatments in a time- and dose-dependent manner (P < 0.01).", "type": "CHEMICAL", "entities": [ "β-ionone" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "23100158", "text": "Thus, the apoptosis induction in SGC-7901 cells by β-ionone may be regulated through a PI3K-AKT pathway.", "type": "CHEMICAL", "entities": [ "β-ionone" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "23100158", "text": "These results demonstrate a potential mechanism by which β-ionone to induce apoptosis initiation in SGC-7901 cells.", "type": "CHEMICAL", "entities": [ "β-ionone" ], "offsets": [ [ 44, 52 ] ] }, { "pmid": "12517247", "text": "Eprosartan for the treatment of hypertension.\n", "type": "CHEMICAL", "entities": [ "Eprosartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12517247", "text": "Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12517247", "text": "The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12517247", "text": "Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature.", "type": "CHEMICAL", "entities": [ "Angiotensin II", "AII", "AII", "AII" ], "offsets": [ [ 0, 14 ], [ 16, 19 ], [ 106, 109 ], [ 170, 173 ] ] }, { "pmid": "12517247", "text": "By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure.", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 77, 88 ] ] }, { "pmid": "12517247", "text": "However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P.", "type": "CHEMICAL", "entities": [ "AII", "bradykinin", "substance P" ], "offsets": [ [ 9, 12 ], [ 149, 159 ], [ 187, 198 ] ] }, { "pmid": "12517247", "text": "Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action.", "type": "CHEMICAL", "entities": [ "AII", "eprosartan", "biphenyl", "tetrazole" ], "offsets": [ [ 20, 23 ], [ 34, 44 ], [ 138, 146 ], [ 152, 161 ] ] }, { "pmid": "12517247", "text": "Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release.", "type": "CHEMICAL", "entities": [ "Eprosartan", "noradrenaline" ], "offsets": [ [ 0, 10 ], [ 144, 157 ] ] }, { "pmid": "12517247", "text": "Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12517247", "text": "In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects.", "type": "CHEMICAL", "entities": [ "eprosartan", "enalapril" ], "offsets": [ [ 20, 30 ], [ 129, 138 ] ] }, { "pmid": "12517247", "text": "Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.", "type": "CHEMICAL", "entities": [ "Eprosartan", "hydrochlorothiazide" ], "offsets": [ [ 0, 10 ], [ 157, 176 ] ] }, { "pmid": "17040106", "text": "Reductive detoxification of arylhydroxylamine carcinogens by human NADH cytochrome b5 reductase and cytochrome b5.\n", "type": "CHEMICAL", "entities": [ "arylhydroxylamine", "NADH" ], "offsets": [ [ 28, 45 ], [ 67, 71 ] ] }, { "pmid": "17040106", "text": "Heterocyclic and aromatic amine carcinogens are thought to lead to tumor initiation via the formation of DNA adducts, and bioactivation to arylhydroxylamine metabolites is necessary for reactivity with DNA.", "type": "CHEMICAL", "entities": [ "Heterocyclic and aromatic amine", "arylhydroxylamine" ], "offsets": [ [ 0, 31 ], [ 139, 156 ] ] }, { "pmid": "17040106", "text": "Carcinogenic arylhydroxylamine metabolites are cleared by a microsomal, NADH-dependent, oxygen-insensitive reduction pathway in humans, which may be a source of interindividual variability in response to aromatic amine carcinogens.", "type": "CHEMICAL", "entities": [ "arylhydroxylamine", "NADH", "oxygen", "aromatic amine" ], "offsets": [ [ 13, 30 ], [ 72, 76 ], [ 88, 94 ], [ 204, 218 ] ] }, { "pmid": "17040106", "text": "The purpose of this study was to characterize the identity of this reduction pathway in human liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17040106", "text": "On the basis of our findings with structurally similar arylhydroxylamine metabolites of therapeutic drugs, we hypothesized that the reductive detoxification of arylhydroxylamine carcinogens was catalyzed by NADH cytochrome b5 reductase (b5R) and cytochrome b5 (cyt b5).", "type": "CHEMICAL", "entities": [ "arylhydroxylamine", "arylhydroxylamine", "NADH" ], "offsets": [ [ 55, 72 ], [ 160, 177 ], [ 207, 211 ] ] }, { "pmid": "17040106", "text": "We found that reduction of the carcinogenic hydroxylamines of the aromatic amine 4-aminobiphenyl (4-ABP; found in cigarette smoke) and the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP; found in grilled meats) was indeed catalyzed by a purified system containing only human b5R and cyt b5.", "type": "CHEMICAL", "entities": [ "PhIP", "hydroxylamines", "aromatic amine", "4-aminobiphenyl", "4-ABP", "heterocyclic amine", "2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine" ], "offsets": [ [ 209, 213 ], [ 44, 58 ], [ 66, 80 ], [ 81, 96 ], [ 98, 103 ], [ 139, 157 ], [ 158, 207 ] ] }, { "pmid": "17040106", "text": "Specific activities were 56-346-fold higher in the purified system as compared to human liver microsomes (HLM), with similar Michaelis-Menten constants (K(m) values) in both systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17040106", "text": "The stoichiometry for b5R and cyt b5 that yielded the highest activity in the purified system was also similar to that found in native HLM ( approximately 1:8 to 1:10).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17040106", "text": "Polyclonal antisera to either b5R or cyt b5 significantly inhibited N-hydroxy-4-aminobiphenyl (NHOH-4-ABP) reduction by 95 and 89%, respectively, and immunoreactive cyt b5 protein content in individual HLM was significantly correlated with individual reduction of both NHOH-4-ABP and N-hydroxy-PhIP (NHOH-PhIP).", "type": "CHEMICAL", "entities": [ "N-hydroxy-4-aminobiphenyl", "NHOH-4-ABP", "NHOH-4-ABP", "N-hydroxy-PhIP", "NHOH-PhIP" ], "offsets": [ [ 68, 93 ], [ 95, 105 ], [ 269, 279 ], [ 284, 298 ], [ 300, 309 ] ] }, { "pmid": "17040106", "text": "Finally, titration of HLM into the purified b5R/cyt b5 system did not enhance the efficiency of reduction activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17040106", "text": "We conclude that b5R and cyt b5 are together solely capable of the reduction of arylhydroxylamine carcinogens, and we further hypothesize that this pathway may be a source of individual variability with respect to cancer susceptibility following 4-ABP or PhIP exposure.", "type": "CHEMICAL", "entities": [ "arylhydroxylamine", "4-ABP", "PhIP" ], "offsets": [ [ 80, 97 ], [ 246, 251 ], [ 255, 259 ] ] }, { "pmid": "23485065", "text": "Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23485065", "text": "A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23485065", "text": "In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23485065", "text": "This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23485065", "text": "However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 122, 130 ] ] }, { "pmid": "7837275", "text": "Conformational transitions linked to active site ligation in human thrombin: effect on the interaction with fibrinogen and the cleavable platelet receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "An experimental strategy based on solution viscosity perturbation allowed us to study the energetics of amide-substrates, p-aminobenzamidine (p-ABZ) and proflavin binding to the catalytic site of two proteolyzed forms of alpha-thrombin, i.e. zeta- and gamma T-thrombin.", "type": "CHEMICAL", "entities": [ "amide", "p-aminobenzamidine", "p-ABZ", "proflavin" ], "offsets": [ [ 104, 109 ], [ 122, 140 ], [ 142, 147 ], [ 153, 162 ] ] }, { "pmid": "7837275", "text": "These thrombin derivatives are cleaved at the Leu144-Gly150 loop and at the fibrinogen recognition exosite (FRS), respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "A phenomenological analysis of thermodynamic data showed that the amide substrates and p-ABZ interactions with zeta-thrombin were respectively, associated with a chemical compensation (i.e. the linear relationship between entropy and enthalpy of binding) and a hydrophobic phenomenon (i.e. a change in the standard heat capacity).", "type": "CHEMICAL", "entities": [ "amide", "p-ABZ" ], "offsets": [ [ 66, 71 ], [ 87, 92 ] ] }, { "pmid": "7837275", "text": "The latter was slightly lower than that previously observed for a alpha-thrombin (0.78 +/- 0.25 versus 1.01 +/- 0.17 kcal/mol K).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "Both phenomenon were absent in gamma T-thrombin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "The interaction of a alpha-, zeta- and gamma T-thrombin with macromolecular substrates that \"bridge-bind\" to both the catalytic site (CS) and fibrinogen recognition exosite (FRS), such as fibrinogen and the cleavable platelet receptor (CPR), was also evaluated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "These interactions were studied by following fibrinopeptide A (FpA) release and by measuring intraplatelet Ca2+ changes induced by thrombin-CPR interaction.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 107, 111 ] ] }, { "pmid": "7837275", "text": "It was found that the free energy of activation (RT ln Kcat/Km) for both fibrinogen and CPR hydrolysis followed the same hierarchy, i.e. alpha > zeta > gamma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7837275", "text": "Moreover, the values of delta Cp for alpha-, zeta- and gamma T-thrombin interaction with p-ABZ were found to be linearly correlated to the free energy of activation for both fibrinogen and CPR cleavage.", "type": "CHEMICAL", "entities": [ "p-ABZ" ], "offsets": [ [ 89, 94 ] ] }, { "pmid": "7837275", "text": "In conclusion, these data demonstrate that: (1) the Leu144-Gly150 loop and the FRS are both involved in the conformational transition linked to the binding of p-aminobenzamidine to the thrombin active site; (2) the extent of thrombin's capacity to undergo conformational transitions in alpha-, zeta- and gamma T forms is positively correlated to the free energy of activation for hydrolysis of macromolecular substrates interacting with both the catalytic domain and the FRS.", "type": "CHEMICAL", "entities": [ "p-aminobenzamidine" ], "offsets": [ [ 159, 177 ] ] }, { "pmid": "11103886", "text": "Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 157, 165 ] ] }, { "pmid": "11103886", "text": "Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11103886", "text": "We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls).", "type": "CHEMICAL", "entities": [ "chlorpromazine", "CPZ", "dopamine", "DA", "dopamine", "DA" ], "offsets": [ [ 81, 95 ], [ 109, 112 ], [ 156, 164 ], [ 166, 168 ], [ 220, 228 ], [ 252, 254 ] ] }, { "pmid": "11103886", "text": "Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11103886", "text": "Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11103886", "text": "Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity.", "type": "CHEMICAL", "entities": [ "DA", "DA" ], "offsets": [ [ 77, 79 ], [ 251, 253 ] ] }, { "pmid": "11103886", "text": "High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 26, 28 ] ] }, { "pmid": "11103886", "text": "This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 66, 68 ] ] }, { "pmid": "11264758", "text": "Clinical effects of pranlukast, an oral leukotriene receptor antagonist, in mild-to-moderate asthma: a 4 week randomized multicentre controlled trial.\n", "type": "CHEMICAL", "entities": [ "pranlukast", "leukotriene" ], "offsets": [ [ 20, 30 ], [ 40, 51 ] ] }, { "pmid": "11264758", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "Leukotriene antagonists are increasingly used in asthma management.", "type": "CHEMICAL", "entities": [ "Leukotriene" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11264758", "text": "Pranlukast is a new, orally active, selective inhibitor of CysLt1 leukotriene receptor.", "type": "CHEMICAL", "entities": [ "leukotriene", "Pranlukast" ], "offsets": [ [ 66, 77 ], [ 0, 10 ] ] }, { "pmid": "11264758", "text": "The present clinical trial was performed to study the effect and safety of pranlukast in mild-to-moderate asthma.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 75, 85 ] ] }, { "pmid": "11264758", "text": "METHODOLOGY:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "A randomized, double-blind, placebo-controlled, parallel group study was performed in eight medical centres in Korea.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "Mild-to-moderate asthma patients who had been treated with beta2-agonists and/or inhaled corticosteroids were studied.", "type": "CHEMICAL", "entities": [ "corticosteroids" ], "offsets": [ [ 89, 104 ] ] }, { "pmid": "11264758", "text": "The patients' symptoms were evaluated by asthma diary and twice-daily peak flow monitoring.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "Of the 206 patients enrolled, 197 were eligible for analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "The pranlukast group (n = 98) showed statistically significant improvement in asthma symptoms, including asthma attack rate, daily living score, and morning and evening asthma scores.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 4, 14 ] ] }, { "pmid": "11264758", "text": "Pranlukast significantly reduced the consumption of beta2-agonist.", "type": "CHEMICAL", "entities": [ "Pranlukast" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "11264758", "text": "Compared with the placebo group, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were not significantly higher in the pranlukast group.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 141, 151 ] ] }, { "pmid": "11264758", "text": "Morning and evening peak expiratory flow (PEF) were significantly increased after pranlukast treatment at weeks 2 and 4 (380.8 +/- 10.1 L/min at baseline, 394.5 +/- 10.1 at week 2, 396.3 +/- 10.4 at week 4).", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 82, 92 ] ] }, { "pmid": "11264758", "text": "There were no serious adverse reactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11264758", "text": "Pranlukast, an oral leukotriene antagonist, was well tolerated and was effective for the management of mild-to-moderate asthma.", "type": "CHEMICAL", "entities": [ "Pranlukast", "leukotriene" ], "offsets": [ [ 0, 10 ], [ 20, 31 ] ] }, { "pmid": "23122081", "text": "Physicochemical parameters that influence carotenoids bioaccessibility from a tomato juice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122081", "text": "In vitro digestion models have been developed to estimate carotenoid bioavailability but most do not consider that their diffusion from fruit matrix to the lipid phase of the bolus could be a limiting step.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122081", "text": "Therefore we designed a model in which tomato juice is mixed with oil or oil/water emulsions, and the carotenoids diffusing to oil are measured by spectrometry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122081", "text": "Temperature, pH and tomato juice/peanut oil ratio were evaluated for their influence on carotenoid diffusion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122081", "text": "When oil/tomato ratio was between 0.11 and 1, extraction of lycopene was limited by the saturation of the oil phase.", "type": "CHEMICAL", "entities": [ "lycopene" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23122081", "text": "With a large excess of oil, diffusion was also limited, as only 31 ± 1% of lycopene could be extracted from the juice.", "type": "CHEMICAL", "entities": [ "lycopene" ], "offsets": [ [ 75, 83 ] ] }, { "pmid": "23122081", "text": "Diffusion did not vary significantly with pH but doubled when temperature rose from 10°C to 37°C.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23122081", "text": "When the juice was mixed in an emulsion stabilised with bovine serum albumin or phospholipids the maximum extraction decreased to 14.5 ± 0.2% and 18.5 ± 1.5% respectively, indicating that in addition to the saturation of the oil phase at low oil/tomato ratio and in addition to intrinsic properties of the tomato juice in non-saturating conditions, lycopene diffusion was limited by the structure of the interface in emulsions.", "type": "CHEMICAL", "entities": [ "lycopene" ], "offsets": [ [ 346, 354 ] ] }, { "pmid": "23587649", "text": "Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "NMDAR-independent MF-LTP", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": ".", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 17, 25 ] ] }, { "pmid": "23587649", "text": "Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23587649", "text": "Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16291873", "text": "Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs.\n", "type": "CHEMICAL", "entities": [ "clofilium", "ibutilide" ], "offsets": [ [ 124, 133 ], [ 138, 147 ] ] }, { "pmid": "16291873", "text": "Block of human ether-a-go-go related gene (hERG) K(+) channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to potentially fatal arrhythmias.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 49, 53 ] ] }, { "pmid": "16291873", "text": "This undesirable long QT side effect has been a major reason for the withdrawal of medications from the pharmaceutical market.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16291873", "text": "Understanding the molecular basis of hERG block is therefore essential to facilitate the design of safe drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16291873", "text": "Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625).", "type": "CHEMICAL", "entities": [ "Tyr", "Phe", "Thr", "Ser", "Val" ], "offsets": [ [ 135, 138 ], [ 144, 147 ], [ 185, 188 ], [ 194, 197 ], [ 203, 206 ] ] }, { "pmid": "16291873", "text": "We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions.", "type": "CHEMICAL", "entities": [ "clofilium", "ibutilide" ], "offsets": [ [ 104, 113 ], [ 118, 127 ] ] }, { "pmid": "16291873", "text": "Although changing the basic nitrogen from quaternary to tertiary accelerated the onset of block, the IC(50) and kinetics for recovery from block were similar.", "type": "CHEMICAL", "entities": [ "nitrogen" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "16291873", "text": "In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block.", "type": "CHEMICAL", "entities": [ "phenyl" ], "offsets": [ [ 61, 67 ] ] }, { "pmid": "16291873", "text": "The highest potency was achieved with polar or electronegative para-substituents, whereas neutral para-substituents had potencies more than 100-fold lower.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16291873", "text": "Results from mutagenesis and molecular modeling studies suggest that phenyl ring para-substituents influence drug interactions with Thr-623, Ser-624, and Tyr-652 and strongly affect binding affinity.", "type": "CHEMICAL", "entities": [ "phenyl", "Thr", "Ser", "Tyr" ], "offsets": [ [ 69, 75 ], [ 132, 135 ], [ 141, 144 ], [ 154, 157 ] ] }, { "pmid": "16291873", "text": "Together, these findings suggest that modifying the para-substituent could be a useful strategy for reducing hERG potency and increasing the safety margin of compounds in development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334864", "text": "Iron overload inhibits osteoblast biological activity through oxidative stress.\n", "type": "CHEMICAL", "entities": [ "Iron" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23334864", "text": "Iron overload has recently been connected with bone mineral density in osteoporosis.", "type": "CHEMICAL", "entities": [ "Iron" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23334864", "text": "However, to date, the effect of iron overload on osteoblasts remains poorly understood.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 32, 36 ] ] }, { "pmid": "23334864", "text": "The purpose of this study is to examine osteoblast biological activity under iron overload.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 77, 81 ] ] }, { "pmid": "23334864", "text": "The osteoblast cells (hFOB1.19) were cultured in a medium supplemented with different concentrations (50, 100, and 200 μM) of ferric ammonium citrate as a donor of ferric ion.", "type": "CHEMICAL", "entities": [ "ferric ammonium citrate", "ferric" ], "offsets": [ [ 126, 149 ], [ 164, 170 ] ] }, { "pmid": "23334864", "text": "Intracellular iron was measured with a confocal laser scanning microscope.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 12, 16 ] ] }, { "pmid": "23334864", "text": "Reactive oxygen species (ROS) were detected by 2,7-dichlorofluorescin diacetate fluorophotometry.", "type": "CHEMICAL", "entities": [ "oxygen", "2,7-dichlorofluorescin diacetate" ], "offsets": [ [ 7, 13 ], [ 45, 77 ] ] }, { "pmid": "23334864", "text": "Osteoblast biological activities were evaluated by measuring the activity of alkaline phosphatase (ALP) and mineralization function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334864", "text": "Results indicated that iron overload could consequently increase intracellular iron concentration and intracellular ROS levels in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "iron", "iron" ], "offsets": [ [ 21, 25 ], [ 77, 81 ] ] }, { "pmid": "23334864", "text": "Additionally, ALP activity was suppressed, and a decline in the number of mineralized nodules was observed in in vitro cultured osteoblast cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334864", "text": "According to these results, it seems that iron overload probably inhibits osteoblast function through higher oxidative stress following increased intracellular iron concentrations.", "type": "CHEMICAL", "entities": [ "iron", "iron" ], "offsets": [ [ 40, 44 ], [ 158, 162 ] ] }, { "pmid": "9509999", "text": "Adrenergic agonists suppress the proliferation of microglia through beta 2-adrenergic receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9509999", "text": "The effects of several cyclic adenosine monophosphate (cAMP)-elevating agents on the proliferation of cultured rat microglia were investigated by immunocytochemical staining with an antibody against proliferating cell nuclear antigen (PCNA).", "type": "CHEMICAL", "entities": [ "cyclic adenosine monophosphate", "cAMP" ], "offsets": [ [ 23, 53 ], [ 55, 59 ] ] }, { "pmid": "9509999", "text": "Epinephrine, isoproterenol, forskolin and 8Br-cAMP suppressed the microglial proliferation.", "type": "CHEMICAL", "entities": [ "Epinephrine", "isoproterenol", "forskolin", "8Br-cAMP" ], "offsets": [ [ 0, 11 ], [ 13, 26 ], [ 28, 37 ], [ 42, 50 ] ] }, { "pmid": "9509999", "text": "A beta2-selective agonist terbutaline but not a beta1-selective agonist dobutamine mimicked the effect of the above cAMP-elevating agents.", "type": "CHEMICAL", "entities": [ "terbutaline", "dobutamine", "cAMP" ], "offsets": [ [ 26, 37 ], [ 72, 82 ], [ 116, 120 ] ] }, { "pmid": "9509999", "text": "Furthermore, a non-selective beta-receptor antagonist oxprenolol and a beta2-selective antagonist acebutalol, but not a beta1-selective antagonist butoxamine, counteracted the suppressive effects of the beta-agonists on microglial proliferation.", "type": "CHEMICAL", "entities": [ "oxprenolol", "acebutalol", "butoxamine" ], "offsets": [ [ 54, 64 ], [ 98, 108 ], [ 147, 157 ] ] }, { "pmid": "9509999", "text": "These findings suggest that the beta-agonists suppress the proliferation of microglia by elevating intracellular cAMP level through an action on beta2-adrenergic receptor.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 113, 117 ] ] }, { "pmid": "23314331", "text": "Copper induced upregulation of apoptosis related genes in zebrafish (Danio rerio) gill.\n", "type": "CHEMICAL", "entities": [ "Copper" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23314331", "text": "Copper (Cu) is an essential micronutrient that, when present in high concentrations, becomes toxic to aquatic organisms.", "type": "CHEMICAL", "entities": [ "Copper", "Cu" ], "offsets": [ [ 0, 6 ], [ 8, 10 ] ] }, { "pmid": "23314331", "text": "It is known that Cu toxicity may induce apoptotic cell death.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 17, 19 ] ] }, { "pmid": "23314331", "text": "However, the precise mechanism and the pathways that are activated, in fish, are still unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314331", "text": "Thus, this study aimed to assess which apoptotic pathways are triggered by Cu, in zebrafish (Danio rerio) gill, the main target of waterborne pollutants.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 75, 77 ] ] }, { "pmid": "23314331", "text": "Fish where exposed to 12.5 and 100 μg/L of Cu during 6, 12, 24 and 48 h. Fish gills were collected to TUNEL assay and mRNA expression analysis of selected genes by real time PCR.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 43, 45 ] ] }, { "pmid": "23314331", "text": "An approach to different apoptosis pathways was done selecting p53, caspase-8, caspase-9 and apoptosis inducing factor (AIF) genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314331", "text": "The higher incidence of TUNEL-positive cells, in gill epithelia of the exposed fish, proved that Cu induced apoptosis.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 96, 98 ] ] }, { "pmid": "23314331", "text": "The results suggest that different apoptosis pathways are triggered by Cu at different time points of the exposure period, as the increase in transcripts was sequential, instead of simultaneous.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 70, 72 ] ] }, { "pmid": "23314331", "text": "Apoptosis seems to be initiated via intrinsic pathway (caspase-9), through p53 activation; then followed by the extrinsic pathway (caspase-8) and finally by the caspase-independent pathway (AIF).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314331", "text": "A possible model for Cu-induce apoptosis pathways is proposed.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 20, 22 ] ] }, { "pmid": "17390078", "text": "Gene expression signature of parathion-transformed human breast epithelial cells.\n", "type": "CHEMICAL", "entities": [ "parathion" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "17390078", "text": "Environmental substances seem to be involved in the etiology of breast cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17390078", "text": "Many studies have found an association between human cancer and exposure to agricultural pesticides such as the organophosphorous pesticides.", "type": "CHEMICAL", "entities": [ "organophosphorous" ], "offsets": [ [ 112, 129 ] ] }, { "pmid": "17390078", "text": "Parathion is a cholinesterase inhibitor that induces the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses.", "type": "CHEMICAL", "entities": [ "Parathion", "choline esters", "acetylcholine" ], "offsets": [ [ 0, 9 ], [ 76, 90 ], [ 102, 115 ] ] }, { "pmid": "17390078", "text": "The primary target of action in insects is the nervous system whereby pesticides inhibit the release of the enzyme acetylcholinesterase at the synaptic junction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17390078", "text": "Atropine is a parasympatholytic alkaloid used as an antidote to acetylcholinesterase inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17390078", "text": "The aim of this study was to determine the effect of parathion and atropine on cell transformation of human breast epithelial cells in vitro.", "type": "CHEMICAL", "entities": [ "parathion", "atropine" ], "offsets": [ [ 53, 62 ], [ 67, 75 ] ] }, { "pmid": "17390078", "text": "These studies showed that parathion alone was able to induce malignant transformation of an immortalized human breast epithelial cell line, MCF-10F as indicated by increased cell proliferation, anchorage independency and invasive capabilities.", "type": "CHEMICAL", "entities": [ "parathion" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "17390078", "text": "There was also an increase in c-kit, Trio, Rho-A, Rac-3, EGFR, Notch-4, Dvl-2, Ezrin, beta catenin and mutant p53 protein expression in the parathion-treated cells.", "type": "CHEMICAL", "entities": [ "parathion" ], "offsets": [ [ 140, 149 ] ] }, { "pmid": "17390078", "text": "However, atropine significantly inhibited this increase.", "type": "CHEMICAL", "entities": [ "atropine" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "17390078", "text": "In a human cell cycle array of 96 genes, 13 of them were altered by parathion treatment.", "type": "CHEMICAL", "entities": [ "parathion" ], "offsets": [ [ 68, 77 ] ] }, { "pmid": "17390078", "text": "Among the genes affected were the cyclins, such as cyclin D3, the cyclin-dependent kinases (CDKs) such as CDK41 and the minichromosome maintenance deficient (MCM) MCM2 and MCM3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17390078", "text": "It is suggested that parathion influences human breast epithelial cell transformation and is an initiator factor in the transformation process in breast cancer.", "type": "CHEMICAL", "entities": [ "parathion" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "9722550", "text": "Purification and multimeric structure of bovine N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase.\n", "type": "CHEMICAL", "entities": [ "N-acetylglucosamine-1-phosphodiester", "N" ], "offsets": [ [ 48, 84 ], [ 91, 92 ] ] }, { "pmid": "9722550", "text": "N-Acetylglucosamine-1-phosphodiester alpha-N-Acetylglucosaminidase (EC 3.1.4.45; phosphodiester alpha-GlcNAcase) catalyzes the second step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome.", "type": "CHEMICAL", "entities": [ "N-Acetylglucosamine-1-phosphodiester", "mannose 6-phosphate", "N" ], "offsets": [ [ 0, 36 ], [ 163, 182 ], [ 43, 44 ] ] }, { "pmid": "9722550", "text": "A partially purified preparation of phosphodiester alpha-GlcNAcase from bovine pancreas was used to generate a panel of murine monoclonal antibodies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9722550", "text": "The anti-phosphodiester alpha-GlcNAcase monoclonal antibody UC1 was coupled to a solid support and used to immunopurify the bovine liver enzyme 670,000-fold in two steps to apparent homogeneity with an overall yield of 14%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9722550", "text": "The purified phosphodiester alpha-GlcNAcase has a specific activity of 498 micromol of [3H]GlcNAc-alpha-phosphomannose-alpha-methyl cleaved per h per mg of protein using 0.5 mM", "type": "CHEMICAL", "entities": [ "[3H]GlcNAc-alpha-phosphomannose-alpha-methyl" ], "offsets": [ [ 87, 131 ] ] }, { "pmid": "9722550", "text": "[3H]GlcNAc-alpha-phosphomannose-alpha-methyl as substrate.", "type": "CHEMICAL", "entities": [ "[3H]GlcNAc-alpha-phosphomannose-alpha-methyl" ], "offsets": [ [ 0, 44 ] ] }, { "pmid": "9722550", "text": "The subunit structure of the enzyme was determined using a combination of analytical gel filtration chromatography, SDS-polyacrylamide gel electrophoresis, and amino-terminal sequencing.", "type": "CHEMICAL", "entities": [ "SDS", "polyacrylamide" ], "offsets": [ [ 116, 119 ], [ 120, 134 ] ] }, { "pmid": "9722550", "text": "The data indicate that bovine phosphodiester alpha-GlcNAcase is a 272,000-Da complex of four identical 68,000-Da glycoprotein subunits arranged as two disulfide-linked homodimers.", "type": "CHEMICAL", "entities": [ "phosphodiester", "disulfide" ], "offsets": [ [ 30, 44 ], [ 151, 160 ] ] }, { "pmid": "9722550", "text": "A soluble form of the enzyme, isolated from fetal bovine serum, showed the same subunit structure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9722550", "text": "Both forms of the enzyme reacted with a rabbit antibody raised to the amino-terminal peptide of the liver enzyme, suggesting that phosphodiester alpha-GlcNAcase is a type I membrane-spanning glycoprotein with its amino terminus in the lumen of the Golgi apparatus.", "type": "CHEMICAL", "entities": [ "amino", "amino" ], "offsets": [ [ 70, 75 ], [ 213, 218 ] ] }, { "pmid": "23339678", "text": "Impact of ketorolac administration around ovarian stimulation on in vivo and in vitro fertilization and subsequent embryo development.\n", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23339678", "text": "Abstract We performed this study to investigate the effect of ketorolac (a non-steroidal anti-inflammatory drug) administration around ovarian stimulation on in vivo and in vitro fertilization process.", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "23339678", "text": "Sixty-four female mice (ICR) were injected with ketorolac (0, 7.5, 15 and 30 µg/d) for 3 d starting from the day of eCG treatment.", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 48, 57 ] ] }, { "pmid": "23339678", "text": "In experiment 1, 41 mice were triggered by hCG and then mated; two-cell embryos were obtained and in vitro development up to blastocyst was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23339678", "text": "In experiment 2, 23 mice were triggered by hCG and mature oocytes were collected; in vitro fertilization rate and subsequent embryo development up to blastocyst was recorded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23339678", "text": "In experiment 1, the blastocyst-forming rates per in vivo fertilized two-cell embryo showed an inverse relationship with a dosage of ketorolac (97.6%, 64.2%, 35.4% and 25.9%).", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "23339678", "text": "In experiment 2, degenerated oocytes were frequently observed in a dose-dependent manner (4.3%, 22.9%, 22.4% and 75.0%).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23339678", "text": "Lower fertilization rates were noted in all the three ketorolac-treating groups; blastocyst-forming rate was significantly lower in 30-µg-treating group when compared with the control group.", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 49, 58 ] ] }, { "pmid": "23339678", "text": "Administration of ketorolac around ovarian stimulation significantly affects the development of in vivo fertilized embryo in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23339678", "text": "High-dose ketorolac could result in a poor oocyte quality and decreased embryo developmental competence.", "type": "CHEMICAL", "entities": [ "ketorolac" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "22776694", "text": "Passive stiffness of airway smooth muscle: the next target for improving airway distensibility and treatment for asthma?\nReduced airway distensibility due to increased airway stiffness is a characteristic of asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "Airway stiffness is determined by the property and structural organization of the various elements of the airway wall, and is often divided into active and passive components.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "Active stiffness is thought to be associated with activation of muscle cells in the airway wall.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "This component of stiffness can be inhibited when active force produced by the muscle is abolished.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "Passive stiffness, on the other hand, is thought to stem from non-muscle component of the airway wall, especially the collagen/elastin fibrous network of the extracellular matrix within which the muscle cells are embedded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "In this brief review, the notion that passive stiffness is exclusively extracellular in origin is challenged.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "Recent evidence suggests that a substantial portion of the passive stiffness of an in vitro preparation of tracheal smooth muscle is calcium sensitive and is regulated by Rho-kinase, although the underlying mechanism and the details of regulation for the development of this intracellular passive stiffness are still largely unknown.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 133, 140 ] ] }, { "pmid": "22776694", "text": "To reduce airway stiffness different lines of attack must be tailored to different components of the stiffness.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "The regulatable passive stiffness is distinct from the relatively permanent stiffness of the extracellular matrix and the stiffness associated with active muscle contraction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22776694", "text": "To improve airway distensibility during asthma exacerbation, a comprehensive approach to reduce overall airway stiffness should therefore include a strategy for targeting the regulatable passive stiffness.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500382", "text": "The vascular protective properties of kinsenoside isolated from Anoectochilus roxburghii under high glucose condition.\n", "type": "CHEMICAL", "entities": [ "glucose", "kinsenoside" ], "offsets": [ [ 100, 107 ], [ 38, 49 ] ] }, { "pmid": "23500382", "text": "Anoectochilus roxburghii is a traditional Chinese herb used for the treatment of diabetes and some other diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500382", "text": "The vascular protective effect of its major active ingredient, kinsenoside, in high glucose conditions was investigated in in vivo and in vitro experiments.", "type": "CHEMICAL", "entities": [ "kinsenoside", "glucose" ], "offsets": [ [ 63, 74 ], [ 84, 91 ] ] }, { "pmid": "23500382", "text": "In in vivo tests, kinsenoside (50 and 100mg/kg) efficiently lowered blood glucose and cholesterol levels and it enhanced the oxidation resistance of diabetic mice induced by streptozotocin.", "type": "CHEMICAL", "entities": [ "kinsenoside", "glucose", "cholesterol", "streptozotocin" ], "offsets": [ [ 18, 29 ], [ 74, 81 ], [ 86, 97 ], [ 174, 188 ] ] }, { "pmid": "23500382", "text": "In the in vitro assay, kinsenoside (20 and 50μg/mL) markedly inhibited changes in various biochemical substances (nitric oxide (NO), lactic dehydrogenase (LDH), superoxide dismutase (SOD), and catalase (CAT)) in human umbilical vein endothelial cells (HUVECs) damaged by high glucose (35mM) and restored vascular endothelial structure by balancing the matrix metalloproteinases-the tissue inhibitors of matrix metalloproteinases (MMP-TIMP) system.", "type": "CHEMICAL", "entities": [ "kinsenoside", "nitric oxide", "NO", "lactic", "superoxide", "glucose" ], "offsets": [ [ 23, 34 ], [ 114, 126 ], [ 128, 130 ], [ 133, 139 ], [ 161, 171 ], [ 276, 283 ] ] }, { "pmid": "23500382", "text": "The vascular protective effects of kinsenoside were speculated to be attributed to oxidative stress inhibition and the reduction of nuclear factor kappa B (NF-κB) mRNA expression levels in high glucose conditions.", "type": "CHEMICAL", "entities": [ "glucose", "kinsenoside" ], "offsets": [ [ 193, 200 ], [ 34, 45 ] ] }, { "pmid": "23500382", "text": "Moreover, histological examination, including hematoxylin-eosin (H&E) staining, masson trichrome (Masson) staining, and periodic Schiff-methenamine (PASM) staining, greatly supported the morphological and functional amelioration of diabetes-related changes in mice aortas after kinsenoside (20 and 50μg/mL) treatment.", "type": "CHEMICAL", "entities": [ "hematoxylin", "eosin", "methenamine", "kinsenoside" ], "offsets": [ [ 44, 55 ], [ 56, 61 ], [ 134, 145 ], [ 276, 287 ] ] }, { "pmid": "23500382", "text": "These results indicated that kinsenoside might be a promising agent for the treatment of diabetic vascular disease.", "type": "CHEMICAL", "entities": [ "kinsenoside" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "23337607", "text": "Prenatal exposure to bisphenol", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23337607", "text": "A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 19, 27 ] ] }, { "pmid": "23337607", "text": "Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor.", "type": "CHEMICAL", "entities": [ "bisphenol-A", "BPA" ], "offsets": [ [ 17, 28 ], [ 30, 33 ] ] }, { "pmid": "23337607", "text": "Some rodent studies have suggested that BPA can exert detrimental effects on brain development.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 40, 43 ] ] }, { "pmid": "23337607", "text": "However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development.", "type": "CHEMICAL", "entities": [ "BPA", "BPA" ], "offsets": [ [ 90, 93 ], [ 160, 163 ] ] }, { "pmid": "23337607", "text": "Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates.", "type": "CHEMICAL", "entities": [ "BPA", "dopamine", "BPA" ], "offsets": [ [ 32, 35 ], [ 59, 67 ], [ 220, 223 ] ] }, { "pmid": "23337607", "text": "Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 64, 67 ] ] }, { "pmid": "23337607", "text": "Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus.", "type": "CHEMICAL", "entities": [ "tyrosine", "dopamine", "BPA" ], "offsets": [ [ 54, 62 ], [ 87, 95 ], [ 124, 127 ] ] }, { "pmid": "23337607", "text": "In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity.", "type": "CHEMICAL", "entities": [ "BPA", "dopamine", "serotonin" ], "offsets": [ [ 31, 34 ], [ 127, 135 ], [ 140, 149 ] ] }, { "pmid": "23337607", "text": "These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA.", "type": "CHEMICAL", "entities": [ "BPA", "BPA" ], "offsets": [ [ 25, 28 ], [ 193, 196 ] ] }, { "pmid": "23071106", "text": "Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: comparison of tolbutamide and gliclazide and a potential role for EPAC activation of a 2-APB-sensitive Ca2+ influx.\n", "type": "CHEMICAL", "entities": [ "gliclazide", "sulfonylurea", "cAMP", "tolbutamide" ], "offsets": [ [ 115, 125 ], [ 16, 28 ], [ 57, 61 ], [ 99, 110 ] ] }, { "pmid": "23071106", "text": "Tolbutamide and gliclazide block the K(ATP) channel K(ir)6.2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells.", "type": "CHEMICAL", "entities": [ "Tolbutamide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23071106", "text": "We examined the ability of the EPAC-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it.", "type": "CHEMICAL", "entities": [ "cAMP", "8-pCPT-2'-O-Me-cAMP-AM" ], "offsets": [ [ 46, 50 ], [ 58, 80 ] ] }, { "pmid": "23071106", "text": "Insulin secretion stimulated by both 200 μM tolbutamide and 20 μM gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 μM) or the L-type Ca(2+) channel blocker nicardipine (2 μM) and was potentiated by 8-pCPT-2'-O-Me-cAMP-AM at concentrations ≥2", "type": "CHEMICAL", "entities": [ "tolbutamide", "gliclazide", "thapsigargin", "Ca(2+)", "nicardipine", "8-pCPT-2'-O-Me-cAMP-AM" ], "offsets": [ [ 44, 55 ], [ 66, 76 ], [ 161, 173 ], [ 195, 201 ], [ 218, 229 ], [ 260, 282 ] ] }, { "pmid": "23071106", "text": "μM in INS-1 cells.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 13, 19 ] ] }, { "pmid": "23071106", "text": "Ca(2+) transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-2'-O-Me-cAMP-AM at 5", "type": "CHEMICAL", "entities": [ "tolbutamide", "gliclazide", "thapsigargin", "nicardipine" ], "offsets": [ [ 32, 43 ], [ 47, 57 ], [ 76, 88 ], [ 92, 103 ] ] }, { "pmid": "23071106", "text": "μM but not 1 μM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23071106", "text": "Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K(ATP) channels, and this activity was partially inhibited by pertussis toxin.", "type": "CHEMICAL", "entities": [ "gliclazide", "gliclazide", "K", "ATP" ], "offsets": [ [ 12, 22 ], [ 74, 84 ], [ 125, 126 ], [ 127, 130 ] ] }, { "pmid": "23071106", "text": "8-pCPT-2'-O-Me-cAMP-AM alone (5 μM) did not stimulate insulin secretion, but did increase intracellular Ca(2+) concentration significantly, and this activity was inhibited by 25 μM 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca(2+).", "type": "CHEMICAL", "entities": [ "Ca(2+)", "2-aminoethoxydiphenylborate", "2-APB", "Ca(2+)" ], "offsets": [ [ 95, 101 ], [ 172, 199 ], [ 201, 206 ], [ 240, 246 ] ] }, { "pmid": "23071106", "text": "8-pCPT-2'-O-Me-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 μM) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 μM).", "type": "CHEMICAL", "entities": [ "tolbutamide", "2-APB", "bisindolylmaleimide I" ], "offsets": [ [ 60, 71 ], [ 98, 103 ], [ 146, 167 ] ] }, { "pmid": "23071106", "text": "Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-2'-O-Me-cAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-2'-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca(2+) influx.", "type": "CHEMICAL", "entities": [ "tolbutamide", "gliclazide", "8-pCPT-2'-O-Me-cAMP-AM", "gliclazide", "8-pCPT-2'-O-Me-cAMP-AM", "2-APB", "Ca(2+)" ], "offsets": [ [ 33, 44 ], [ 49, 59 ], [ 88, 110 ], [ 117, 127 ], [ 229, 251 ], [ 315, 320 ], [ 331, 337 ] ] }, { "pmid": "22972179", "text": "Energy depletion of bovine mammary epithelial cells activates AMPK and suppresses protein synthesis through inhibition of mTORC1 signaling.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "The molecular mechanisms by which cellular energy status regulates global protein synthesis in mammary epithelial cells have not been characterized.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "The objective of this study was to examine the effect of AMP-activated protein kinase (AMPK) activation by 2-deoxyglucose on protein synthesis and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in bovine mammary epithelial cells.", "type": "CHEMICAL", "entities": [ "2-deoxyglucose", "rapamycin" ], "offsets": [ [ 107, 121 ], [ 171, 180 ] ] }, { "pmid": "22972179", "text": "Phosphorylation of AMPK at Thr172 increased by 1.4-fold within 5 min, and remained elevated throughout a 30-min time course, in response to 2-deoxyglucose.", "type": "CHEMICAL", "entities": [ "Thr", "2-deoxyglucose" ], "offsets": [ [ 27, 30 ], [ 140, 154 ] ] }, { "pmid": "22972179", "text": "Global rates of protein synthesis declined by 78% of control values.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "The decline in protein synthesis was associated with repression of mTORC1 signaling, as indicated by reduced phosphorylation of ribosomal protein S6 kinase 1 and eIF4E binding protein-1", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "(4E-BP1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "Phosphorylation of ER-stress marker eIF2α was also increased but only at 30 min of 2-deoxyglucose exposure.", "type": "CHEMICAL", "entities": [ "2-deoxyglucose" ], "offsets": [ [ 83, 97 ] ] }, { "pmid": "22972179", "text": "2-Deoxyglucose increased phosphorylation of tuberous sclerosis complex 2 (TSC2) on AMPK consensus sites but did not change the amount of TSC1 bound to TSC2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "Activation of AMPK did not result in changes in the amount of raptor bound to mTOR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22972179", "text": "The inhibitory effects of AMPK activation on mTORC1 signaling were associated with a marked increase in Ser792 phosphorylation on raptor.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 103, 106 ] ] }, { "pmid": "22972179", "text": "Collectively, the results suggest that activation of AMPK represses global protein synthesis in mammary epithelial cells through inhibition of mTORC1 signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected].\n", "type": "CHEMICAL", "entities": [ "Conivaptan", "vasopressin" ], "offsets": [ [ 0, 10 ], [ 19, 30 ] ] }, { "pmid": "17919259", "text": "Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis.", "type": "CHEMICAL", "entities": [ "arginine vasopressin", "AVP" ], "offsets": [ [ 203, 223 ], [ 225, 228 ] ] }, { "pmid": "17919259", "text": "The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b.", "type": "CHEMICAL", "entities": [ "AVP" ], "offsets": [ [ 15, 18 ] ] }, { "pmid": "17919259", "text": "The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "The V1b receptor regulates adrenocorticotropin hormone release.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist.", "type": "CHEMICAL", "entities": [ "Conivaptan", "AVP" ], "offsets": [ [ 0, 10 ], [ 39, 42 ] ] }, { "pmid": "17919259", "text": "It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "It is approved only for short-term intravenous use.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "Infusion site reaction is the most common reason for discontinuation of the drug.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "In animals conivaptan increased urine volume and free water clearance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "In heart failure models it improved hemodynamic parameters and free water excretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients.", "type": "CHEMICAL", "entities": [ "Conivaptan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17919259", "text": "Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17919259", "text": "Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication.", "type": "CHEMICAL", "entities": [ "AVP" ], "offsets": [ [ 43, 46 ] ] }, { "pmid": "17919259", "text": "Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1977506", "text": "Histamine and asthma: an appraisal based on specific H1-receptor antagonism.\n", "type": "CHEMICAL", "entities": [ "Histamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "1977506", "text": "H1-receptor antagonists have been utilized, following their initial chemical synthesis in 1933, both in the treatment of conditions in which histamine is considered to be of pathogenic importance and conversely to help elucidate the role of histamine in disease, through an evaluation of their influence on disease expression.", "type": "CHEMICAL", "entities": [ "histamine", "histamine" ], "offsets": [ [ 141, 150 ], [ 241, 250 ] ] }, { "pmid": "1977506", "text": "While there is considerable indirect evidence to implicate histamine in the pathogenesis of asthma, a critical evaluation of H1-receptor antagonism in this condition has, until recently, proved difficult, as many of the early H1-receptor antagonists possessed additional actions, such as anti-cholinergic, local anaesthetic, alpha-adrenoceptor antagonistic and anti-serotonin activity.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 59, 68 ] ] }, { "pmid": "1977506", "text": "In addition, H1-receptor antagonists have been shown to have effects on mast cell function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1977506", "text": "In low concentrations in vitro, antihistamines have been found to inhibit immunologically stimulated mast cell mediator release, with the IC50 in the nanomolar to micromolar range, while at higher concentrations they induce histamine release.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 224, 233 ] ] }, { "pmid": "1977506", "text": "The potency of these drugs in producing such effects is unrelated to their H1-receptor blocking activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1977506", "text": "Furthermore the sedative effects of these therapeutic agents limit the tolerable administrable dose and thus the degree of H1-receptor blockade achievable within the airways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1977506", "text": "The recent development of H1-receptor antagonists devoid of clinical sedative effects has enabled the administration of doses of H1-antihistamines which achieve a greater degree of H1-receptor blockade within the airways, thus permitting a better appraisal of the role of histamine in this condition.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 272, 281 ] ] }, { "pmid": "1977506", "text": "Furthermore, the receptor specificity of many of these agents has been focused such that terfenadine, astemizole, loratadine and cetirizine are devoid of anticholinergic activity and exhibit little alpha-antagonistic or anti-serotonin activity of clinical relevance.", "type": "CHEMICAL", "entities": [ "terfenadine", "astemizole", "loratadine", "cetirizine", "serotonin" ], "offsets": [ [ 89, 100 ], [ 102, 112 ], [ 114, 124 ], [ 129, 139 ], [ 225, 234 ] ] }, { "pmid": "1977506", "text": "However, of these agents both loratadine and cetirizine possess additional actions likely to be of relevance to asthma.", "type": "CHEMICAL", "entities": [ "loratadine", "cetirizine" ], "offsets": [ [ 30, 40 ], [ 45, 55 ] ] }, { "pmid": "1977506", "text": "Pretreatment with loratadine has been shown to reduce the recovery of both histamine and prostaglandin D2 (PGD2) in nasal lavage fluid following nasal allergen challenge, a finding interpreted as indicative of in vivo mast cell stabilization, and cetirizine has been shown in vivo at therapeutic doses to inhibit allergen-induced eosinophil chemotaxis.", "type": "CHEMICAL", "entities": [ "loratadine", "histamine", "prostaglandin D2", "PGD2", "cetirizine" ], "offsets": [ [ 18, 28 ], [ 75, 84 ], [ 89, 105 ], [ 107, 111 ], [ 247, 257 ] ] }, { "pmid": "1977506", "text": "Thus while both these agents offer the potential of an oral therapy for asthma based on an H1-receptor antagonist, their additional actions do not make them ideally suited to the exploration of the role of histamine in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 206, 215 ] ] }, { "pmid": "23567961", "text": "Identification of novel FLT3 kinase inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567961", "text": "FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "23567961", "text": "Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567961", "text": "In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567961", "text": "This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 222, 230 ] ] }, { "pmid": "23639738", "text": "Enzyme-responsive surface erosion of poly(ethylene carbonate) for controlled drug release.\n", "type": "CHEMICAL", "entities": [ "poly(ethylene carbonate)" ], "offsets": [ [ 37, 61 ] ] }, { "pmid": "23639738", "text": "Cholesterol esterase (CE) induced surface erosion of poly(ethylene carbonate) (PEC) and drug release from PEC under mild physiological environment was investigated.", "type": "CHEMICAL", "entities": [ "Cholesterol", "PEC", "poly(ethylene carbonate)", "PEC" ], "offsets": [ [ 0, 11 ], [ 106, 109 ], [ 53, 77 ], [ 79, 82 ] ] }, { "pmid": "23639738", "text": "The degradation process was monitored by changes of mass and molecular weight (MW) and surface morphology of polymer films.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639738", "text": "During the whole period of degradation, MW of PEC was unchanged.", "type": "CHEMICAL", "entities": [ "PEC" ], "offsets": [ [ 46, 49 ] ] }, { "pmid": "23639738", "text": "Water uptake of the polymer was only 2.8 and 0.2% for PEC with the MW of 200 kDa (PEC200) and PEC with the MW of 41 kDa (PEC41), respectively.", "type": "CHEMICAL", "entities": [ "PEC", "PEC", "PEC", "PEC" ], "offsets": [ [ 54, 57 ], [ 82, 85 ], [ 94, 97 ], [ 121, 124 ] ] }, { "pmid": "23639738", "text": "Degradation of less hydrophilic PEC41 with higher density was slower than that of PEC200.", "type": "CHEMICAL", "entities": [ "PEC", "PEC" ], "offsets": [ [ 32, 35 ], [ 82, 85 ] ] }, { "pmid": "23639738", "text": "By this mechanism, CE-responsive drug in vitro release from PEC in situ forming depots (ISFD) was conducted successfully.", "type": "CHEMICAL", "entities": [ "PEC" ], "offsets": [ [ 60, 63 ] ] }, { "pmid": "23639738", "text": "As expected, less bovine serum albumin (BSA) was released from PEC41 compared with that of PEC200 in the same time period.", "type": "CHEMICAL", "entities": [ "PEC", "PEC" ], "offsets": [ [ 63, 66 ], [ 91, 94 ] ] }, { "pmid": "23639738", "text": "In conclusion, this work enabled the in vitro drug release evaluation of existing PEC devices and implied a new candidate for the development of enzyme-responsive systems.", "type": "CHEMICAL", "entities": [ "PEC" ], "offsets": [ [ 82, 85 ] ] }, { "pmid": "23410126", "text": "Genome-wide integrated analyses of androgen receptor signaling in prostate cancer based on high-throughput technology.\n", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "23410126", "text": "The androgen receptor (AR) is a steroid hormone receptor that functions as a ligand-dependent transcriptional factor, which plays a key role in the development and progression of prostate cancer.", "type": "CHEMICAL", "entities": [ "steroid", "androgen" ], "offsets": [ [ 32, 39 ], [ 4, 12 ] ] }, { "pmid": "23410126", "text": "Recent advancement in high throughput technologies including microarrays and deep-sequencing provides unbiased genome-wide knowledge on the AR signaling including datasets for androgen-regulated gene expression and genomic binding sites for AR.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 176, 184 ] ] }, { "pmid": "23410126", "text": "In the present review, we will briefly summarize the main features of the AR signaling as well as the individual AR target genes identified by the integration of multiple datasets in prostate cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23410126", "text": "Cap analysis gene expression (CAGE) is also featured as a unique transcriptome method, which particularly determines the androgen-dependent transcription start points in prostate cancer.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 121, 129 ] ] }, { "pmid": "17479245", "text": "Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "AIMS/HYPOTHESIS: Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 72, 79 ] ] }, { "pmid": "17479245", "text": "Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "MATERIALS AND METHODS: After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine.", "type": "CHEMICAL", "entities": [ "glucose", "arginine" ], "offsets": [ [ 75, 82 ], [ 124, 132 ] ] }, { "pmid": "17479245", "text": "Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 56, 63 ] ] }, { "pmid": "17479245", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "Fasting plasma glucose levels were reduced by GRA (6.0 +/- 0.2 vs 7.4 +/- 0.5 mmol/l; p = 0.017).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "17479245", "text": "The acute insulin response to intravenous glucose was augmented (1,300 +/- 110 vs 790 +/- 64 pmol/l; p < 0.001).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 42, 49 ] ] }, { "pmid": "17479245", "text": "The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 +/- 160 vs 3,040 +/- 420 pmol/l; p = 0.012), but glucose excursions were improved.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 35, 42 ], [ 132, 139 ] ] }, { "pmid": "17479245", "text": "Intravenous arginine significantly increased the acute glucagon response (129 +/- 12 vs 36 +/- 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose.", "type": "CHEMICAL", "entities": [ "arginine", "glucose" ], "offsets": [ [ 12, 20 ], [ 159, 166 ] ] }, { "pmid": "17479245", "text": "GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 +/- 0.007 vs 0.030 +/- 0.004 pmol islet(-1) h(-1) at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation.", "type": "CHEMICAL", "entities": [ "glucose", "glucose", "glucose" ], "offsets": [ [ 35, 42 ], [ 164, 171 ], [ 209, 216 ] ] }, { "pmid": "17479245", "text": "CONCLUSIONS/INTERPRETATION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17479245", "text": "Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 83, 90 ], [ 182, 189 ] ] }, { "pmid": "23552101", "text": "Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease characterized by ataxia, variously associating heart disease, diabetes mellitus and/or glucose intolerance.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 157, 164 ] ] }, { "pmid": "23552101", "text": "It results from intronic expansion of GAA triplet repeats at the FXN locus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "Homozygous expansions cause silencing of the FXN gene and subsequent decreased expression of the encoded mitochondrial frataxin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "Detailed analyses in fibroblasts and neuronal tissues from FRDA patients have revealed profound cytoskeleton anomalies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "So far, however, the molecular mechanism underlying these cytoskeleton defects remains unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "We show here that gene silencing spreads in cis over the PIP5K1B gene in cells from FRDA patients (circulating lymphocytes and primary fibroblasts), correlating with expanded GAA repeat size.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase β type I (pip5k1β), an enzyme functionally linked to actin cytoskeleton dynamics that phosphorylates phosphatidylinositol 4-phosphate [PI(4)P] to generate phosphatidylinositol-4,5-bisphosphate", "type": "CHEMICAL", "entities": [ "phosphatidylinositol-4,5-bisphosphate", "phosphatidylinositol 4-phosphate", "phosphatidylinositol 4-phosphate", "PI(4)P" ], "offsets": [ [ 213, 250 ], [ 16, 48 ], [ 159, 191 ], [ 193, 199 ] ] }, { "pmid": "23552101", "text": "[PI(4,5)P2].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "Accordingly, loss of pip5k1β function in FRDA cells was accompanied by decreased PI(4,5)P2 levels and was shown instrumental for destabilization of the actin network and delayed cell spreading.", "type": "CHEMICAL", "entities": [ "PI(4,5)P2" ], "offsets": [ [ 79, 88 ] ] }, { "pmid": "23552101", "text": "Knockdown of PIP5K1B in control fibroblasts using shRNA reproduced abnormal actin cytoskeleton remodeling, whereas over-expression of PIP5K1B, but not FXN, suppressed this phenotype in FRDA cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552101", "text": "In addition to provide new insights into the consequences of the FXN gene expansion, these findings raise the question whether PIP5K1B silencing may contribute to the variable manifestation of this complex disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Involvement of regucalcin in lipid metabolism and diabetes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Regucalcin (RGN/SMP30) was originally discovered in 1978 as a unique calcium-binding protein that does not contain the EF-hand motif of calcium-binding domain.", "type": "CHEMICAL", "entities": [ "calcium", "calcium" ], "offsets": [ [ 136, 143 ], [ 69, 76 ] ] }, { "pmid": "23453039", "text": "The regucalcin gene (rgn) is localized on the X chromosome and is identified in over 15 species consisting the regucalcin family.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Regucalcin has been shown to play a multifunctional role in cell regulation; maintaining of intracellular calcium homeostasis and suppressing of signal transduction, translational protein synthesis, nuclear deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, proliferation, and apoptosis in many cell types.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 106, 113 ] ] }, { "pmid": "23453039", "text": "Moreover, regucalcin may play a pathophysiological role in metabolic disorder.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "The expression of regucalcin is stimulated through the action of insulin in liver cells in vitro and in vivo and it is decreased in the liver of rats with type I diabetes induced by streptozotocin administration in vivo.", "type": "CHEMICAL", "entities": [ "streptozotocin" ], "offsets": [ [ 182, 196 ] ] }, { "pmid": "23453039", "text": "Overexpression of endogenous regucalcin stimulates glucose utilization and lipid production in liver cells with glucose supplementation in vitro.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 112, 119 ], [ 51, 58 ] ] }, { "pmid": "23453039", "text": "Regucalcin reveals insulin resistance in liver cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Deficiency of regucalcin induces an impairment of glucose tolerance and lipid accumulation in the liver of mice in vivo.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 50, 57 ] ] }, { "pmid": "23453039", "text": "Overexpression of endogenous regucalcin has been shown to decrease triglyceride, total cholesterol and glycogen contents in the liver of rats, inducing hyperlipidemia.", "type": "CHEMICAL", "entities": [ "triglyceride", "cholesterol" ], "offsets": [ [ 67, 79 ], [ 87, 98 ] ] }, { "pmid": "23453039", "text": "Leptin and adiponectin mRNA expressions in the liver tissues are decreased in regucalcin transgenic rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Decrease in hepatic regucalcin is associated with the development and progression of nonalcoholic fatty liver disease and fibrosis in human patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23453039", "text": "Regucalcin may be a key molecule in lipid metabolic disorder and diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19428322", "text": "AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C.\n", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "19428322", "text": "We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines.", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 100, 103 ] ] }, { "pmid": "19428322", "text": "Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation.", "type": "CHEMICAL", "entities": [ "phosphatidylserine" ], "offsets": [ [ 123, 141 ] ] }, { "pmid": "19428322", "text": "The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19428322", "text": "Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase.", "type": "CHEMICAL", "entities": [ "acetyl CoA" ], "offsets": [ [ 118, 128 ] ] }, { "pmid": "19428322", "text": "AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C.", "type": "CHEMICAL", "entities": [ "metformin", "AICAR" ], "offsets": [ [ 16, 25 ], [ 30, 35 ] ] }, { "pmid": "19428322", "text": "The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19428322", "text": "In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "The covalent attachment of polyethylene glycol to filgrastim results in a new molecule pegfilgrastim, which has a significantly longer half-life than filgrastim.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "It is likely that the clearance of both filgrastim and pegfilgrastim involves granulocyte colony simulating factor (G-CSF) receptor binding, but the pharmacokinetics of these drugs have not been compared in mice with and without a functional G-CSF receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "We sought to clarify the role of receptor-mediated clearance of filgrastim and pegfilgrastim using wild-type (WT) mice or mice with a non-functional G-CSF-R (knockout, KO).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "We administered single doses of filgrastim or pegfilgrastim (10 or 100 microg kg(-1)) intravenously to WT and KO mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "Plasma levels of protein were measured by enzyme-linked immunosorbent assay (ELISA) at preset time points, and AUC, MRT, CL, V(d), and T(1/2) were calculated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "When compared with WT mice, the G-CSF-R KO mice had significantly greater AUC, longer MRT, longer T(1/2), and lower clearance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "This was the case whether animals received 10 or 100 microg kg(-1) and whether they received filgrastim or pegfilgrastim.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "The volume of protein distribution was identical among WT and KO mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "However, the V(d) was larger after pegfilgrastim dosing than after filgrastim dosing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "In both WT and KO mice, increasing the dose of figrastim or pegfilgrastim resulted in a proportional increase in the AUC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15082029", "text": "A functional G-CSF-R is an important mechanism in the plasma clearance of both filgrastim and pegfilgrastim.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder.\n", "type": "CHEMICAL", "entities": [ "Duloxetine hydrochloride" ], "offsets": [ [ 0, 24 ] ] }, { "pmid": "16199241", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "Duloxetine hydrochloride has recently been approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD).", "type": "CHEMICAL", "entities": [ "Duloxetine hydrochloride" ], "offsets": [ [ 0, 24 ] ] }, { "pmid": "16199241", "text": "Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake.", "type": "CHEMICAL", "entities": [ "Duloxetine", "serotonin", "norepinephrine", "dopamine" ], "offsets": [ [ 0, 10 ], [ 36, 45 ], [ 50, 64 ], [ 96, 104 ] ] }, { "pmid": "16199241", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "This article reviews the literature on duloxetine with regard to its pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability.", "type": "CHEMICAL", "entities": [ "duloxetine" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "16199241", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "A comprehensive search of MEDLINE was performed using the terms duloxetine, Cymbalta, and major depressive disorder, with no restriction on year.", "type": "CHEMICAL", "entities": [ "duloxetine", "Cymbalta" ], "offsets": [ [ 64, 74 ], [ 76, 84 ] ] }, { "pmid": "16199241", "text": "The Eli Lilly and Company clinical trial registry, and abstracts and posters from recent American Psychiatric Association meetings were also reviewed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "Duloxetine exhibits linear, dose-dependent pharmacokinetics across the approved oral dosage range of 40 to 60 mg/d.", "type": "CHEMICAL", "entities": [ "Duloxetine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16199241", "text": "No dose adjustment appears to be needed based on age.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "Duloxetine has shown efficacy in reducing depressive symptoms compared with placebo, and duloxetine recipients have shown significant improvements in global functioning compared with placebo (both, P < 0.05).", "type": "CHEMICAL", "entities": [ "Duloxetine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16199241", "text": "Response and remission rates have been comparable to or greater than those seen with fluoxetine or paroxetine.", "type": "CHEMICAL", "entities": [ "fluoxetine", "paroxetine" ], "offsets": [ [ 85, 95 ], [ 99, 109 ] ] }, { "pmid": "16199241", "text": "Duloxetine is generally well tolerated, with nausea, dry mouth, and fatigue being the most common treatment-emergent adverse effects.", "type": "CHEMICAL", "entities": [ "Duloxetine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16199241", "text": "Cardiovascular adverse effects do not appear to result in sustained blood pressure elevations, QTc-interval prolongation, or other electrocardiographic changes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16199241", "text": "CONCLUSIONS: Based on the available evidence, duloxetine is a well-tolerated and effective treatment for MDD in adults.", "type": "CHEMICAL", "entities": [ "duloxetine" ], "offsets": [ [ 46, 56 ] ] }, { "pmid": "16199241", "text": "Randomized head-to-head comparisons against established antidepressants are needed to determine the relative safety and efficacy of duloxetine.", "type": "CHEMICAL", "entities": [ "duloxetine" ], "offsets": [ [ 132, 142 ] ] }, { "pmid": "17391279", "text": "In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems.", "type": "CHEMICAL", "entities": [ "amtolmetin guacyl" ], "offsets": [ [ 19, 36 ] ] }, { "pmid": "17391279", "text": "Comparison with non-selective and COX-2 selective NSAIDs.\n1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17391279", "text": "The in vivo effects of the non-steroid anti-inflammatory drug (NSAID) amtolmetin guacyl, a pro-drug of the NSAID tolmetin, on lipid peroxidation, glutathione levels and activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) in rat gastric mucosa, colon mucosa and liver, were compared with the effects of non-selective (indomethacin, diclofenac) and COX-2 selective (celecoxib) NSAIDs.", "type": "CHEMICAL", "entities": [ "tolmetin", "glutathione", "superoxide", "glutathione", "glutathione", "steroid", "indomethacin", "diclofenac", "celecoxib", "amtolmetin guacyl" ], "offsets": [ [ 113, 121 ], [ 146, 157 ], [ 202, 212 ], [ 234, 245 ], [ 261, 272 ], [ 31, 38 ], [ 380, 392 ], [ 394, 404 ], [ 427, 436 ], [ 70, 87 ] ] }, { "pmid": "17391279", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17391279", "text": "Indomethacin treatment led to an increase in lipid peroxidation, glutathione peroxidase and glucose-6-phosphate dehydrogenase activities and to a decrease in catalase activity and glutathione levels in gastric mucosa.", "type": "CHEMICAL", "entities": [ "Indomethacin", "glutathione", "glucose-6-phosphate", "glutathione" ], "offsets": [ [ 0, 12 ], [ 65, 76 ], [ 92, 111 ], [ 180, 191 ] ] }, { "pmid": "17391279", "text": "In contrast, amtolmetin guacyl treatment was without effects in gastric and colon mucosa, or liver from control animals.", "type": "CHEMICAL", "entities": [ "amtolmetin guacyl" ], "offsets": [ [ 13, 30 ] ] }, { "pmid": "17391279", "text": "Like amtolmetin guacyl, celecoxib had no effect on the lipid peroxidation, or on enzyme and non-enzyme antioxidant defence systems in gastric mucosa.", "type": "CHEMICAL", "entities": [ "amtolmetin guacyl", "celecoxib" ], "offsets": [ [ 5, 22 ], [ 24, 33 ] ] }, { "pmid": "17391279", "text": "3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17391279", "text": "It is suggested that the lack of pro-oxidant effects in vivo associated with amtolmetin guacyl treatment contribute improved gastric tolerability.", "type": "CHEMICAL", "entities": [ "amtolmetin guacyl" ], "offsets": [ [ 77, 94 ] ] }, { "pmid": "23386702", "text": "Reversible inhibition of human carboxylesterases by acyl glucuronides.\n", "type": "CHEMICAL", "entities": [ "acyl glucuronides" ], "offsets": [ [ 52, 69 ] ] }, { "pmid": "23386702", "text": "Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively.", "type": "CHEMICAL", "entities": [ "alcohols", "amines", "thiols", "esters", "amides", "thioesters", "carboxylic acids" ], "offsets": [ [ 101, 109 ], [ 111, 117 ], [ 123, 129 ], [ 28, 34 ], [ 36, 42 ], [ 48, 58 ], [ 70, 86 ] ] }, { "pmid": "23386702", "text": "Uridine 5'-diphosphate- glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases.", "type": "CHEMICAL", "entities": [ "Uridine 5'-diphosphate", "carboxylic acids", "acyl glucuronides", "acyl glucuronides", "esters" ], "offsets": [ [ 0, 22 ], [ 133, 149 ], [ 153, 170 ], [ 203, 220 ], [ 228, 234 ] ] }, { "pmid": "23386702", "text": "Objective:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386702", "text": "This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2).", "type": "CHEMICAL", "entities": [ "acyl glucuronides" ], "offsets": [ [ 35, 52 ] ] }, { "pmid": "23386702", "text": "Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7.4, 37°C) were investigated.", "type": "CHEMICAL", "entities": [ "acyl glucuronides", "potassium phosphate" ], "offsets": [ [ 30, 47 ], [ 106, 125 ] ] }, { "pmid": "23386702", "text": "Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied.", "type": "CHEMICAL", "entities": [ "4-nitrophenyl acetate", "acyl glucuronides" ], "offsets": [ [ 24, 45 ], [ 64, 81 ] ] }, { "pmid": "23386702", "text": "Diclofenac-β-d-glucuronide was used to explore potential time-dependent inactivation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386702", "text": "Results:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386702", "text": "The chemical stability half-life values for CGP 47292-β-d-glucuronide, diclofenac-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, (S)-naproxen-β-d-glucuronide, ibuprofen-β-d-glucuronide (racemic), clopidogrel-β-d-glucuronide, and valproate-β-d-glucuronide were found to be 0.252, 0.537, 0.996, 1.77, 3.67, 5.02, and 15.2 hours, respectively.", "type": "CHEMICAL", "entities": [ "(R)-naproxen-β-d-glucuronide", "(S)-naproxen-β-d-glucuronide", "ibuprofen-β-d-glucuronide (racemic)", "clopidogrel-β-d-glucuronide", "valproate-β-d-glucuronide", "CGP 47292-β-d-glucuronide", "diclofenac-β-d-glucuronide" ], "offsets": [ [ 97, 125 ], [ 127, 155 ], [ 157, 192 ], [ 194, 221 ], [ 227, 252 ], [ 42, 67 ], [ 69, 95 ] ] }, { "pmid": "23386702", "text": "Diclofenac-β-d-glucuronide, clopidogrel-β-d-glucuronide, ibuprofen-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, and (S)-naproxen-β-d-glucuronide selectively inhibited hCES1, with Ki values of 4.32 ± 0.47, 24.8 ± 4.2, 355 ± 38, 468 ± 21, 707 ± 64 µM, respectively, but did not significantly inhibit hCES2.", "type": "CHEMICAL", "entities": [ "clopidogrel-β-d-glucuronide", "ibuprofen-β-d-glucuronide", "(R)-naproxen-β-d-glucuronide", "(S)-naproxen-β-d-glucuronide" ], "offsets": [ [ 19, 46 ], [ 48, 73 ], [ 75, 103 ], [ 109, 137 ] ] }, { "pmid": "23386702", "text": "Valproate-β-d-glucuronide and CGP 47292-β-d-glucuronide did not inhibit either hCES.", "type": "CHEMICAL", "entities": [ "CGP 47292-β-d-glucuronide" ], "offsets": [ [ 10, 35 ] ] }, { "pmid": "23386702", "text": "Time-dependent inactivation of hCES1 by diclofenac-β-d-glucuronide was not observed.", "type": "CHEMICAL", "entities": [ "diclofenac-β-d-glucuronide" ], "offsets": [ [ 18, 44 ] ] }, { "pmid": "23386702", "text": "Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied.", "type": "CHEMICAL", "entities": [ "acyl glucuronides" ], "offsets": [ [ 55, 72 ] ] }, { "pmid": "23386702", "text": "Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs.", "type": "CHEMICAL", "entities": [ "acyl glucuronides" ], "offsets": [ [ 65, 82 ] ] }, { "pmid": "23274771", "text": "NF-κB-associated mechanisms underlying the response of embryonic cells to Doxorubicin.\n", "type": "CHEMICAL", "entities": [ "Doxorubicin" ], "offsets": [ [ 74, 85 ] ] }, { "pmid": "23274771", "text": "The involvement of NF-κB in the regulation of teratogen-induced apoptosis has not been established yet.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23274771", "text": "Therefore, we tried to assess the involvement of the p65 subunit of NF-κB in the embryonic response to the anti-cancer drug Doxorubicin (DOX).", "type": "CHEMICAL", "entities": [ "Doxorubicin", "DOX" ], "offsets": [ [ 122, 133 ], [ 135, 138 ] ] }, { "pmid": "23274771", "text": "Thus, exposure of p65 knockout (p65(-/-)) or wild type (WT) mouse embryonic fibroblasts (MEFs) to DOX resulted in a decrease in cell survival, culture density and cell proliferation, which was found to be more prominent in p65(-/-) MEFs.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 95, 98 ] ] }, { "pmid": "23274771", "text": "Those phenomena were accompanied by a DOX-induced increase in the proportion of apoptotic cells, which was demonstrated only in p65(-/-) cells and a G2/M arrest, which was found to be more prominent in WT cells.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 35, 38 ] ] }, { "pmid": "23274771", "text": "Furthermore, DOX-treated WT and p65(-/-) MEFs differed in their expression of various apoptosis-associated molecules, when the former demonstrated a decrease in the percentage of p65-positive and a more prominent decrease in the percentage of p53-positive cells, while a decreased percentage of IκBα-positive and a more prominent decrease in the percentage of bcl-2-positive cells was detected among the latter.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 10, 13 ] ] }, { "pmid": "23274771", "text": "The fact that the response of the cells to the teratogen was clearly p65-dependent implicates this molecule to be involved in the response of the embryonic cells to DOX.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 160, 163 ] ] }, { "pmid": "23523949", "text": "Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure.\n", "type": "CHEMICAL", "entities": [ "crocin", "diazinon" ], "offsets": [ [ 21, 27 ], [ 31, 39 ] ] }, { "pmid": "23523949", "text": "This study was designed to evaluate the effectiveness of crocin, main component of Crocus sativus L. (Saffron) against subchronic diazinon (DZN) induced cardiotoxicity in rats.", "type": "CHEMICAL", "entities": [ "diazinon", "DZN", "crocin" ], "offsets": [ [ 130, 138 ], [ 140, 143 ], [ 57, 63 ] ] }, { "pmid": "23523949", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23523949", "text": "Rats were divided into 7 groups; control (corn oil, gavage), DZN (15mg/kg/day, gavage,), crocin (12.5, 25 or 50mg/kg/day, i.p) plus DZN, vitamin E (200IU/kg, i.p, three times per week) plus DZN and crocin (50mg/kg/day, i.p) groups.", "type": "CHEMICAL", "entities": [ "crocin", "DZN", "vitamin E", "DZN", "crocin" ], "offsets": [ [ 89, 95 ], [ 132, 135 ], [ 137, 146 ], [ 190, 193 ], [ 198, 204 ] ] }, { "pmid": "23523949", "text": "Treatments were continued for 4weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23523949", "text": "Creatine phosphokinase MB (CK-MB), malondealdehyde (MDA) and glutathione (GSH) levels were evaluated in heart tissue at the end of treatments.", "type": "CHEMICAL", "entities": [ "Creatine", "malondealdehyde", "MDA", "glutathione", "GSH" ], "offsets": [ [ 0, 8 ], [ 35, 50 ], [ 52, 55 ], [ 61, 72 ], [ 74, 77 ] ] }, { "pmid": "23523949", "text": "Levels of apoptotic proteins (Bax, Bcl2, caspase 3) and cytosolic cytochrome c were analyzed by Western blotting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23523949", "text": "Transcript levels of Bax and Bcl2 were also determined using qRT PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23523949", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23523949", "text": "DZN induced histophatological damages and elevated the level of cardiac marker CK-MB.", "type": "CHEMICAL", "entities": [ "DZN" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23523949", "text": "These effects were associated with increased MDA level, lower level of reduced GSH and induction of apoptosis through elevation of Bax/Bcl2 ratio (both protein and mRNA levels), cytochrome c release to the cytosol and activation caspase 3 in cardiac tissue.", "type": "CHEMICAL", "entities": [ "MDA", "GSH" ], "offsets": [ [ 45, 48 ], [ 79, 82 ] ] }, { "pmid": "23523949", "text": "Crocin (25 and 50mg/kg) or vitamin E improved histopathological damages, decreased MDA and CK-MB, increased GSH content and attenuated the increase of Bax/Bcl2 ratio, activation of caspase 3 and release of cytochrome c to the cytosol induced by DZN.", "type": "CHEMICAL", "entities": [ "Crocin", "vitamin E", "MDA", "GSH", "DZN" ], "offsets": [ [ 0, 6 ], [ 27, 36 ], [ 83, 86 ], [ 108, 111 ], [ 245, 248 ] ] }, { "pmid": "23523949", "text": "In summary, DZN induced mitochondrial-mediated apoptosis in heart tissue of rat following subchronic exposure.", "type": "CHEMICAL", "entities": [ "DZN" ], "offsets": [ [ 12, 15 ] ] }, { "pmid": "23523949", "text": "Crocin, as an antioxidant, showed protective effects against DZN cardiotoxicity by reducing lipid peroxidation and alleviating apoptosis.", "type": "CHEMICAL", "entities": [ "Crocin", "DZN" ], "offsets": [ [ 0, 6 ], [ 61, 64 ] ] }, { "pmid": "23601399", "text": "Nutrients and bioactive compounds of Thai indigenous fruits.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "This study determined the nutritional potential of Thai indigenous fruits in terms of nutrients, bioactive compounds, and antioxidant activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "Three indigenous fruits were collected at two conservation areas in Kanchanaburi province, Thailand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "The results showed that Phyllanthus emblica L. exhibited the highest levels of vitamin C (575±452mg/100g), total phenolics (TP) (3703±1244mGAE/100g), and antioxidant activities, as measured by DPPH, FRAP and ORAC assays.", "type": "CHEMICAL", "entities": [ "vitamin C", "phenolics", "DPPH" ], "offsets": [ [ 79, 88 ], [ 113, 122 ], [ 193, 197 ] ] }, { "pmid": "23601399", "text": "Compared to the other two fruits, Antidesma velutinosum Blume contained higher levels of most nutrients and dietary fibre (15.6±5.9g/100g), as well as carotenoids (335±98μg/100g) and phytosterols (22.1±3.9mg/100g).", "type": "CHEMICAL", "entities": [ "phytosterols" ], "offsets": [ [ 181, 193 ] ] }, { "pmid": "23601399", "text": "Spondias pinnata (L.f.)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "Kurz was high in total phenolics (3178±887mGAE/100g) and antioxidant activity.", "type": "CHEMICAL", "entities": [ "phenolics" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "23601399", "text": "Moreover, high correlations were found between TP and antioxidant activities (r>0.9).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "These Thai indigenous fruits are potentially good sources of nutrients, bioactive compounds, and antioxidant activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23601399", "text": "Conservation and utilisation should be promoted for food security and consumption as part of a healthy diet.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "However, the underlying mechanisms remain unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO.", "type": "CHEMICAL", "entities": [ "calcium", "calcium" ], "offsets": [ [ 51, 58 ], [ 72, 79 ] ] }, { "pmid": "23415228", "text": "Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23415228", "text": "Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 77, 84 ] ] }, { "pmid": "11730729", "text": "Effect of fenoterol-induced constitutive beta(2)-adrenoceptor activity on contractile receptor function in airway smooth muscle.\n", "type": "CHEMICAL", "entities": [ "fenoterol" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "11730729", "text": "In the present study, we investigated the effect of fenoterol-induced constitutive beta(2)-adrenoceptor activity on muscarinic receptor agonist- and histamine-induced bovine tracheal smooth muscle contractions.", "type": "CHEMICAL", "entities": [ "histamine", "fenoterol" ], "offsets": [ [ 149, 158 ], [ 52, 61 ] ] }, { "pmid": "11730729", "text": "Bovine tracheal smooth muscle strips were incubated with 10 microM fenoterol or vehicle for various periods of time (5, 30 min, 18 h) at 37 degrees C. After extensive washout (3 h, 37 degrees C), isometric contractions were measured to the full muscarinic receptor agonist methacholine, the partial muscarinic receptor agonist 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) and histamine.", "type": "CHEMICAL", "entities": [ "fenoterol", "methacholine", "4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium", "McN-A-343", "histamine" ], "offsets": [ [ 67, 76 ], [ 273, 285 ], [ 327, 385 ], [ 387, 396 ], [ 402, 411 ] ] }, { "pmid": "11730729", "text": "Fenoterol treatment significantly reduced the sensitivity (pEC(50)) to methacholine in a time-dependent manner, without affecting maximal contraction (E(max)).", "type": "CHEMICAL", "entities": [ "Fenoterol", "methacholine" ], "offsets": [ [ 0, 9 ], [ 71, 83 ] ] }, { "pmid": "11730729", "text": "Fenoterol treatment similarly reduced the pEC(50) of McN-A-343 and histamine; however, E(max) values were also reduced, to approximately 70% of control after 18-h treatment.", "type": "CHEMICAL", "entities": [ "Fenoterol", "McN-A-343", "histamine" ], "offsets": [ [ 0, 9 ], [ 53, 62 ], [ 67, 76 ] ] }, { "pmid": "11730729", "text": "The inverse agonist timolol, having no effect on control preparations, consistently restored the reduced pEC(50) and E(max) values of the contractile agonists.", "type": "CHEMICAL", "entities": [ "timolol" ], "offsets": [ [ 20, 27 ] ] }, { "pmid": "11730729", "text": "Remarkably, in the presence of timolol the pEC(50) values of McN-A-343 and histamine in fenoterol-treated airways were significantly enhanced compared to controls.", "type": "CHEMICAL", "entities": [ "McN-A-343", "histamine", "fenoterol" ], "offsets": [ [ 61, 70 ], [ 75, 84 ], [ 88, 97 ] ] }, { "pmid": "11730729", "text": "In conclusion, fenoterol-induced constitutive beta(2)-adrenoceptor activity reduces muscarinic receptor agonist- and histamine-induced contractions of bovine tracheal smooth muscle, which can be reversed by the inverse agonist timolol.", "type": "CHEMICAL", "entities": [ "fenoterol", "histamine", "timolol" ], "offsets": [ [ 15, 24 ], [ 117, 126 ], [ 227, 234 ] ] }, { "pmid": "11730729", "text": "Moreover, after beta(2)-adrenoceptor agonist treatment, inverse agonism by beta-adrenoceptor antagonists may cause enhanced airway reactivity to contractile mediators.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247009", "text": "Beta-glucogallin reduces the expression of lipopolysaccharide-induced inflammatory markers by inhibition of aldose reductase in murine macrophages and ocular tissues.\n", "type": "CHEMICAL", "entities": [ "Beta-glucogallin", "aldose" ], "offsets": [ [ 0, 16 ], [ 108, 114 ] ] }, { "pmid": "23247009", "text": "Aldose reductase (AR) catalyzes the reduction of toxic lipid aldehydes to their alcohol products and mediates inflammatory signals triggered by lipopolysaccharide (LPS).", "type": "CHEMICAL", "entities": [ "Aldose", "aldehydes", "alcohol" ], "offsets": [ [ 0, 6 ], [ 61, 70 ], [ 80, 87 ] ] }, { "pmid": "23247009", "text": "Beta-glucogallin (BGG), a recently described AR inhibitor, was purified from extracts of the Indian gooseberry (Emblica officinalis).", "type": "CHEMICAL", "entities": [ "Beta-glucogallin", "BGG" ], "offsets": [ [ 0, 16 ], [ 18, 21 ] ] }, { "pmid": "23247009", "text": "In this study, we found that BGG showed low cytotoxicity in Raw264.7 murine macrophages and effectively inhibited AR activity as measured by a decrease in sorbitol accumulation.", "type": "CHEMICAL", "entities": [ "BGG", "sorbitol" ], "offsets": [ [ 29, 32 ], [ 155, 163 ] ] }, { "pmid": "23247009", "text": "In addition, BGG-mediated inhibition of AR prevented LPS-induced activation of JNK and p38 and lowered ROS levels, which could inhibit LPS-induced apoptosis.", "type": "CHEMICAL", "entities": [ "BGG" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23247009", "text": "Uveitis is a disease of the eye associated with chronic inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247009", "text": "In this study, we also demonstrated that treatment with BGG decreased the number of inflammatory cells that infiltrate the ocular media of mice with experimental uveitis.", "type": "CHEMICAL", "entities": [ "BGG" ], "offsets": [ [ 56, 59 ] ] }, { "pmid": "23247009", "text": "Accordingly, these results suggest BGG is a potential therapy for inflammatory diseases.", "type": "CHEMICAL", "entities": [ "BGG" ], "offsets": [ [ 35, 38 ] ] }, { "pmid": "23459167", "text": "Differential phosphoproteome of the striatum from pleiotrophin knockout and midkine knockout mice treated with amphetamine:", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 111, 122 ] ] }, { "pmid": "23459167", "text": "Correlations with amphetamine-induced neurotoxicity.\n", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "23459167", "text": "The neurotrophic factors pleiotrophin (PTN) and midkine (MK) have been shown to modulate amphetamine-induced neurotoxicity.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 89, 100 ] ] }, { "pmid": "23459167", "text": "Accordingly, PTN-/- and MK-/- mice show an increased vulnerability to amphetamine-induced neurotoxic effects.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 70, 81 ] ] }, { "pmid": "23459167", "text": "In an effort to uncover new pharmacological targets to prevent amphetamine neurotoxic effects, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN-/-, MK-/- and wild type (WT) mice treated with amphetamine.", "type": "CHEMICAL", "entities": [ "amphetamine", "amphetamine" ], "offsets": [ [ 63, 74 ], [ 453, 464 ] ] }, { "pmid": "23459167", "text": "We identified 13 differentially expressed phosphoproteins that are judged to be relevant in the neuroprotective roles of PTN and MK against amphetamine-induced neurotoxicity.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 140, 151 ] ] }, { "pmid": "23459167", "text": "It is very interesting to note that 4 of these phosphoproteins, annexin A7 (ANXA7), COP9 signalosome subunit 5 (COPS5), aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and creatine kinase U-type (CKMT1), are known to be involved in Parkinson's disease, a result of significant importance since PTN and MK have been also demonstrated to limit Parkinson's disease (PD) progress and have been suggested to be among the important genetic factors possibly preventing the development of PD in methamphetamine abusers.", "type": "CHEMICAL", "entities": [ "creatine", "methamphetamine", "aldehyde" ], "offsets": [ [ 176, 184 ], [ 491, 506 ], [ 120, 128 ] ] }, { "pmid": "23459167", "text": "The data identify phosphoproteins differentially regulated by amphetamine treatment and/or the presence of endogenous PTN/MK which may be relevant mediators of PTN/MK neuroprotective effects against amphetamine-induced neurotoxicity.", "type": "CHEMICAL", "entities": [ "amphetamine", "amphetamine" ], "offsets": [ [ 62, 73 ], [ 199, 210 ] ] }, { "pmid": "23459167", "text": "The data support further studies to validate the phosphoproteins here identified as possible new pharmacological targets to prevent amphetamine neurotoxic effects.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 132, 143 ] ] }, { "pmid": "23530006", "text": "Universal rule on chirality-dependent bandgaps in graphene antidot lattices.\n", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23530006", "text": "Graphene with periodically patterned antidots has attracted intense research attention as it represents a facile route to open a bandgap for graphene electronics.", "type": "CHEMICAL", "entities": [ "Graphene", "graphene" ], "offsets": [ [ 0, 8 ], [ 141, 149 ] ] }, { "pmid": "23530006", "text": "However, not all graphene antidot lattices (GALs) can open a bandgap and a guiding rule is missing.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 17, 25 ] ] }, { "pmid": "23530006", "text": "Here, through systematic first-principles calculations, it is found that bandgaps in triangular GALs are surprisingly well defined by a chirality vector R = n a1 + ma2 connecting two neighboring antidots, where a1 and a2 are the basis vectors of graphene.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 246, 254 ] ] }, { "pmid": "23530006", "text": "The bandgap opens in the GALs with (n-m)mod3 = 0 but remains closed in those with (n-m)mod3 = ±1, reminiscent of the gap-chirality rule in carbon nanotubes.", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 139, 145 ] ] }, { "pmid": "23530006", "text": "Remarkably, the gap value in GALs allows ample modulation by adjusting the length of chirality vectors, shape and size of the antidots.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530006", "text": "The gap-chirality relation in GALs stems from the chirality-dependent atomic structures of GALs as revealed by a super-atom model as well as Clar sextet analyses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23530006", "text": "This chirality-dependent bandgap is further shown to be a generic behavior in any parallelogram GAL and thus serves as an essential stepping stone for experimenters to realize graphene devices by antidot engineering.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 175, 183 ] ] }, { "pmid": "9480923", "text": "Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway.\n", "type": "CHEMICAL", "entities": [ "C2-ceramide" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "9480923", "text": "Ceramide is an important regulatory molecule implicated in a variety of biological processes in response to stress and cytokines.", "type": "CHEMICAL", "entities": [ "Ceramide" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "9480923", "text": "To understand the signal transduction pathway of ceramide to the nucleus, in the present study, we examined whether C2-ceramide, a cell permeable ceramide, activates c-fos serum response element (SRE).", "type": "CHEMICAL", "entities": [ "ceramide", "C2-ceramide", "ceramide" ], "offsets": [ [ 49, 57 ], [ 116, 127 ], [ 146, 154 ] ] }, { "pmid": "9480923", "text": "Treatment of Rat-2 fibroblast cells with C2-ceramide caused the stimulation of c-fos SRE-dependent reporter gene activity in a dose- and time-dependent manner by transient transfection analysis.", "type": "CHEMICAL", "entities": [ "C2-ceramide" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "9480923", "text": "Next, we examined the role of Rho family GTPases in the ceramide-induced signalling to SRE activation.", "type": "CHEMICAL", "entities": [ "ceramide" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "9480923", "text": "By reporter gene analysis following transient transfections with various plasmids expressing a dominant negative mutant form of Cdc42, Rac1 or RhoA, C2-ceramide-induced SRE activation was shown to be selectively repressed by pEXV-RacN17 encoding a dominant negative mutant of Rac1, suggesting that Rac activity is essential for the signalling cascade of ceramide to the nucleus.", "type": "CHEMICAL", "entities": [ "C2-ceramide", "ceramide" ], "offsets": [ [ 149, 160 ], [ 354, 362 ] ] }, { "pmid": "9480923", "text": "In a further study to analyse the downstream mediator of Rac in the ceramide-signalling pathway, we observed that either pretreatment with mepacrine, a potent and specific inhibitor of phospholipase A2, or co-transfection with antisense cytosolic phospholipase A2 (cPLA2) oligonucleotide repressed the C2-ceramide-induced SRE activation selectively, implying a critical role of cPLA2 in C2-ceramide-induced signalling to nucleus.", "type": "CHEMICAL", "entities": [ "ceramide", "mepacrine", "C2-ceramide", "C2-ceramide" ], "offsets": [ [ 68, 76 ], [ 139, 148 ], [ 302, 313 ], [ 387, 398 ] ] }, { "pmid": "9480923", "text": "Consistent with these results, the translocation of cPLA2 protein as well as the release of arachidonic acid, a principal product of phospholipase A2, was rapidly induced by the addition of C2-ceramide in a Rac-dependent manner.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "C2-ceramide" ], "offsets": [ [ 92, 108 ], [ 190, 201 ] ] }, { "pmid": "9480923", "text": "Together, our findings suggest the critical role of 'Rac and subsequent activation of phospholipase A2' in ceramide-signalling to nucleus.", "type": "CHEMICAL", "entities": [ "ceramide" ], "offsets": [ [ 107, 115 ] ] }, { "pmid": "16730121", "text": "Effect of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, on motor performance in mice.\n", "type": "CHEMICAL", "entities": [ "ramelteon", "TAK-375" ], "offsets": [ [ 10, 19 ], [ 21, 28 ] ] }, { "pmid": "16730121", "text": "Effect of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide (ramelteon, TAK-375), a selective MT1/MT2 receptor agonist, on motor coordination was studied using rota-rod performance in mice.", "type": "CHEMICAL", "entities": [ "(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide", "ramelteon", "TAK-375" ], "offsets": [ [ 10, 85 ], [ 87, 96 ], [ 98, 105 ] ] }, { "pmid": "16730121", "text": "Ramelteon did not impair rota-rod performance at doses of 3, 10 and 30 mg/kg, p.o. Melatonin and N-acetyl-5-hydroxytryptamine (N-acetyl-5-HT), a ligand of MT3 biding site, also had no impairment on the performance, per se.", "type": "CHEMICAL", "entities": [ "Ramelteon", "Melatonin", "N-acetyl-5-hydroxytryptamine", "N-acetyl-5-HT" ], "offsets": [ [ 0, 9 ], [ 83, 92 ], [ 97, 125 ], [ 127, 140 ] ] }, { "pmid": "16730121", "text": "However, in combination with a low dose of diazepam (3mg/kg, p.o.), treatment with melatonin and N-acetyl-5-HT exacerbated the impairment by diazepam.", "type": "CHEMICAL", "entities": [ "diazepam", "melatonin", "N-acetyl-5-HT", "diazepam" ], "offsets": [ [ 43, 51 ], [ 83, 92 ], [ 97, 110 ], [ 141, 149 ] ] }, { "pmid": "16730121", "text": "Ramelteon had no significant effect on the diazepam-induced impairment of motor coordination.", "type": "CHEMICAL", "entities": [ "Ramelteon", "diazepam" ], "offsets": [ [ 0, 9 ], [ 43, 51 ] ] }, { "pmid": "23514378", "text": "The role of platelet/lymphocyte serotonin transporter in depression and beyond.\n", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "23514378", "text": "A large amount of the data gathered in the last 50 years support the hypothesis that alterations of the serotonin (5-HT) neurotransmission play a crucial role in the pathophysiology of not only major depression (MD), but also of different neuropsychiatric disorders.", "type": "CHEMICAL", "entities": [ "serotonin", "5-HT" ], "offsets": [ [ 104, 113 ], [ 115, 119 ] ] }, { "pmid": "23514378", "text": "Research in this field has been substantially promoted by the evidence that the reuptake protein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in the synaptic cleft.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23514378", "text": "For this reason, it was specifically targeted for the development of second-generation antidepressants, in particular of selective 5-HT reuptake inhibitors (SSRIs), with the aim of increasing the intrasynaptic 5-HT concentrations.", "type": "CHEMICAL", "entities": [ "5-HT", "5-HT" ], "offsets": [ [ 131, 135 ], [ 210, 214 ] ] }, { "pmid": "23514378", "text": "Moreover, since a lot of studies showed that circulating platelets and, more recently, lymphocytes possess functional SERT proteins, they have been widely used as peripheral mirrors of the same structures located in the central nervous system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23514378", "text": "The presence of functional SERT in blood cells suggests strict relationships between the nervous and the immune system that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by different drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23514378", "text": "This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possible role of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosological involvement of this structure in different conditions spanning from normality to pathology.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 56, 60 ] ] }, { "pmid": "23410005", "text": "Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.\n", "type": "CHEMICAL", "entities": [ "5-morpholino-7H-thieno[3,2-b]pyran-7-ones" ], "offsets": [ [ 61, 102 ] ] }, { "pmid": "23410005", "text": "Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23410005", "text": "Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials.", "type": "CHEMICAL", "entities": [ "LY294002", "SF1126" ], "offsets": [ [ 71, 79 ], [ 149, 155 ] ] }, { "pmid": "23410005", "text": "This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23410005", "text": "We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.", "type": "CHEMICAL", "entities": [ "5-morpholino-7H-thieno[3,2-b]pyran-7-one" ], "offsets": [ [ 183, 223 ] ] }, { "pmid": "23265893", "text": "Heterobivalent dual-target probe for targeting GRP and Y1 receptors on tumor cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265893", "text": "Receptor targeting ligands for imaging and/or therapy of cancer are limited by heterogeneity of receptor expression by tumor cells, both inter-patient and intra-patient.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265893", "text": "It is often more important for imaging agents to identify local and distant spread of disease than it is to identify a specific receptor presence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265893", "text": "Two natural hormone peptide receptors, GRPR and Y1, are specifically interesting because expression of GRPR, Y1 or both is up-regulated in most breast cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265893", "text": "We describe here the design and development of a new heterobivalent peptide ligand, truncated bombesin (t-BBN)/BVD15-DO3A, for dual-targeting of GRPR and Y1, and validation of its dual binding capability.", "type": "CHEMICAL", "entities": [ "bombesin" ], "offsets": [ [ 94, 102 ] ] }, { "pmid": "23265893", "text": "Such a probe should be useful in imaging cells, tissues and tumors that are GRPR and/or Y1 positive and should target radioisotopes, for example, (68)Ga and/or (177)Lu, to more tumors cells than single GRPR or Y1 targeted probes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265893", "text": "A GRP targeting ligand, J-G-Abz4-QWAVGHLM-NH(2) (J-G-Abz4-t-BBN), and an Y1 targeting ligand, INP-K[ε-J-(α-DO3A-ε-DGa)-K]-YRLRY-NH(2)([ε-J-(α-DO3A-ε-DGa)-K]-BVD-15), were synthesized and coupled to produce the heterobivalent ligand, t-BBN/BVD15-DO3A. Competitive displacement binding assays using t-BBN/BVD15-DO3A against (125)I-Tyr(4)-BBN yielded an IC(50) value of 18 ± 0.7 nM for GRPR in T-47D cells, a human breast cancer cell line.", "type": "CHEMICAL", "entities": [ "(125)I", "Tyr" ], "offsets": [ [ 322, 328 ], [ 329, 332 ] ] }, { "pmid": "23265893", "text": "A similar assay using t-BBN/BVD15-DO3A against porcine (125)I-NPY showed IC(50) values of 80 ± 11 nM for Y1 receptor in MCF7 cells, another human breast cancer cell line.", "type": "CHEMICAL", "entities": [ "(125)I" ], "offsets": [ [ 48, 54 ] ] }, { "pmid": "23265893", "text": "In conclusion, it is possible to construct a single DO3A chelate containing probe that can target both GRPR and Y1 on human tumor cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "Induction of the metabolic regulator Txnip in fasting-induced and natural torpor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "Torpor is a physiological state characterised by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "The hypothalamus coordinates energy homeostasis and thermoregulation, and plays a key role in directing torpor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "We recently showed that mice lacking the orphan G protein coupled receptor Gpr50 readily enter torpor in response to fasting, and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "This revealed a strong induction of thioredoxin interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "In situ hybridisation identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "To characterise further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster.", "type": "CHEMICAL", "entities": [ "2-deoxyglucose" ], "offsets": [ [ 149, 163 ] ] }, { "pmid": "23584857", "text": "Strikingly, pronounced upregulation of Txnip expression was only observed in WT mice when driven into torpor, and during torpor in the Siberian hamster.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584857", "text": "Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel utilisation during the extreme hypometabolic state of torpor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567959", "text": "Design, synthesis and antiproliferative properties of some new 5-substituted-2-iminobenzimidazole derivatives.\n", "type": "CHEMICAL", "entities": [ "5-substituted-2-iminobenzimidazole" ], "offsets": [ [ 63, 97 ] ] }, { "pmid": "23567959", "text": "Some new 1,3,5-substituted-2,3-dihydro-2-imino-benzimidazoles were synthesized under solid-liquid phase transfer catalysis conditions using 5-substituted-2-aminobenzimidazoles as precursors in order to assess their cytotoxicity respectively proliferative activity.", "type": "CHEMICAL", "entities": [ "5-substituted-2-aminobenzimidazoles", "1,3,5-substituted-2,3-dihydro-2-imino-benzimidazoles" ], "offsets": [ [ 140, 175 ], [ 9, 61 ] ] }, { "pmid": "23567959", "text": "The structures of the compounds were confirmed by IR, (1)H NMR, (13)C NMR and elemental analysis.", "type": "CHEMICAL", "entities": [ "(1)H", "(13)C" ], "offsets": [ [ 54, 58 ], [ 64, 69 ] ] }, { "pmid": "23567959", "text": "Compounds 9-10, 12 and 16-17 were evaluated for their cytotoxical effect on four cancer cell lines: HT-29, breast cancer cells MDA-MB-231, HeLa, HepG2 and as well as human diploid cell line Lep-3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567959", "text": "Significant cytotoxicity of hydrazone 16 against MDA-MB-231 was established by biologically study, the IC50 was 6.2 nM while the EC50 value to Lep 3 is 0.21 nM. Relative high antiproliferative effects of the acetate 12 and compound 16 against HT-29 were ascertained and the calculated IC50 values were IC50 - 0.85 nM and IC50 - 2.83 nM respectively.", "type": "CHEMICAL", "entities": [ "hydrazone", "acetate" ], "offsets": [ [ 28, 37 ], [ 208, 215 ] ] }, { "pmid": "23567959", "text": "Cytotoxic activity against HeLa and HepG2 cells was demonstrated by hydrazone 17, IC50 was 7.2 nM and 117 nM respectively.", "type": "CHEMICAL", "entities": [ "hydrazone" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "23567959", "text": "All tested compounds revealed proliferative activities to human diploid cell line Lep-3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567959", "text": "The EC50 values were in the range from 0.05 to 16.91 nM. The obtained results prove the selective cytotoxicity of the tested compounds and are promising for further evaluation of the investigated compounds in vivo experiments using experimentally induced tumors in laboratory animals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "Immunomodulatory properties of multi-walled carbon nanotubes in peripheral blood mononuclear cells from healthy subjects and allergic patients.\n", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 44, 50 ] ] }, { "pmid": "23266719", "text": "In the present study, we investigated the immunomodulatory activity of multi-walled carbon nanotubes (MWCNTs) in peripheral blood mononuclear cells (PBMCs) from healthy donors and mite-allergic subjects.", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 84, 90 ] ] }, { "pmid": "23266719", "text": "Freshly prepared PBMCs, stimulated or not with Toll-like receptor (TLR)1-9 agonists, a T cell mitogen (phytohemagglutinin A) or mite allergen extract were cultured in the presence or absence of MWCNTs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "Secretion of TNF-α, IL-2, IL-5, IL-6, IL-12/23p40 or IFN-γ was quantified in the culture supernatants by ELISA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "Basal secretion of all the cytokines was not altered by MWCNTs in PBMCs from both healthy donors and allergic subjects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "In PBMCs from healthy donors, TNF-α, IL-6 and IL-12/23p40 secretion in response to the TLR4 agonist, lipopolysaccharide was however increased in a dose-dependent manner by MWCNTs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "Significant increases in the release of these cytokines were also observed in PBMCs stimulated with a TLR2 or TLR3 agonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "MWCNTs also increased the release of IL-2 and IFN-γ by PBMCs stimulated with a T cell mitogen.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "In contrast, MWCNTs inhibited allergen-induced IL-5 secretion by PBMCs from mite-allergic subjects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "As well, MWCNTs altered the capacity of PBMC-derived monocytes to differentiate into functional dendritic cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "All together, our data suggest that according to its immune cell target, MWCNTs may either promote or suppress immune responses in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266719", "text": "Further investigations are necessary to fully understand the complexity behind interactions of engineered nanoparticles with the immune system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23509039", "text": "2-aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease.\n", "type": "CHEMICAL", "entities": [ "2-aminothiazoles" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23509039", "text": "Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40 %, and high exposure in the brains of mice.", "type": "CHEMICAL", "entities": [ "aminothiazole", "(4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine" ], "offsets": [ [ 27, 40 ], [ 46, 104 ] ] }, { "pmid": "23509039", "text": "Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP(Sc) .", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23509039", "text": "Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23509039", "text": "Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.", "type": "CHEMICAL", "entities": [ "(6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine", "cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide" ], "offsets": [ [ 62, 129 ], [ 134, 191 ] ] }, { "pmid": "16978033", "text": "Immunotherapy for De Novo renal transplantation: what's in the pipeline?\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials.", "type": "CHEMICAL", "entities": [ "tacrolimus" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "16978033", "text": "It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation.", "type": "CHEMICAL", "entities": [ "tacrolimus" ], "offsets": [ [ 102, 112 ] ] }, { "pmid": "16978033", "text": "Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids.", "type": "CHEMICAL", "entities": [ "ciclosporin", "cyclosporine", "mycophenolate mofetil", "MMF" ], "offsets": [ [ 51, 62 ], [ 64, 76 ], [ 129, 150 ], [ 152, 155 ] ] }, { "pmid": "16978033", "text": "Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 32, 40 ] ] }, { "pmid": "16978033", "text": "The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16978033", "text": "CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.", "type": "CHEMICAL", "entities": [ "CP-690550" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16978033", "text": "FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials.", "type": "CHEMICAL", "entities": [ "FK778", "malononitrilamide", "pyrimidine", "dihydroorotic acid", "tyrosine" ], "offsets": [ [ 0, 5 ], [ 22, 39 ], [ 88, 98 ], [ 110, 128 ], [ 168, 176 ] ] }, { "pmid": "16978033", "text": "FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy.", "type": "CHEMICAL", "entities": [ "FK778" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "16978033", "text": "Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials.", "type": "CHEMICAL", "entities": [ "Fingolimod", "FTY720", "sphingosine phosphate" ], "offsets": [ [ 0, 10 ], [ 12, 18 ], [ 33, 54 ] ] }, { "pmid": "16978033", "text": "Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation.", "type": "CHEMICAL", "entities": [ "fingolimod", "MMF", "ciclosporin" ], "offsets": [ [ 25, 35 ], [ 50, 53 ], [ 90, 101 ] ] }, { "pmid": "16978033", "text": "Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.", "type": "CHEMICAL", "entities": [ "FK778" ], "offsets": [ [ 106, 111 ] ] }, { "pmid": "16978033", "text": "Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15686475", "text": "Effect of apocalmodulin on recombinant human brain glutamic acid decarboxylase.\n", "type": "CHEMICAL", "entities": [ "glutamic acid" ], "offsets": [ [ 51, 64 ] ] }, { "pmid": "15686475", "text": "In this work, we report that the recombinant glutathione S-transferase (GST)-human L-glutamic acid decarboxylase (HGAD) isoforms, 65-kDa L-glutamic acid decarboxylase (GAD) (GST-HGAD65) fusion protein or free truncated HGAD65, were activated by apocalmodulin (ApoCaM) to an extent of 60%.", "type": "CHEMICAL", "entities": [ "L-glutamic acid", "glutathione", "S", "L-glutamic acid" ], "offsets": [ [ 137, 152 ], [ 45, 56 ], [ 57, 58 ], [ 83, 98 ] ] }, { "pmid": "15686475", "text": "Both truncated forms of GAD67 (tGAD67), HGAD67(Delta1-70) and HGAD67(Delta1-90), were markedly activated by ApoCaM to an extent of 141 and 85%, respectively, while GST-HGAD67 was not significantly affected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15686475", "text": "The activation appears to be due to an increase of GAD affinity for its cofactor, pyridoxal phosphate (PLP).", "type": "CHEMICAL", "entities": [ "pyridoxal phosphate", "PLP" ], "offsets": [ [ 82, 101 ], [ 103, 106 ] ] }, { "pmid": "15686475", "text": "This conclusion is based on the following observations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15686475", "text": "Firstly, the V(max) of GAD was increased when ApoCaM was present whereas the affinity for the substrate, glutamate, was not affected.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 105, 114 ] ] }, { "pmid": "15686475", "text": "Secondly, the affinity of GAD for PLP was increased in the presence of ApoCaM. Thirdly, results from calmodulin-agarose affinity column chromatography studies indicated a direct interaction or binding between ApoCaM and GAD.", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 34, 37 ] ] }, { "pmid": "15686475", "text": "Fourthly, ApoCaM was found to be copurified with GAD65/GAD67 by anti-GAD65/67 immunoaffinity column using rat brain extract.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15686475", "text": "Hence, it is proposed that a conformational change is induced when ApoCaM interacts with GAD65 or tGAD67, resulting in an increase of GAD affinity for PLP and the activation of GAD.", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 151, 154 ] ] }, { "pmid": "15686475", "text": "The physiological significance of the interaction between GAD and ApoCaM is discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17488480", "text": "Hydrogen sulfide acts as a mediator of inflammation in acute pancreatitis: in vitro studies using isolated mouse pancreatic acinar cells.\n", "type": "CHEMICAL", "entities": [ "Hydrogen sulfide" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17488480", "text": "Hydrogen sulphide (H(2)S) is synthesized from L-cysteine via the action of cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS).", "type": "CHEMICAL", "entities": [ "Hydrogen sulphide", "cystathionine", "H(2)S", "L-cysteine", "cystathionine" ], "offsets": [ [ 0, 17 ], [ 111, 124 ], [ 19, 24 ], [ 46, 56 ], [ 75, 88 ] ] }, { "pmid": "17488480", "text": "We have earlier shown that H(2)S acts as a mediator of inflammation.", "type": "CHEMICAL", "entities": [ "H(2)S" ], "offsets": [ [ 27, 32 ] ] }, { "pmid": "17488480", "text": "However the mechanism remains unclear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17488480", "text": "In this study, we investigated the presence of H(2)S and the expression of H(2)S synthesizing enzymes, CSE and CBS, in isolated mouse pancreatic acini.", "type": "CHEMICAL", "entities": [ "H(2)S", "H(2)S" ], "offsets": [ [ 47, 52 ], [ 75, 80 ] ] }, { "pmid": "17488480", "text": "Pancreatic acinar cells from mice were incubated with or without caerulein (10(-7) M for 30 and 60 min).", "type": "CHEMICAL", "entities": [ "caerulein" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "17488480", "text": "Caerulein increased the levels of H(2)S and CSE mRNA expression while CBS mRNA expression was decreased.", "type": "CHEMICAL", "entities": [ "Caerulein", "H(2)S" ], "offsets": [ [ 0, 9 ], [ 34, 39 ] ] }, { "pmid": "17488480", "text": "In addition, cells pre-treated with DL-propargylglycine (PAG, 3 mM), a CSE inhibitor, reduced the formation of H(2)S in caerulein treated cells, suggesting that CSE may be the main enzyme involved in H(2)S formation in mouse acinar cells.", "type": "CHEMICAL", "entities": [ "DL-propargylglycine", "PAG", "H(2)S", "caerulein", "H(2)S" ], "offsets": [ [ 36, 55 ], [ 57, 60 ], [ 111, 116 ], [ 120, 129 ], [ 200, 205 ] ] }, { "pmid": "17488480", "text": "Furthermore, substance P (SP) concentration in the acini and expression of SP gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for SP, are increased in secretagogue caerulein-treated acinar cells.", "type": "CHEMICAL", "entities": [ "SP", "caerulein", "substance P", "SP", "SP" ], "offsets": [ [ 171, 173 ], [ 205, 214 ], [ 13, 24 ], [ 26, 28 ], [ 75, 77 ] ] }, { "pmid": "17488480", "text": "Inhibition of endogenous production of H(2)S by PAG significantly suppressed SP concentration, PPT-A expression and NK1-R expression in the acini.", "type": "CHEMICAL", "entities": [ "H(2)S", "PAG", "SP" ], "offsets": [ [ 39, 44 ], [ 48, 51 ], [ 77, 79 ] ] }, { "pmid": "17488480", "text": "To determine whether H(2)S itself provoked inflammation in acinar cells, the cells were treated with H(2)S donor drug, sodium hydrosulphide (NaHS), (10, 50 and 100 muM), that resulted in a significant increase in SP concentration and expression of PPT-A and NK1-R in acinar cells.", "type": "CHEMICAL", "entities": [ "H(2)S", "H(2)S", "sodium hydrosulphide", "NaHS", "SP" ], "offsets": [ [ 21, 26 ], [ 101, 106 ], [ 119, 139 ], [ 141, 145 ], [ 213, 215 ] ] }, { "pmid": "17488480", "text": "These results suggest that the pro-inflammatory effect of H(2)S may be mediated by SP-NK-1R related pathway in mouse pancreatic acinar cells.", "type": "CHEMICAL", "entities": [ "H(2)S" ], "offsets": [ [ 58, 63 ] ] }, { "pmid": "17618628", "text": "Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method.\n", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 56, 67 ] ] }, { "pmid": "17618628", "text": "Somatic angiotensin I-converting enzyme (s-ACE) plays a central role in blood pressure regulation and has been the target of most antihypertensive drugs.", "type": "CHEMICAL", "entities": [ "angiotensin I" ], "offsets": [ [ 8, 21 ] ] }, { "pmid": "17618628", "text": "A displacement isothermal titration calorimetry method has been used to accurately determine the binding constant of three strong s-ACE inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17618628", "text": "Under the experimental conditions studied in this work, the relative potency of the inhibitors was determined to be enalaprilat>lisinopril>captopril.", "type": "CHEMICAL", "entities": [ "enalaprilat", "lisinopril", "captopril" ], "offsets": [ [ 116, 127 ], [ 128, 138 ], [ 139, 148 ] ] }, { "pmid": "17618628", "text": "We analyze the thermodynamic behaviour of the binding process using the new structural information provided by the ACE structures, as well as the conformational changes that occur upon binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "Antiaggressive activity of central oxytocin in male rats.\n", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "23624810", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 62, 70 ] ] }, { "pmid": "23624810", "text": "However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 63, 71 ] ] }, { "pmid": "23624810", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "Resident animals were intracerebroventricularly (icv) administered with different doses of synthetic oxytocin and oxytocin receptor antagonist, alone and in combination, in order to manipulate brain oxytocin functioning and to assess their behavioral response to an intruder.", "type": "CHEMICAL", "entities": [ "oxytocin", "oxytocin", "oxytocin" ], "offsets": [ [ 101, 109 ], [ 114, 122 ], [ 199, 207 ] ] }, { "pmid": "23624810", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "Our data clearly demonstrate that acute icv administered oxytocin produces dose-dependent and receptor-selective changes in social behavior, reducing aggression and potentiating social exploration.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 57, 65 ] ] }, { "pmid": "23624810", "text": "These antiaggressive effects are stronger in the more offensive rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "On the other hand, administration of an oxytocin receptor antagonist tends to increase (nonsignificantly) aggression only in low-medium aggressive animals.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "23624810", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "These results suggest that transiently enhancing brain oxytocin function has potent antiaggressive effects, whereas its attenuation tends to enhance aggressiveness.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 55, 63 ] ] }, { "pmid": "23624810", "text": "In addition, a possible inverse relationship between trait aggression and endogenous oxytocinergic signaling is revealed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "Overall, this study emphasizes the importance of brain oxytocinergic signaling for regulating intermale offensive aggression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23624810", "text": "This study supports the suggestion that oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "23631499", "text": "Possible Therapeutic Uses of Salvia triloba and Piper nigrum in Alzheimer's Disease-Induced Rats.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "Abstract This study aimed to investigate the role of Salvia triloba L. and Piper nigrum extracts in ameliorating neuroinflammatory insults characteristic of Alzheimer's disease (AD) in an experimentally induced rat model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "Adult male Sprague-Dawley rats were classified into Group 1 (n=10): normal healthy animals serving as the negative control group; Group 2 (n=60): the AD-induced group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "After AD induction, animals in the AD-induced group were divided randomly and equally into 6 subgroups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "The first subgroup served as AD control; the second one, which served as positive control, was treated orally with the conventional therapy for AD (rivastigmine) at a dose of 0.3 mg/kg body weight (b.w.)", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 148, 160 ] ] }, { "pmid": "23631499", "text": "daily for 3 months.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "The third and fourth subgroups were, respectively, treated orally with the S. triloba extract at a dose of 750 and 375 mg/kg b.w. daily for 3 months.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "The fifth and sixth subgroups were, respectively, treated orally with the P. nigrum extract at a dose of 187.5 and 93.75 mg/kg b.w. daily for 3 months.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "Levels of brain acetylcholine (Ach), serum and brain acetylcholinesterase (AchE) activity, C-reactive protein (CRP), total nuclear factor kappa-B (NF-κB), and monocyte chemoattractant protein-1", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 10, 23 ] ] }, { "pmid": "23631499", "text": "(MCP-1) were estimated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "The results showed that administration of AlCl3 resulted in a significant elevation in the levels of AchE activity, CRP, NF-κB, and MCP-1 accompanied with a significant depletion in the Ach level.", "type": "CHEMICAL", "entities": [ "AlCl3" ], "offsets": [ [ 35, 40 ] ] }, { "pmid": "23631499", "text": "Treatment of AD rats with each of the selected medicinal plant extracts caused marked improvement in the measured biochemical parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631499", "text": "In conclusion, S. triloba and P. nigrum methanolic extracts have potent anti-inflammatory effects against neuroinflammation characterizing AD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578607", "text": "Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger.\n", "type": "CHEMICAL", "entities": [ "Glutathione", "6-dehydroshogaol" ], "offsets": [ [ 0, 11 ], [ 60, 76 ] ] }, { "pmid": "23578607", "text": "6-Dehydroshogaol (6-DHSG) is a bioactive α,β-unsaturated carbonyl compound isolated from fresh ginger with anti-inflammatory and phase II enzyme inducing activities.", "type": "CHEMICAL", "entities": [ "6-Dehydroshogaol", "6-DHSG", "α,β-unsaturated carbonyl" ], "offsets": [ [ 0, 16 ], [ 18, 24 ], [ 41, 65 ] ] }, { "pmid": "23578607", "text": "Here we describe the glutathione (GSH)-dependent metabolism and the effect of this metabolic transformation on the biological activities of 6-DHSG.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH", "6-DHSG" ], "offsets": [ [ 19, 30 ], [ 32, 35 ], [ 138, 144 ] ] }, { "pmid": "23578607", "text": "Compared with other ginger compounds, such as 6-gingerol and 6-shogaol, 6-DHSG showed the most potent anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells.", "type": "CHEMICAL", "entities": [ "6-gingerol", "6-shogaol", "6-DHSG" ], "offsets": [ [ 44, 54 ], [ 59, 68 ], [ 70, 76 ] ] }, { "pmid": "23578607", "text": "The biological activities of 6-DHSG were attenuated by sulfhydryl antioxidants such as glutathione (GSH) or N-acetyl cysteine (NAC), but not ascorbic acid (ASC).", "type": "CHEMICAL", "entities": [ "6-DHSG", "sulfhydryl", "glutathione", "GSH", "N-acetyl cysteine", "NAC", "ascorbic acid", "ASC" ], "offsets": [ [ 27, 33 ], [ 53, 63 ], [ 85, 96 ], [ 98, 101 ], [ 106, 123 ], [ 125, 128 ], [ 139, 152 ], [ 154, 157 ] ] }, { "pmid": "23578607", "text": "6-DHSG was metabolised by GSH to form a GSH conjugate (GS-6-DHSG) in RAW 264.7 cells, via a potential mechanism involving the catalytic activity of glutathione-S-transferase (GST).", "type": "CHEMICAL", "entities": [ "GSH", "GSH", "GS-6-DHSG", "glutathione", "S" ], "offsets": [ [ 24, 27 ], [ 38, 41 ], [ 53, 62 ], [ 146, 157 ], [ 158, 159 ] ] }, { "pmid": "23578607", "text": "GS-6-DHSG showed reduced biological activities compared with 6-DHSG in multiple biological assays.", "type": "CHEMICAL", "entities": [ "6-DHSG" ], "offsets": [ [ 59, 65 ] ] }, { "pmid": "23578607", "text": "Together, these results indicate that GSH conjugation attenuates the biological activities of 6-DHSG and other α,β-unsaturated carbonyl compounds.", "type": "CHEMICAL", "entities": [ "6-DHSG", "α,β-unsaturated carbonyl", "GSH" ], "offsets": [ [ 92, 98 ], [ 109, 133 ], [ 36, 39 ] ] }, { "pmid": "23115325", "text": "Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation.\n", "type": "CHEMICAL", "entities": [ "Hydrogen sulfide", "ATP", "potassium" ], "offsets": [ [ 0, 16 ], [ 47, 50 ], [ 61, 70 ] ] }, { "pmid": "23115325", "text": "The ATP-sensitive potassium channel (K(ATP)) in mouse colonic smooth muscle cell is a complex containing a pore-forming subunit (Kir6.1) and a sulfonylurea receptor subunit (SUR2B).", "type": "CHEMICAL", "entities": [ "sulfonylurea", "potassium", "K", "ATP", "ATP" ], "offsets": [ [ 143, 155 ], [ 18, 27 ], [ 37, 38 ], [ 39, 42 ], [ 4, 7 ] ] }, { "pmid": "23115325", "text": "These channels contribute to the cellular excitability of smooth muscle cells and hence regulate the motility patterns in the colon.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23115325", "text": "Whole-cell voltage-clamp techniques were used to study the alterations in K(ATP) channels in smooth muscle cells in experimental colitis.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 74, 75 ], [ 76, 79 ] ] }, { "pmid": "23115325", "text": "Colonic inflammation was induced in BALB/C mice after intracolonic administration of trinitrobenzene sulfonic acid.", "type": "CHEMICAL", "entities": [ "trinitrobenzene sulfonic acid" ], "offsets": [ [ 85, 114 ] ] }, { "pmid": "23115325", "text": "K(ATP) currents were measured at a holding potential of -60 mV in high K(+) external solution.", "type": "CHEMICAL", "entities": [ "K", "ATP", "K(+)" ], "offsets": [ [ 0, 1 ], [ 2, 5 ], [ 71, 75 ] ] }, { "pmid": "23115325", "text": "The concentration response to levcromakalim (LEVC), a K(ATP) channel opener, was significantly shifted to the left in the inflamed smooth-muscle cells.", "type": "CHEMICAL", "entities": [ "levcromakalim", "LEVC", "K", "ATP" ], "offsets": [ [ 30, 43 ], [ 45, 49 ], [ 54, 55 ], [ 56, 59 ] ] }, { "pmid": "23115325", "text": "Both the potency and maximal currents induced by LEVC were enhanced in inflammation.", "type": "CHEMICAL", "entities": [ "LEVC" ], "offsets": [ [ 49, 53 ] ] }, { "pmid": "23115325", "text": "The EC(50) values in control were 6259 nM (n = 10) and 422 nM (n = 8) in inflamed colon, and the maximal currents were 9.9 ± 0.71 pA/pF (60 μM) in control and 39.7 ± 8.8 pA/pF (3 μM) after inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23115325", "text": "As was seen with LEVC, the potency and efficacy of sodium hydrogen sulfide (NaHS) (10-1000 μM) on K(ATP) currents were significantly greater in inflamed colon compared with controls.", "type": "CHEMICAL", "entities": [ "LEVC", "sodium hydrogen sulfide", "NaHS", "K", "ATP" ], "offsets": [ [ 13, 17 ], [ 47, 70 ], [ 72, 76 ], [ 94, 95 ], [ 96, 99 ] ] }, { "pmid": "23115325", "text": "In control cells, pretreatment with 100 µM NaHS shifted the EC(50) for LEV-induced currents from 2838 (n = 6) to 154 (n = 8) nM. Sulfhydration of sulfonylurea receptor 2B (SUR2B) was induced by NaHS and colonic inflammation.", "type": "CHEMICAL", "entities": [ "NaHS", "sulfonylurea", "NaHS" ], "offsets": [ [ 38, 42 ], [ 141, 153 ], [ 189, 193 ] ] }, { "pmid": "23115325", "text": "These data suggest that sulfhydration of SUR2B induces allosteric modulation of K(ATP) currents in colonic inflammation.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 74, 75 ], [ 76, 79 ] ] }, { "pmid": "17497253", "text": "[Short QT syndrome].\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Short QT syndrome is a new genetic disorder associated with familial atrial fibrillation and/or sudden death or syncope.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "To date, different mutations in genes encoding for cardiac ion channels (KCNH2, KCNQ1, and KCNJ2) have been identified to cause the short QT syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "The mutations lead to a gain of function of the affected current (IKr, IKs, and IK1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "The phenotype is characterized by a shortened QT interval<335", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "ms after correction for heart rate at rates<80 beats/min.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Furthermore, the QT interval poorly adapts to heart rate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Patients exhibit shortened atrial and ventricular effective refractory periods and, in the majority, inducibility of ventricular fibrillation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Death occurs already in newborns.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Therapy of choice seems to be the implantable cardioverter defibrillator because of the high incidence of sudden death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17497253", "text": "Pharmacological treatment has been studied and it could be demonstrated, that some mutant currents may be insufficiently suppressed by drugs targeted to block the specific current such as, e.g., sotalol or ibutilide in patients with a mutation in the IKr-coding gene KCNH2 (HERG).", "type": "CHEMICAL", "entities": [ "sotalol", "ibutilide" ], "offsets": [ [ 195, 202 ], [ 206, 215 ] ] }, { "pmid": "17497253", "text": "Quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods in some patients.", "type": "CHEMICAL", "entities": [ "Quinidine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "6374639", "text": "The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review.\n", "type": "CHEMICAL", "entities": [ "RU 23908", "Anandron" ], "offsets": [ [ 22, 30 ], [ 32, 40 ] ] }, { "pmid": "6374639", "text": "The nonsteroidal antiandrogen RU 23908 ( Anandron ) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate.", "type": "CHEMICAL", "entities": [ "RU 23908", "Anandron", "androgen" ], "offsets": [ [ 30, 38 ], [ 41, 49 ], [ 98, 106 ] ] }, { "pmid": "6374639", "text": "When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 176, 185 ] ] }, { "pmid": "6374639", "text": "In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6374639", "text": "This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 101, 110 ] ] }, { "pmid": "6374639", "text": "In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles.", "type": "CHEMICAL", "entities": [ "androgens", "testosterone" ], "offsets": [ [ 82, 91 ], [ 121, 133 ] ] }, { "pmid": "6374639", "text": "In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment.", "type": "CHEMICAL", "entities": [ "testosterone", "RU 23908", "testosterone" ], "offsets": [ [ 20, 32 ], [ 110, 118 ], [ 139, 151 ] ] }, { "pmid": "6374639", "text": "Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6374639", "text": "Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.", "type": "CHEMICAL", "entities": [ "estrogen", "progestins", "androgen" ], "offsets": [ [ 53, 61 ], [ 66, 76 ], [ 253, 261 ] ] }, { "pmid": "23104244", "text": "Cytochrome P450-mediated herb-drug interaction potential of Galgeun-tang.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential of GGT extracts were determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "As measured by LC-ESI/MS/MS, GGT extracts (0-300μg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1week was examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated.", "type": "CHEMICAL", "entities": [ "7-ethoxyresorufin", "O", "7-pentoxyresorufin", "O", "chlorzoxazone", "midazolam" ], "offsets": [ [ 21, 38 ], [ 39, 40 ], [ 53, 71 ], [ 72, 73 ], [ 91, 104 ], [ 128, 137 ] ] }, { "pmid": "23104244", "text": "These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23104244", "text": "Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144.", "type": "CHEMICAL", "entities": [ "7-ethoxyresorufin", "7-pentoxyresorufin", "chlorzoxazone" ], "offsets": [ [ 61, 78 ], [ 93, 111 ], [ 131, 144 ] ] }, { "pmid": "23104244", "text": "Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14600253", "text": "Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice.\n", "type": "CHEMICAL", "entities": [ "cefadroxil" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "14600253", "text": "The choroid plexus uptake of [(3)H]cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability.", "type": "CHEMICAL", "entities": [ "[(3)H]cefadroxil" ], "offsets": [ [ 29, 45 ] ] }, { "pmid": "14600253", "text": "At normal pH (7.4) and temperature (37 degrees C), the uptake of 1 microM cefadroxil was reduced by 83% in PEPT2(-/-) mice as compared with PEPT2(+/+) mice (p < 0.001).", "type": "CHEMICAL", "entities": [ "cefadroxil" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "14600253", "text": "A further reduction was achieved in null animals by reducing the temperature to 4 degrees C, or by adding saturating concentrations of unlabeled cefadroxil or p-aminohippurate (p < 0.05).", "type": "CHEMICAL", "entities": [ "cefadroxil", "p-aminohippurate" ], "offsets": [ [ 145, 155 ], [ 159, 175 ] ] }, { "pmid": "14600253", "text": "Glycylsarcosine coadministration could inhibit the uptake of cefadroxil in PEPT2(+/+) mice (p < 0.01) but not PEPT2(-/-) mice.", "type": "CHEMICAL", "entities": [ "Glycylsarcosine", "cefadroxil" ], "offsets": [ [ 0, 15 ], [ 61, 71 ] ] }, { "pmid": "14600253", "text": "Although a proton-stimulated uptake of cefadroxil was demonstrated in PEPT2(+/+) mice (pH 6.5 versus pH 7.4; p < 0.01), no pH dependence was observed in PEPT2(-/-) mice.", "type": "CHEMICAL", "entities": [ "cefadroxil" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "14600253", "text": "Kinetic parameters for cefadroxil (without p-aminohippurate) in wild-type mice were: V(max)", "type": "CHEMICAL", "entities": [ "cefadroxil", "p-aminohippurate" ], "offsets": [ [ 23, 33 ], [ 43, 59 ] ] }, { "pmid": "14600253", "text": "= 5.4 pmol/mg/min, K(m) = 34 microM, and K(d) = 0.0069 microl/mg/min; in the presence of p-aminohippurate, the parameters were: V(max)", "type": "CHEMICAL", "entities": [ "p-aminohippurate" ], "offsets": [ [ 89, 105 ] ] }, { "pmid": "14600253", "text": "= 4.1 pmol/mg/min, K(m) = 27 microM, and K(d) = 0.0064 microl/mg/min.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14600253", "text": "In null animals, the kinetic parameters of cefadroxil (without p-aminohippurate) were: V(max)", "type": "CHEMICAL", "entities": [ "cefadroxil", "p-aminohippurate" ], "offsets": [ [ 43, 53 ], [ 63, 79 ] ] }, { "pmid": "14600253", "text": "= 2.7 pmol/mg/min, K(m) = 110 microM, and K(d) = 0.0084 microl/mg/min; in the presence of p-aminohippurate, only a K(d) = 0.010 microl/mg/min was observed.", "type": "CHEMICAL", "entities": [ "p-aminohippurate" ], "offsets": [ [ 90, 106 ] ] }, { "pmid": "14600253", "text": "Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of cefadroxil's uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14600253", "text": "These findings demonstrate that PEPT2 is the primary transporter responsible for cefadroxil uptake in the choroid plexus.", "type": "CHEMICAL", "entities": [ "cefadroxil" ], "offsets": [ [ 81, 91 ] ] }, { "pmid": "14600253", "text": "Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "Comparative proteomics of ovarian epithelial tumors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "We analyzed 12 ovarian epithelial tumors using 2D PAGE-based comparative proteomics to construct intra- and inter-tumoral distance map trees and to discover surrogate biomarkers indicative of an ovarian tumor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "The analysis was performed after laser microdissection of 12 fresh-frozen tissue samples, including 4 serous, 5 mucinous, and 3 endometrioid tumors, with correlation with their histopathological characteristics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "Ovarian epithelial tumors and normal tissues showed an apparent separation on the distance map tree.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "Mucinous carcinomas were closest to the normal group, whereas serous carcinomas were located furthest from the normal group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "All mucinous tumors with aggressive histology were separated from the low malignant potential (LMP) group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "The benign-looking cysts adjacent to the intraepithelial carcinoma (IEC) showed an expression pattern identical to that of the IEC area.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "The extent of change on the lineages leading to the mucinous and serous carcinoma was 1.98-fold different.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "The overall gene expression profiles of serous or endometrioid carcinomas appeared to be less affected by grade or stage than by histologic type.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "The potential candidate biomarkers screened in ovarian tumors and found to be significantly up-regulated in comparison to normal tissues were as follows: NM23, annexin-1, protein phosphatase-1, ferritin light chain, proteasome alpha-6, and NAGK (N-acetyl glucosamine kinase).", "type": "CHEMICAL", "entities": [ "N-acetyl glucosamine" ], "offsets": [ [ 246, 266 ] ] }, { "pmid": "16674097", "text": "In conclusion, ovarian mucinous tumors are distinct from other ovarian epithelial tumors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16674097", "text": "LMP mucinous tumors showing histologically aggressive features belong to mucinous carcinoma on the proteomic basis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23625750", "text": "The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate-induced experimental acute pancreatitis.\n", "type": "CHEMICAL", "entities": [ "adenosine", "IB-MECA", "sodium taurocholate" ], "offsets": [ [ 19, 28 ], [ 49, 56 ], [ 60, 79 ] ] }, { "pmid": "23625750", "text": "The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated.", "type": "CHEMICAL", "entities": [ "adenosine" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23625750", "text": "Most of the reports discuss their role in intestinal inflammations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23625750", "text": "However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established.", "type": "CHEMICAL", "entities": [ "adenosine" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "23625750", "text": "The aim of this study is (Ed note: Purpose statements should be in present tense) to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP).", "type": "CHEMICAL", "entities": [ "adenosine", "sodium taurocholate" ], "offsets": [ [ 113, 122 ], [ 160, 179 ] ] }, { "pmid": "23625750", "text": "The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C-control rats, I-EAP group, and II-EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p.", "type": "CHEMICAL", "entities": [ "adenosine", "IB-MECA", "(1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide" ], "offsets": [ [ 166, 175 ], [ 196, 203 ], [ 204, 289 ] ] }, { "pmid": "23625750", "text": "at 48, 24, 12 and 1 h before and 1 h after the injection of 5 % sodium taurocholate solution into the biliary-pancreatic duct.", "type": "CHEMICAL", "entities": [ "sodium taurocholate" ], "offsets": [ [ 63, 82 ] ] }, { "pmid": "23625750", "text": "Serum for α-amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23625750", "text": "In the IB-MECA group, α-amylase activity was decreased with statistically high significance compared to group I.", "type": "CHEMICAL", "entities": [ "IB-MECA" ], "offsets": [ [ 1, 8 ] ] }, { "pmid": "23625750", "text": "The activity of lipase was not significantly different among the experimental groups but higher than in the control group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23625750", "text": "The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals.", "type": "CHEMICAL", "entities": [ "IB-MECA" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "23625750", "text": "The use of A3 receptor agonist IB-MECA attenuates EAP.", "type": "CHEMICAL", "entities": [ "IB-MECA" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23625750", "text": "Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats.", "type": "CHEMICAL", "entities": [ "adenosine", "sodium taurocholate" ], "offsets": [ [ 34, 43 ], [ 86, 105 ] ] }, { "pmid": "23350847", "text": "Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors.\n", "type": "CHEMICAL", "entities": [ "Pyrrolopyrazines", "Tyrosine" ], "offsets": [ [ 0, 16 ], [ 37, 45 ] ] }, { "pmid": "23350847", "text": "We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies.", "type": "CHEMICAL", "entities": [ "pyrrolopyrazines" ], "offsets": [ [ 37, 53 ] ] }, { "pmid": "23350847", "text": "Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354393", "text": "Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354393", "text": "Crude composition, fatty acids, sterols, total phenolic content (TPC), individual polyphenols and terpenic acids were determined in five wild edible mushrooms species (Lactarius deliciosus, Lactarius sanguifluus, Lactarius semisanguifluus, Russula delica, Suillus bellinii) from Lesvos Island, Greece.", "type": "CHEMICAL", "entities": [ "fatty acids", "sterols", "polyphenols", "terpenic acids" ], "offsets": [ [ 19, 30 ], [ 32, 39 ], [ 82, 93 ], [ 98, 112 ] ] }, { "pmid": "23354393", "text": "In addition, the DPPH scavenging capacity, the ferric ion reducing power (FRAP) and the ferrous ion chelating activity of mushroom methanolic extracts were assessed.", "type": "CHEMICAL", "entities": [ "DPPH", "ferric", "ferrous" ], "offsets": [ [ 17, 21 ], [ 47, 53 ], [ 88, 95 ] ] }, { "pmid": "23354393", "text": "Among sterols, ergosterol predominated at concentrations 9.2-18.0mg/100g fw.", "type": "CHEMICAL", "entities": [ "sterols", "ergosterol" ], "offsets": [ [ 6, 13 ], [ 15, 25 ] ] }, { "pmid": "23354393", "text": "Total phenolic content of mushroom extracts ranged from 6.0 to 20.8mg GAE/100g fw.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23354393", "text": "Up to 19 simple polyphenols were determined in mushrooms extracts, the more abundant being p-OH-benzoic acid, p-OH-phenylacetic acid, o-coumaric acid, ferulic acid and chrysin.", "type": "CHEMICAL", "entities": [ "polyphenols", "p-OH-benzoic acid", "p-OH-phenylacetic acid", "o-coumaric acid", "ferulic acid", "chrysin" ], "offsets": [ [ 16, 27 ], [ 91, 108 ], [ 110, 132 ], [ 134, 149 ], [ 151, 163 ], [ 168, 175 ] ] }, { "pmid": "23354393", "text": "In addition, the triterpenic acids oleanolic and ursolic were detected for the first time in mushrooms.", "type": "CHEMICAL", "entities": [ "triterpenic acids", "oleanolic", "ursolic" ], "offsets": [ [ 17, 34 ], [ 35, 44 ], [ 49, 56 ] ] }, { "pmid": "23354393", "text": "All species exerted antioxidant activity and ferrous ion chelating capacity.", "type": "CHEMICAL", "entities": [ "ferrous" ], "offsets": [ [ 45, 52 ] ] }, { "pmid": "23354393", "text": "Principal component analysis revealed good correlations between TPC, DPPH and FRAP but not with metal chelating activity.", "type": "CHEMICAL", "entities": [ "DPPH" ], "offsets": [ [ 69, 73 ] ] }, { "pmid": "23354393", "text": "It seems that mushrooms polyphenols exert antiradical and reducing activities, but they are not strong metal chelators, the observed chelating ability being probably due to other classes of compounds.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "23354393", "text": "To our knowledge, this is the first report on the bioactive microconstituents and antioxidant activity of wild Greek edible mushrooms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18559268", "text": "Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel.\n", "type": "CHEMICAL", "entities": [ "paclitaxel", "taxane" ], "offsets": [ [ 134, 144 ], [ 16, 22 ] ] }, { "pmid": "18559268", "text": "The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance.", "type": "CHEMICAL", "entities": [ "taxanes" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "18559268", "text": "As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cumulative.", "type": "CHEMICAL", "entities": [ "epothilones" ], "offsets": [ [ 27, 38 ] ] }, { "pmid": "18559268", "text": "By combining the most favorable substitutions we increased the binding affinity of paclitaxel 500-fold.", "type": "CHEMICAL", "entities": [ "paclitaxel" ], "offsets": [ [ 83, 93 ] ] }, { "pmid": "18559268", "text": "Insight into the structural basis for this improvement was gained with molecular modeling and NMR data obtained for microtubule-bound docetaxel.", "type": "CHEMICAL", "entities": [ "docetaxel" ], "offsets": [ [ 134, 143 ] ] }, { "pmid": "18559268", "text": "Taxanes with affinities for microtubules well above their affinities for P-glycoprotein are shown not to be affected by multidrug resistance.", "type": "CHEMICAL", "entities": [ "Taxanes" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "18559268", "text": "This finding strongly indicates that optimization of the ligand-target interaction is a good strategy to overcome multidrug resistance mediated by efflux pumps.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23182954", "text": "Effects of ozone and fine particulate matter (PM(2.5)) on rat system inflammation and cardiac function.\n", "type": "CHEMICAL", "entities": [ "ozone" ], "offsets": [ [ 11, 16 ] ] }, { "pmid": "23182954", "text": "In order to understand the toxic mechanisms of cardiovascular system injuries induced by ambient PM(2.5) and/or ozone, a subacute toxicological animal experiment was designed with exposure twice a week for 3 continuous weeks.", "type": "CHEMICAL", "entities": [ "ozone" ], "offsets": [ [ 112, 117 ] ] }, { "pmid": "23182954", "text": "Wistar rats were randomly categorized into 8 groups (n=6): 1 control group, 3 groups exposed to fine particulate matters (PM(2.5)) alone at 3 doses (0.2, 0.8, or 3.2 mg/rat), 1 group to ozone (0.81 ppm) alone and 3 groups to ozone plus PM(2.5) at 3 doses (0.2, 0.8, or 3.2 mg/rat).", "type": "CHEMICAL", "entities": [ "ozone", "ozone" ], "offsets": [ [ 186, 191 ], [ 225, 230 ] ] }, { "pmid": "23182954", "text": "Heart rate (HR) and electrocardiogram (ECG) was monitored at approximately 24-h both after the 3rd exposure and the last (6th) exposure, and systolic blood pressure (SBP) was monitored at approximately 24-h after the 6th exposure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23182954", "text": "Biomarkers of systemic inflammation and injuries (CRP, IL-6, LDH, CK), heart oxidative stress (MDA, SOD) and endothelial function (ET-1, VEGF) were analyzed after the 6th exposure.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 95, 98 ] ] }, { "pmid": "23182954", "text": "Additionally, myocardial ultrastructural alterations were observed under transmission electron microscopy (TEM) for histopathological analyses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23182954", "text": "Results showed that PM(2.5) alone exposure could trigger the significant increase of CRP, MDA, CK, ET-1 and SBP and decrease of heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 90, 93 ] ] }, { "pmid": "23182954", "text": "Ozone alone exposure in rats did not show significant alterations in any indicators.", "type": "CHEMICAL", "entities": [ "Ozone" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23182954", "text": "Ozone plus PM(2.5) exposure, however, induced CRP, IL-6, CK, LDH and MDA increase, SOD and HRV decrease significantly in a dose-response way.", "type": "CHEMICAL", "entities": [ "Ozone", "MDA" ], "offsets": [ [ 0, 5 ], [ 69, 72 ] ] }, { "pmid": "23182954", "text": "Meanwhile, abnormal ECG types were monitored in rats exposed to PM(2.5) with and without ozone and obvious myocardial ultrastructural changes were observed by TEM.", "type": "CHEMICAL", "entities": [ "ozone" ], "offsets": [ [ 89, 94 ] ] }, { "pmid": "23182954", "text": "In conclusion, PM(2.5) alone exposure could cause inflammation, endothelial function and ANS injuries, and ozone potentiated these effects induced by PM(2.5).", "type": "CHEMICAL", "entities": [ "ozone" ], "offsets": [ [ 107, 112 ] ] }, { "pmid": "18465538", "text": "Flavopiridol Hoechst AG.\n", "type": "CHEMICAL", "entities": [ "Flavopiridol" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "18465538", "text": "Hoechst is developing flavopiridol, a synthetic flavonoid based on an extract from an Indian plant, for the potential treatment of cancer.", "type": "CHEMICAL", "entities": [ "flavopiridol", "flavonoid" ], "offsets": [ [ 22, 34 ], [ 48, 57 ] ] }, { "pmid": "18465538", "text": "Flavopiridol, a cyclin-dependent kinase inhibitor, arrests cell division and causes apoptosis in non-small lung cancer cells [283660].", "type": "CHEMICAL", "entities": [ "Flavopiridol" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "18465538", "text": "A phase II trial, in collaboration with the National Cancer Institute, has commenced at the University of Chicago Medical Center, which involves patients with high or intermediate-grade lymphoma or multiple myeloma [272937], [277372].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18465538", "text": "In ex vivo experiments with tumor cells from refractory chronic lymphoblastic leukemia, dose-dependent CDK2 inhibition associated with apoptotic changes was seen at concentrations greater than 100 nM of flavopiridol.", "type": "CHEMICAL", "entities": [ "flavopiridol" ], "offsets": [ [ 203, 215 ] ] }, { "pmid": "18465538", "text": "In vitro pharmacokinetic studies have shown that flavopiridol undergoes hepatic biotransformation to its corresponding glucoronide by uridine diphosphate glucoronosyltransferases [283791].", "type": "CHEMICAL", "entities": [ "flavopiridol", "glucoronide", "uridine diphosphate" ], "offsets": [ [ 49, 61 ], [ 119, 130 ], [ 134, 153 ] ] }, { "pmid": "18465538", "text": "Flavopiridol inhibits CDK with an IC50 value of 0.4 mM", "type": "CHEMICAL", "entities": [ "Flavopiridol" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "18465538", "text": "[285707].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18465538", "text": "Preclinical toxicology studies in rats and dogs demonstrated dose-related leukopenia and drug-related lesions in the thymus, spleen and bone marrow.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18465538", "text": "The gastrointestinal and bone marrow toxicity was dose-limiting [178579].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18465538", "text": "Hoechst Marion Roussel expects to launch flavopiridol in the year 2001, with potential sales in excess of DM 750 million [288651].", "type": "CHEMICAL", "entities": [ "flavopiridol" ], "offsets": [ [ 41, 53 ] ] }, { "pmid": "15110853", "text": "Carbonic anhydrase inhibitors: aromatic and heterocyclic sulfonamides incorporating adamantyl moieties with strong anticonvulsant activity.\n", "type": "CHEMICAL", "entities": [ "aromatic and heterocyclic sulfonamides", "adamantyl" ], "offsets": [ [ 31, 69 ], [ 84, 93 ] ] }, { "pmid": "15110853", "text": "A series of aromatic/heterocyclic sulfonamides incorporating adamantyl moieties were prepared by reaction of aromatic/heterocyclic aminosulfonamides with the acyl chlorides derived from adamantyl-1-carboxylic acid and 1-adamantyl-acetic acid.", "type": "CHEMICAL", "entities": [ "aromatic/heterocyclic aminosulfonamides", "aromatic/heterocyclic sulfonamides", "acyl chlorides", "adamantyl-1-carboxylic acid", "1-adamantyl-acetic acid", "adamantyl" ], "offsets": [ [ 109, 148 ], [ 12, 46 ], [ 158, 172 ], [ 186, 213 ], [ 218, 241 ], [ 61, 70 ] ] }, { "pmid": "15110853", "text": "Related derivatives were obtained from the above-mentioned aminosulfonamides with adamantyl isocyanate and adamantyl isothiocyanate, respectively.", "type": "CHEMICAL", "entities": [ "aminosulfonamides", "adamantyl isocyanate", "adamantyl isothiocyanate" ], "offsets": [ [ 59, 76 ], [ 82, 102 ], [ 107, 131 ] ] }, { "pmid": "15110853", "text": "Some of these derivatives showed good inhibitory potency against two human CA isozymes involved in important physiological processes, CA I, and CA II, of the same order of magnitude as the clinically used drugs acetazolamide and methazolamide.", "type": "CHEMICAL", "entities": [ "acetazolamide", "methazolamide" ], "offsets": [ [ 211, 224 ], [ 229, 242 ] ] }, { "pmid": "15110853", "text": "The lipophilicity of the best CA inhibitors was determined and expressed as their experimental log k' IAM and theoretical ClogP value.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15110853", "text": "Their lipophilicity was propitious with the crossing of the blood-brain barrier (log k' >", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15110853", "text": "IAM > 1.35).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15110853", "text": "The anticonvulsant activity of some of the best CA inhibitors reported here has been evaluated in a MES test in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15110853", "text": "After intraperitoneal injection (30 mg kg(-1)), compounds A8 and A9 exhibited a high protection against electrically induced convulsions (> 90%).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15110853", "text": "Their ED50 was 3.5 and 2.6 mg kg(-1), respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "Enzymatic characterization of a recombinant isoform hybrid of glutamic acid decarboxylase (rGAD67/65) expressed in yeast.\nBACKGROUND AND AIMS:", "type": "CHEMICAL", "entities": [ "glutamic acid" ], "offsets": [ [ 62, 75 ] ] }, { "pmid": "12067524", "text": "Glutamic acid decarboxylase (GAD, EC 4.1.1.15) catalyses the conversion of glutamate to gamma-aminobutyric acid (GABA).", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid", "GABA", "Glutamic acid", "glutamate" ], "offsets": [ [ 88, 111 ], [ 113, 117 ], [ 0, 13 ], [ 75, 84 ] ] }, { "pmid": "12067524", "text": "The 65 kDa isoform, GAD65 is a potent autoantigen in type 1 diabetes, whereas GAD67 is not.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "A hybrid cDNA was created by fusing a human cDNA for amino acids 1-101 of GAD67 to a human cDNA for amino acids 96-585 of GAD65; the recombinant (r) protein was expressed in yeast and was shown to have equivalent immunoreactivity to mammalian brain GAD with diabetes sera.", "type": "CHEMICAL", "entities": [ "amino acids", "amino acids" ], "offsets": [ [ 53, 64 ], [ 100, 111 ] ] }, { "pmid": "12067524", "text": "We here report on enzymatic and molecular properties of rGAD67/65.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "Studies were performed on enzymatic activity of rGAD67/65 by production of 3H-GABA from 3H-glutamate, enzyme kinetics, binding to the enzyme cofactor pyridoxal phosphate (PLP), stability according to differences in pH, temperature and duration of storage, and antigenic reactivity with various GAD-specific antisera.", "type": "CHEMICAL", "entities": [ "3H-GABA", "3H-glutamate", "pyridoxal phosphate", "PLP" ], "offsets": [ [ 75, 82 ], [ 88, 100 ], [ 150, 169 ], [ 171, 174 ] ] }, { "pmid": "12067524", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "The properties of rGAD67/65 were compared with published data for mammalian brain GAD (brackets).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "These included a specific enzyme activity of 22.7 (16.7) nKat, optimal pH for enzymatic activity 7.4 (6.8), K(m) of 1.3 (1.3) mM, efficient non-covalent binding to the cofactor PLP, and high autoantigenic potency.", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 177, 180 ] ] }, { "pmid": "12067524", "text": "The stability of rGAD67/65 was optimal over 3 months at -80 degrees C, or in lyophilized form at -20 degrees C. CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12067524", "text": "Hybrid rGAD67/65 has enzymatic and other properties similar to those of the mixed isoforms of GAD in preparations from mammalian brain as described elsewhere, in addition to its previously described similar immunoreactivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23421930", "text": "Bioactive phenolics from Seriphidium stenocephalum.\n", "type": "CHEMICAL", "entities": [ "phenolics" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23421930", "text": "Chromatographic separation of the ethyl acetate soluble part of the methanolic extract from Seriphidium stenocephalum yielded three new compounds: stenocepflavone (1), stenocepflavan (2), and stenocephol (3), together with cirsimaritin (4), 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone (5), 5,6,7,5'-tetrahydroxy-4'-methoxyflavone (6), and axillaroside (7).", "type": "CHEMICAL", "entities": [ "stenocepflavone", "stenocepflavan", "stenocephol", "cirsimaritin", "5,7,5'-trihydroxy-3',4',6-trimethoxyflavone", "5,6,7,5'-tetrahydroxy-4'-methoxyflavone", "axillaroside", "ethyl acetate" ], "offsets": [ [ 147, 162 ], [ 168, 182 ], [ 192, 203 ], [ 223, 235 ], [ 241, 284 ], [ 290, 329 ], [ 339, 351 ], [ 34, 47 ] ] }, { "pmid": "23421930", "text": "All isolates were characterized with the help of spectroscopic data including 1D, 2D NMR, and high resolution mass spectrometry and/or in comparison with the related compounds in literature.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23421930", "text": "All compounds were tested for in vitro enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23421930", "text": "Compounds 1 and 4-7 exhibited significant activity against all the tested enzymes, whereas compounds 2 and 3 were found inactive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "Anti-inflammatory effect of essential oil and its constituents from fingered citron (Citrus medica L. var. sarcodactylis) through blocking JNK, ERK and NF-κB signaling pathways in LPS-activated RAW 264.7 cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "We investigated the composition of essential oil from fingered citron (Citrus medica L. var. sarcodactylis)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "(FCEO) peels by GC-MS and its anti-inflammatory effects on lipopolysaccharide (LPS) - stimulated mouse macrophage (RAW 264.7) cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "Fifteen compounds, representing 98.97% of the essential oil, were tentatively identified; the main constituents were limonene (52.44%) and γ-terpinene (28.41%).", "type": "CHEMICAL", "entities": [ "limonene", "γ-terpinene" ], "offsets": [ [ 116, 124 ], [ 138, 149 ] ] }, { "pmid": "23541436", "text": "FCEO significantly inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) by suppressing the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, respectively.", "type": "CHEMICAL", "entities": [ "nitric oxide", "NO", "prostaglandin E2", "PGE2", "nitric oxide" ], "offsets": [ [ 27, 39 ], [ 41, 43 ], [ 49, 65 ], [ 67, 71 ], [ 124, 136 ] ] }, { "pmid": "23541436", "text": "Additionally, FCEO suppressed the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "FCEO attenuated LPS-induced nuclear factor-κB (NF-κB) activation via inhibition of inhibitor κB-α phosphorylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "Furthermore, FCEO blocked activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) but not that of p38 mitogen-activated protein kinase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541436", "text": "These results indicate that FCEO inhibits LPS-stimulated inflammation by blocking the NF-κB, JNK, and ERK pathways in macrophages, and demonstrate that FCEO possesses anti-inflammatory properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "Modulation of TNF and GM-CSF release from dispersed human nasal polyp cells and human whole blood by inhibitors of different PDE isoenzymes and glucocorticoids.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "The aim of this study was to investigate the role of the inhibitors of different PDE isoenzymes (PDE 1-5) on the production of two pro-inflammatory cytokines - tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "Two in vitro models were used to compare the antiinflammatory properties of PDE inhibitors with that of glucocorticoids.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "The effect on TNF release from diluted human blood following lipopolysaccharide (LPS from Salmonella abortus equi) stimulation as well as the GM-CSF and TNF release from human nasal polyp cells following allergic stimulation were investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "Amrinone and milrinone, selective PDE3 inhibitors, suppressed TNF secretion to a lesser extent.", "type": "CHEMICAL", "entities": [ "Amrinone", "milrinone" ], "offsets": [ [ 0, 8 ], [ 13, 22 ] ] }, { "pmid": "11969359", "text": "The effects of theophylline (unspecific PDE inhibitor), vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor) and the PDE5 inhibitors zaprinast and E 4021 were weak.", "type": "CHEMICAL", "entities": [ "theophylline", "vinpocetine", "zaprinast", "E 4021" ], "offsets": [ [ 15, 27 ], [ 56, 67 ], [ 132, 141 ], [ 146, 152 ] ] }, { "pmid": "11969359", "text": "In human blood, the tested glucocorticoids beclomethasone, dexamethasone and fluticasone inhibited the LPS induced TNF release potently in a concentration dependent manner, whereas in dispersed human nasal polyp cells, the effect of the glucocorticoids on allergically induced TNF release, with the exception of dexamethasone, was much less pronounced.", "type": "CHEMICAL", "entities": [ "beclomethasone", "dexamethasone", "fluticasone", "dexamethasone" ], "offsets": [ [ 43, 57 ], [ 59, 72 ], [ 77, 88 ], [ 312, 325 ] ] }, { "pmid": "11969359", "text": "Glucocorticoids were the most potent inhibitors of GM-CSF release and the effect correlates well with the affinity to the glucocorticoid receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11969359", "text": "The selective PDE 4 inhibitors, and to a certain extent the PDE3 inhibitors amrinone and milrinone, reduced the GM-CSF release in a concentration dependent manner.", "type": "CHEMICAL", "entities": [ "amrinone", "milrinone" ], "offsets": [ [ 76, 84 ], [ 89, 98 ] ] }, { "pmid": "11969359", "text": "In all investigations selective PDE4 inhibitors reduced TNF release to a much higher degree (4-10 fold) than GM-CSF release.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23538162", "text": "Activating glucocorticoid receptor-ERK signaling pathway contributes to ginsenoside Rg1 protection against β-amyloid peptide-induced human endothelial cells apoptosis.\n", "type": "CHEMICAL", "entities": [ "ginsenoside Rg1" ], "offsets": [ [ 72, 87 ] ] }, { "pmid": "23538162", "text": "The deposition of β-amyloid (Aβ) in neurons and vascular cells of the brain has been characterized in Alzheimer's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23538162", "text": "Ginsenoside Rg1 (Rg1) is an active components in Panax ginseng, a famous traditional Chinese medicines recorded in Compendium of Materia Medica.", "type": "CHEMICAL", "entities": [ "Rg1" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "23538162", "text": "Present study attempted to evaluate the potential mechanisms of Aβ-mediated insult and the protective effects of Rg1 on human endothelial cells.", "type": "CHEMICAL", "entities": [ "Rg1", "Rg1" ], "offsets": [ [ 110, 113 ], [ 142, 145 ] ] }, { "pmid": "23538162", "text": "Rg1 attenuated the Aβ25-35-associated mitochondrial apoptotic events, accompanied by inhibiting HIF-1α expression followed by intracellular reactive nitrogen species generation, and protein nitrotyrosination.", "type": "CHEMICAL", "entities": [ "nitrogen" ], "offsets": [ [ 145, 153 ] ] }, { "pmid": "23538162", "text": "These protective effects were abolished by glucocorticoid receptor (GR) antagonist RU486 or p-ERK inhibitor U0126 rather than estrogen receptor α antagonist ICI 82,780.", "type": "CHEMICAL", "entities": [ "RU486", "U0126", "estrogen", "ICI 82,780" ], "offsets": [ [ 77, 82 ], [ 102, 107 ], [ 120, 128 ], [ 151, 161 ] ] }, { "pmid": "23538162", "text": "Taken together, our results suggested that Rg1 protected against Aβ25-35-induced apoptosis at least in part by two complementary GR-dependent ERK phosphorylation pathways: (1) down-regulating HIF-1α initiated protein nitrotyrosination, and (2) inhibiting mitochondrial apoptotic cascades.", "type": "CHEMICAL", "entities": [ "Rg1" ], "offsets": [ [ 36, 39 ] ] }, { "pmid": "23538162", "text": "These data provided a novel insight to the mechanisms of Rg1protective effects on Aβ25-35-induced endothelial cells apoptosis, suggesting that GR-ERK signaling pathway might play an important role in it.", "type": "CHEMICAL", "entities": [ "Rg1" ], "offsets": [ [ 48, 51 ] ] }, { "pmid": "23232123", "text": "Aberrant transcription of the LHCGR gene caused by a mutation in exon 6A leads to Leydig cell hypoplasia type II.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is essential for normal male sex differentiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "Recently, the additional primate-specific exon 6A of the LHCGR was discovered and it was shown to act as regulatory element at the transcriptional level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "Compound heterozygous mutations in exon 6A (c.580 A>G) and exon 11 (c.1244T>C) were identified in the LHCGR of a male 46,XY patient with genital malformation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "Analysis revealed that mutation c.580A>G in exon 6A affects the splicing pattern resulting in an increase of transcripts containing the internal variants of exon 6A prone to nonsense-mediated decay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "In contrast, mutation c.1244T>C results in an amino acid substitution (Ile415Thr), which abolishes signal transduction due to structural changes.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 46, 56 ] ] }, { "pmid": "23232123", "text": "When inherited in a compound heterozygous fashion these mutations result in Leydig cell hypoplasia (LCH) type II.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23232123", "text": "Thus this study provides proof that mutations causing aberrant transcription can impair receptor function and thereby be causative of LCH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1386491", "text": "Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure.\n", "type": "CHEMICAL", "entities": [ "candoxatril" ], "offsets": [ [ 43, 54 ] ] }, { "pmid": "1386491", "text": "Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP).", "type": "CHEMICAL", "entities": [ "Candoxatril" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "1386491", "text": "The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study.", "type": "CHEMICAL", "entities": [ "candoxatril" ], "offsets": [ [ 78, 89 ] ] }, { "pmid": "1386491", "text": "On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures.", "type": "CHEMICAL", "entities": [ "candoxatril", "aldosterone" ], "offsets": [ [ 16, 27 ], [ 76, 87 ] ] }, { "pmid": "1386491", "text": "After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased.", "type": "CHEMICAL", "entities": [ "aldosterone" ], "offsets": [ [ 62, 73 ] ] }, { "pmid": "1386491", "text": "Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1386491", "text": "On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased).", "type": "CHEMICAL", "entities": [ "candoxatril", "aldosterone" ], "offsets": [ [ 38, 49 ], [ 115, 126 ] ] }, { "pmid": "1386491", "text": "Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.", "type": "CHEMICAL", "entities": [ "candoxatril" ], "offsets": [ [ 6, 17 ] ] }, { "pmid": "23357976", "text": "Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "23357976", "text": "Type 2 11β-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids.", "type": "CHEMICAL", "entities": [ "glucose", "11β-hydroxysteroid", "cortisol", "cortisone" ], "offsets": [ [ 164, 171 ], [ 7, 25 ], [ 77, 85 ], [ 98, 107 ] ] }, { "pmid": "23357976", "text": "We investigated the association of HSD11B2 variant with glucose homeostasis.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 55, 62 ] ] }, { "pmid": "23357976", "text": "Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 20, 27 ], [ 56, 63 ] ] }, { "pmid": "23357976", "text": "Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4DF) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 68, 75 ] ] }, { "pmid": "23357976", "text": "In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-β.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357976", "text": "Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "14680444", "text": "Efficacy and safety of tamsulosin in the treatment of urological diseases.\n", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 23, 33 ] ] }, { "pmid": "14680444", "text": "The alpha(1)-adrenoceptor antagonist, tamsulosin, is selective for alpha(1A)- and alpha(1D)- over alpha(1B)-adrenoceptors.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "14680444", "text": "Both placebo-controlled and comparative studies with other agents have demonstrated tamsulosin to be an effective treatment for patients with lower urinary symptoms suggestive of benign prostatic hyperplasia.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 84, 94 ] ] }, { "pmid": "14680444", "text": "Its effectiveness appears to be maintained over many years.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14680444", "text": "Tamsulosin may also effectively reduce lower urinary tract symptoms in other urological diseases.", "type": "CHEMICAL", "entities": [ "Tamsulosin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "14680444", "text": "A dose of tamsulosin 0.4 mg/day has a tolerability close to that of placebo and has little, if any, blood pressure lowering effects.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "14680444", "text": "Tolerability and lack of blood pressure lowering are maintained even in high-risk patients such as those with cardiovascular comorbidity and/or comedication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14680444", "text": "Apart from adrenoceptor subtype-selectivity, a smooth pharmacokinetic profile of its modified-release formulation and a selective accumulation in target tissues may contribute to an excellent efficacy:tolerability ratio.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22989705", "text": "Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.\n", "type": "CHEMICAL", "entities": [ "Pioglitazone", "cisplatin" ], "offsets": [ [ 0, 12 ], [ 30, 39 ] ] }, { "pmid": "22989705", "text": "Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment.", "type": "CHEMICAL", "entities": [ "Cisplatin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22989705", "text": "The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity.", "type": "CHEMICAL", "entities": [ "pioglitazone", "cisplatin" ], "offsets": [ [ 72, 84 ], [ 99, 108 ] ] }, { "pmid": "22989705", "text": "The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated.", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "22989705", "text": "Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection.", "type": "CHEMICAL", "entities": [ "Pioglitazone", "Bisphenol A diglycidyl ether", "BADGE", "cisplatin" ], "offsets": [ [ 0, 12 ], [ 14, 42 ], [ 44, 49 ], [ 199, 208 ] ] }, { "pmid": "22989705", "text": "Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22989705", "text": "The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats.", "type": "CHEMICAL", "entities": [ "pioglitazone", "malondialdehyde", "MDA", "cisplatin" ], "offsets": [ [ 32, 44 ], [ 100, 115 ], [ 117, 120 ], [ 211, 220 ] ] }, { "pmid": "22989705", "text": "It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH" ], "offsets": [ [ 29, 40 ], [ 42, 45 ] ] }, { "pmid": "22989705", "text": "In contrast to the data obtained by prior administration of BADGE.", "type": "CHEMICAL", "entities": [ "BADGE" ], "offsets": [ [ 56, 61 ] ] }, { "pmid": "22989705", "text": "Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration.", "type": "CHEMICAL", "entities": [ "cisplatin", "BADGE" ], "offsets": [ [ 50, 59 ], [ 129, 134 ] ] }, { "pmid": "22989705", "text": "In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects.", "type": "CHEMICAL", "entities": [ "pioglitazone", "cisplatin" ], "offsets": [ [ 40, 52 ], [ 71, 80 ] ] }, { "pmid": "22989705", "text": "Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.", "type": "CHEMICAL", "entities": [ "pioglitazone", "cisplatin" ], "offsets": [ [ 8, 20 ], [ 87, 96 ] ] }, { "pmid": "20801130", "text": "A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex.\n", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 62, 66 ] ] }, { "pmid": "20801130", "text": "The Ca(2+) dependent interaction between troponin I (cTnI) and troponin C (cTnC) triggers contraction in heart muscle.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 4, 10 ] ] }, { "pmid": "20801130", "text": "Heart failure is characterized by a decrease in cardiac output, and compounds that increase the sensitivity of cardiac muscle to Ca(2+) have therapeutic potential.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 129, 135 ] ] }, { "pmid": "20801130", "text": "The Ca(2+)-sensitizer, levosimendan, targets cTnC; however, detailed understanding of its mechanism has been obscured by its instability.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "levosimendan" ], "offsets": [ [ 4, 10 ], [ 23, 35 ] ] }, { "pmid": "20801130", "text": "In order to understand how this class of positive inotropes function, we investigated the mode of action of two fluorine containing novel analogs of levosimendan; 2',4'-difluoro(1,1'-biphenyl)-4-yloxy acetic acid (dfbp-o) and 2',4'-difluoro(1,1'-biphenyl)-4-yl acetic acid (dfbp).", "type": "CHEMICAL", "entities": [ "fluorine", "levosimendan", "2',4'-difluoro(1,1'-biphenyl)-4-yloxy acetic acid", "dfbp-o", "2',4'-difluoro(1,1'-biphenyl)-4-yl acetic acid", "dfbp" ], "offsets": [ [ 112, 120 ], [ 149, 161 ], [ 163, 212 ], [ 214, 220 ], [ 226, 272 ], [ 274, 278 ] ] }, { "pmid": "20801130", "text": "The affinities of dfbp and dfbp-o for the regulatory domain of cTnC were measured in the absence and presence of cTnI by NMR spectroscopy, and dfbp-o was found to bind more strongly than dfbp.", "type": "CHEMICAL", "entities": [ "dfbp", "dfbp-o", "dfbp-o", "dfbp" ], "offsets": [ [ 18, 22 ], [ 27, 33 ], [ 143, 149 ], [ 187, 191 ] ] }, { "pmid": "20801130", "text": "Dfbp-o also increased the affinity of cTnI for cTnC. Dfbp-o increased the Ca(2+)-sensitivity of demembranated cardiac trabeculae in a manner similar to levosimendan.", "type": "CHEMICAL", "entities": [ "levosimendan", "Dfbp-o", "Dfbp-o", "Ca(2+)" ], "offsets": [ [ 152, 164 ], [ 0, 6 ], [ 53, 59 ], [ 74, 80 ] ] }, { "pmid": "20801130", "text": "The high resolution NMR solution structure of the cTnC-cTnI-dfbp-o ternary complex showed that dfbp-o bound at the hydrophobic interface formed by cTnC and cTnI making critical interactions with residues such as Arg147 of cTnI. In the absence of cTnI, docking localized dfbp-o to the same position in the hydrophobic groove of cTnC. The structural and functional data reveal that the levosimendan class of Ca(2+)-sensitizers work by binding to the regulatory domain of cTnC and stabilizing the pivotal cTnC-cTnI regulatory unit via a network of hydrophobic and electrostatic interactions, in contrast to the destabilizing effects of antagonists such as W7 at the same interface.", "type": "CHEMICAL", "entities": [ "dfbp-o", "dfbp-o", "dfbp-o", "levosimendan", "Ca(2+)" ], "offsets": [ [ 60, 66 ], [ 95, 101 ], [ 270, 276 ], [ 384, 396 ], [ 406, 412 ] ] }, { "pmid": "17327465", "text": "Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro.\nExpression of Cyp1a1 and its related enzyme activity have long been used as a biomarker for aryl hydrocarbon receptor (AhR) activation and a warning of dioxin-like toxicity.", "type": "CHEMICAL", "entities": [ "dioxin", "aryl hydrocarbon", "aryl hydrocarbon" ], "offsets": [ [ 328, 334 ], [ 268, 284 ], [ 50, 66 ] ] }, { "pmid": "17327465", "text": "As a result, induction of Cyp1a1 by pharmaceutical drug candidates or environmental contaminants raises significant concern in risk assessment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17327465", "text": "The current study evaluates the specificity of Cyp1a1 induction as a marker for AhR affinity and activation and provides context to assess the relevancy of AhR activation to risk assessment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17327465", "text": "In vivo experiments examined the expression of Cyp1a1 and other AhR-regulated genes in liver, kidney, and heart in response to 596 compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17327465", "text": "From this data set, a subset of 147 compounds was then evaluated for their ability to activate or bind to the AhR using a combination of gel shift, reporter gene, and competitive receptor binding assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17327465", "text": "Whereas in vivo Cyp1a1 mRNA expression is a sensitive marker for AhR activation, it lacks specificity, because 81 (59%) of 137 compounds were found to significantly induce Cyp1a1 in vivo but were not verified to bind or activate the AhR in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17327465", "text": "Combining in vivo and in vitro findings, we identified nine AhR agonists, six of which are marketed therapeutics and have been approved by the U.S. Food and Drug Administration, including leflunomide, flutamide, and nimodipine.", "type": "CHEMICAL", "entities": [ "leflunomide", "flutamide", "nimodipine" ], "offsets": [ [ 188, 199 ], [ 201, 210 ], [ 216, 226 ] ] }, { "pmid": "17327465", "text": "These drugs do not produce dioxin-like toxicity in rats or in humans.", "type": "CHEMICAL", "entities": [ "dioxin" ], "offsets": [ [ 27, 33 ] ] }, { "pmid": "17327465", "text": "These data demonstrate that induction of Cyp1a1 is a nonspecific biomarker of direct AhR affinity and activation and lend further support to the hypothesis that Cyp1a1 induction and/or AhR activation is not synonymous with dioxin-like toxicity.", "type": "CHEMICAL", "entities": [ "dioxin" ], "offsets": [ [ 223, 229 ] ] }, { "pmid": "23563356", "text": "No mutations in the serotonin related TPH1 and HTR1B genes in patients with monogenic sclerosing bone disorders.\n", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "23563356", "text": "Since the identification of LRP5 as the causative gene for the osteoporosis pseudoglioma syndrome (OPPG) as well as the high bone mass (HBM) phenotype, LRP5 and the Wnt/β-catenin signaling have been extensively studied for their role in the differentiation and proliferation of osteoblasts, in the apoptosis of osteoblasts and osteocytes and in the response of bone to mechanical loading.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563356", "text": "However, more recently the direct effect of LRP5 on osteoblasts and bone formation has been questioned.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563356", "text": "Gene expression studies showed that mice lacking lrp5 have increased expression of tph1, the rate limiting enzyme for the production of serotonin in the gut.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 135, 144 ] ] }, { "pmid": "23563356", "text": "Furthermore mice lacking either tph1 or htr1B, the receptor for serotonin on the osteoblasts, were reported to have an increased bone mass due to increased bone formation.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 63, 72 ] ] }, { "pmid": "23563356", "text": "This led to the still controversial hypothesis that LRP5 influences bone formation indirectly by regulating the expression of thp1 and as a consequence influencing the production of serotonin in the gut.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 181, 190 ] ] }, { "pmid": "23563356", "text": "Based on these data we decided to evaluate the role of TPH1 and HTR1B in the development of craniotubular hyperostoses, a group of monogenic sclerosing bone dysplasias.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563356", "text": "We screened the coding regions of both genes in 53 patients lacking a mutation in the known causative genes LRP5, LRP4 and SOST.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23563356", "text": "We could not find disease-causing coding variants in neither of the tested genes and therefore, we cannot provide support for an important function of TPH1 and HTR1B in the pathogenesis of sclerosing bone dysplasias in our tested patient cohort.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "Grb10-mediated Negative Regulation of IGF1R-Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats.\nGrowth factor receptor-bound protein 10(Grb10)is a Src homology 2 (SH2) domain-containing protein and one of the binding partners for several trans-membrane tyrosine-kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R).", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 278, 286 ] ] }, { "pmid": "23614367", "text": "The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of Grb10 in the central nervous system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF1-IR pathway has been shown to be critical for the neuropathogenic process of cognitive disorder in diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "However, the role of endogenous Grb10 in regulating the IGF1-IR pathway and neurobehavioral changes is not explicit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "The objective of this study was to determine the in vivo function of endogenous Grb10 in diabetic encephalopathy and the underlying mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA (shRNA), we could steadily knock down Grb10 expression in the hippocampus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "More importantly, we demonstrated that hippocampus-specific modulation of Grb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "Our findings indicate that endogenous overexpression of Grb10 functions as a suppressor of the IGF1-IR pathway, which may represent an important mechanism that regulates cognitive disorder in diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "This article is protected by copyright.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614367", "text": "All rights reserved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Drug cocktail interaction study on the effect of the orally administered lavender oil preparation silexan on cytochrome p450 enzymes in healthy volunteers.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "This cocktail study evaluated the interaction potential of the oral lavender oil preparation silexan with major P450 (cytochrome P450) enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Subjects and Methods: Sixteen healthy male or female Caucasians completed this double-blind, randomized, 2-fold crossover study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Silexan (160 mg) or placebo were administered once daily for 11 days.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Additionally, on day 11 of both study periods, 150 mg caffeine (CYP1A2), 125 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan-HBr (CYP2D6), and 2 mg midazolam (CYP3A4) were administered orally.", "type": "CHEMICAL", "entities": [ "caffeine", "tolbutamide", "omeprazole", "dextromethorphan-HBr", "midazolam" ], "offsets": [ [ 54, 62 ], [ 80, 91 ], [ 108, 118 ], [ 136, 156 ], [ 176, 185 ] ] }, { "pmid": "23401474", "text": "Formal interaction was excluded if the 90% confidence interval (CI) for the silexan over placebo ratios for phenotyping metrics (primary: AUC0-t) was within a 0.70-1.43 range.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Results:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "According to the AUC0-t comparisons, silexan had no relevant effect on CYP1A2, 2C9, 2D6, and 3A4 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Secondary phenotyping metrics confirmed this result.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Mean ratios for all omeprazole-derived metrics were close to unity.", "type": "CHEMICAL", "entities": [ "omeprazole" ], "offsets": [ [ 20, 30 ] ] }, { "pmid": "23401474", "text": "The 90% CI for the AUC0-t ratio of omeprazole but not for omeprazole/5-OH-omeprazole plasma ratio 3 hours post-dose or omeprazole/5-OH-omeprazole AUC0-t ratio (secondary CYP2C19 metrics) was above the predefined threshold of 1.43, probably caused by the inherent high variability of omeprazole pharmacokinetics.", "type": "CHEMICAL", "entities": [ "omeprazole", "omeprazole", "5-OH-omeprazole", "omeprazole", "5-OH-omeprazole", "omeprazole" ], "offsets": [ [ 35, 45 ], [ 58, 68 ], [ 69, 84 ], [ 119, 129 ], [ 130, 145 ], [ 283, 293 ] ] }, { "pmid": "23401474", "text": "Silexan and the phenotyping drugs were well tolerated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401474", "text": "Repeated silexan (160 mg/day) administration has no clinically relevant inhibitory or inducing effects on the CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes in vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16546990", "text": "Sulindac independently modulates extracellular signal-regulated kinase 1/2 and cyclic GMP-dependent protein kinase signaling pathways.\n", "type": "CHEMICAL", "entities": [ "Sulindac", "cyclic GMP" ], "offsets": [ [ 0, 8 ], [ 79, 89 ] ] }, { "pmid": "16546990", "text": "Colorectal cancer is the second leading cause of cancer mortality in the United States.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16546990", "text": "Substantial human and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16546990", "text": "The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways.", "type": "CHEMICAL", "entities": [ "sulindac", "sulindac" ], "offsets": [ [ 63, 71 ], [ 136, 144 ] ] }, { "pmid": "16546990", "text": "Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP-dependent protein kinase (PKG); (b) activate c-jun NH2-terminal kinase (JNK); (c) inhibit extracellular signal-regulated kinase 1/2 (ERK1/2); and (d) decrease beta-catenin protein expression at times and doses consistent with apoptosis.", "type": "CHEMICAL", "entities": [ "Sulindac", "cyclic GMP", "cyclic GMP", "NH2" ], "offsets": [ [ 0, 8 ], [ 58, 68 ], [ 95, 105 ], [ 157, 160 ] ] }, { "pmid": "16546990", "text": "The purpose of this study was to determine if PKG, ERK1/2, JNK, and beta-catenin are independent targets for sulindac in vitro.", "type": "CHEMICAL", "entities": [ "sulindac" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "16546990", "text": "Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or beta-catenin protein expression.", "type": "CHEMICAL", "entities": [ "YC-1" ], "offsets": [ [ 37, 41 ] ] }, { "pmid": "16546990", "text": "Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate beta-catenin protein expression.", "type": "CHEMICAL", "entities": [ "U0126" ], "offsets": [ [ 26, 31 ] ] }, { "pmid": "16546990", "text": "Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and beta-catenin.", "type": "CHEMICAL", "entities": [ "U0126", "YC-1", "sulindac" ], "offsets": [ [ 17, 22 ], [ 27, 31 ], [ 128, 136 ] ] }, { "pmid": "16546990", "text": "These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway.", "type": "CHEMICAL", "entities": [ "sulindac", "sulindac" ], "offsets": [ [ 28, 36 ], [ 164, 172 ] ] }, { "pmid": "16546990", "text": "Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16546990", "text": "Such therapies could dramatically reduce the incidence and death rate from colorectal cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10530931", "text": "Synthesis and antagonistic activity at muscarinic receptor subtypes of some 2-carbonyl derivatives of diphenidol.\n", "type": "CHEMICAL", "entities": [ "diphenidol", "2-carbonyl" ], "offsets": [ [ 102, 112 ], [ 76, 86 ] ] }, { "pmid": "10530931", "text": "A series of 2-carbonyl analogues of the muscarinic antagonist diphenidol bearing 1-substituents of different lipophilic, electronic, and steric properties was synthesized and their affinity for the M2 and M3 muscarinic receptor subtypes was evaluated by functional tests.", "type": "CHEMICAL", "entities": [ "2-carbonyl", "diphenidol" ], "offsets": [ [ 12, 22 ], [ 62, 72 ] ] }, { "pmid": "10530931", "text": "Two derivatives (2g and 2d) showed an M2-selective profile which was confirmed by functional tests on the M1 and M4 receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10530931", "text": "A possible relationship between M2 selectivity and lipophilicity of the 1-substituent was suggested by structure-activity analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10530931", "text": "This work showed that appropriate structural modification of diphenidol can lead to M2-selective muscarinic antagonists of possible interest in the field of Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "diphenidol" ], "offsets": [ [ 61, 71 ] ] }, { "pmid": "23266505", "text": "Activation of an apoptotic signal transduction pathway involved in the upregulation of calpain and apoptosis-inducing factor in aldosterone-induced primary cultured cardiomyocytes.\n", "type": "CHEMICAL", "entities": [ "aldosterone" ], "offsets": [ [ 128, 139 ] ] }, { "pmid": "23266505", "text": "In this study, aldosterone (ALD)-induced apoptosis of cardiomyocyte was evaluated based on the previous studies, and the roles of calpain signaling were clarified.", "type": "CHEMICAL", "entities": [ "aldosterone", "ALD" ], "offsets": [ [ 15, 26 ], [ 28, 31 ] ] }, { "pmid": "23266505", "text": "Primary cultured rat cardiomyocytes were injured by ALD (0.01-10 μM) for varying time periods.", "type": "CHEMICAL", "entities": [ "ALD" ], "offsets": [ [ 52, 55 ] ] }, { "pmid": "23266505", "text": "Then, the effects of ethylene glycol tetraacetic acid (EGTA) (0.5 mM), calpeptin (2.5 μM), and spironoclactone (10 μM) were evaluated on cardiomyocytes activated by ALD.", "type": "CHEMICAL", "entities": [ "ethylene glycol tetraacetic acid", "EGTA", "calpeptin", "spironoclactone", "ALD" ], "offsets": [ [ 20, 52 ], [ 54, 58 ], [ 70, 79 ], [ 94, 109 ], [ 164, 167 ] ] }, { "pmid": "23266505", "text": "Cardiomyocytes that were injured by ALD were assayed by the MTT and LDH leakage ratio.", "type": "CHEMICAL", "entities": [ "ALD", "MTT" ], "offsets": [ [ 33, 36 ], [ 57, 60 ] ] }, { "pmid": "23266505", "text": "Apoptosis was evaluated by a TUNEL assay, annexin V/PI staining, and caspase-3 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266505", "text": "The expression of cleavage of Bid (tBid), calpain and apoptosis-inducing factor (AIF) was evaluated by western blot analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266505", "text": "ALD increased calpain expression and caspase-3 activity and promoted Bid cleavage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266505", "text": "It also induced the release of AIF from mitochondria into the cytosol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266505", "text": "The upregulation of calpain, tBid and caspase-3 activity were further inhibited by treatment with EGTA in the presence of ALD.", "type": "CHEMICAL", "entities": [ "ALD", "EGTA" ], "offsets": [ [ 119, 122 ], [ 95, 99 ] ] }, { "pmid": "23266505", "text": "Additionally, AIF levels in the cytosol decreased due to EGTA but not due to calpeptin.", "type": "CHEMICAL", "entities": [ "EGTA", "calpeptin" ], "offsets": [ [ 54, 58 ], [ 74, 83 ] ] }, { "pmid": "23266505", "text": "This was also accompanied by a significant decrease in apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23266505", "text": "Furthermore, treatment with spironoclactone not only attenuated the pro-apoptotic effect of ALD but reversed the ALD-induced increase of calpain and AIF levels.", "type": "CHEMICAL", "entities": [ "spironoclactone", "ALD", "ALD" ], "offsets": [ [ 25, 40 ], [ 89, 92 ], [ 110, 113 ] ] }, { "pmid": "2855105", "text": "Loperamide, an opiate analog, differently modifies the adrenocorticotropin responses to corticotropin-releasing hormone and lysine vasopressin in patients with Addison's disease.\n", "type": "CHEMICAL", "entities": [ "Loperamide", "lysine vasopressin" ], "offsets": [ [ 0, 10 ], [ 124, 142 ] ] }, { "pmid": "2855105", "text": "Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion.", "type": "CHEMICAL", "entities": [ "Loperamide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "2855105", "text": "In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison's disease.", "type": "CHEMICAL", "entities": [ "loperamide", "lysine vasopressin", "LVP" ], "offsets": [ [ 39, 49 ], [ 78, 96 ], [ 98, 101 ] ] }, { "pmid": "2855105", "text": "After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 micrograms/kg i.v. as bolus).", "type": "CHEMICAL", "entities": [ "loperamide", "LVP" ], "offsets": [ [ 6, 16 ], [ 79, 82 ] ] }, { "pmid": "2855105", "text": "In all patients loperamide induced a significant fall in plasma ACTH levels.", "type": "CHEMICAL", "entities": [ "loperamide" ], "offsets": [ [ 16, 26 ] ] }, { "pmid": "2855105", "text": "LVP increased ACTH levels after both loperamide (from 48 +/- 17.3 to a peak of 95 +/- 21 pmol/l) and placebo (from 231 +/- 59.5 to 365 +/- 86.6 pmol/l): the interaction between treatments and time was not significant.", "type": "CHEMICAL", "entities": [ "LVP", "loperamide" ], "offsets": [ [ 0, 3 ], [ 37, 47 ] ] }, { "pmid": "2855105", "text": "CRH caused a rise in plasma ACTH after both loperamide (from 30 +/- 16.6 to a peak of 108 +/- 31 pmol/l) and placebo (from 98.5 +/- 47 to 211 +/- 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide.", "type": "CHEMICAL", "entities": [ "loperamide", "loperamide" ], "offsets": [ [ 301, 311 ], [ 44, 54 ] ] }, { "pmid": "2855105", "text": "These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way.", "type": "CHEMICAL", "entities": [ "loperamide", "LVP", "LVP", "loperamide", "loperamide" ], "offsets": [ [ 28, 38 ], [ 86, 89 ], [ 125, 128 ], [ 133, 143 ], [ 185, 195 ] ] }, { "pmid": "2855105", "text": "Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.", "type": "CHEMICAL", "entities": [ "loperamide" ], "offsets": [ [ 132, 142 ] ] }, { "pmid": "8103526", "text": "Comparisons of beta-adrenergic blocking properties of S- and R-timolol in humans.\n", "type": "CHEMICAL", "entities": [ "S- and R-timolol" ], "offsets": [ [ 54, 70 ] ] }, { "pmid": "8103526", "text": "In animals, the R-enantiomer of timolol causes a significant reduction in intraocular pressure but had only 1/80 the activity of the S-enantiomer at extraocular receptors.", "type": "CHEMICAL", "entities": [ "R-enantiomer of timolol" ], "offsets": [ [ 16, 39 ] ] }, { "pmid": "8103526", "text": "The beta 1- and beta 2-adrenoceptor blocking properties of orally administered R- and S-timolol were compared in a double-blind placebo controlled trial in two groups of healthy men.", "type": "CHEMICAL", "entities": [ "R- and S-timolol" ], "offsets": [ [ 79, 95 ] ] }, { "pmid": "8103526", "text": "Each subject in group A (n = 6) received placebo, 1 and 3 mg S-timolol and 25 and 75 mg R-timolol in random order, group B (n = 5) received placebo, 0.5, and 1 mg S-timolol and 3 and 10 mg R-timolol.", "type": "CHEMICAL", "entities": [ "S-timolol", "R-timolol", "S-timolol", "R-timolol" ], "offsets": [ [ 61, 70 ], [ 88, 97 ], [ 163, 172 ], [ 189, 198 ] ] }, { "pmid": "8103526", "text": "In both groups, R- and S-timolol comparably inhibited isoproterenol-induced increases in heart rate (P < .05), forearm blood flow (P < .05, except at 3 micrograms/minute of isoproterenol after the R-doses in group B), and finger tremor (P < .05) in comparison with placebo.", "type": "CHEMICAL", "entities": [ "R- and S-timolol", "isoproterenol", "isoproterenol" ], "offsets": [ [ 16, 32 ], [ 54, 67 ], [ 173, 186 ] ] }, { "pmid": "8103526", "text": "The findings for the R-enantiomer in this study were unexpected based on the animal studies and previous studies that demonstrated marked differences in beta blocking effects of other beta-blockers in which the R-enantiomers were less inhibitory.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116643", "text": "Rosmarinic acid ameliorates acute liver damage and fibrogenesis in carbon tetrachloride-intoxicated mice.\n", "type": "CHEMICAL", "entities": [ "Rosmarinic acid", "carbon tetrachloride" ], "offsets": [ [ 0, 15 ], [ 67, 87 ] ] }, { "pmid": "23116643", "text": "The aim of this study was to investigate the therapeutic potential of rosmarinic acid (RA), a natural phenolic, in the treatment of acute liver toxicity.", "type": "CHEMICAL", "entities": [ "rosmarinic acid" ], "offsets": [ [ 70, 85 ] ] }, { "pmid": "23116643", "text": "RA at 10, 25 and 50mg/kg was administered by gavage once daily for 2 consecutive days, 6h after CCl(4) intoxication.", "type": "CHEMICAL", "entities": [ "CCl(4)" ], "offsets": [ [ 96, 102 ] ] }, { "pmid": "23116643", "text": "CCl(4) intoxication caused hepatic necrosis and increased serum ALT activity.", "type": "CHEMICAL", "entities": [ "CCl(4)" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23116643", "text": "In the livers, oxidative/nitrosative stress was evidenced by increased 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances (TBARS) formation and a significant decrease in Cu/Zn superoxide dismutase (SOD) activity.", "type": "CHEMICAL", "entities": [ "3-nitrotyrosine", "3-NT", "thiobarbituric acid", "Cu", "Zn", "superoxide" ], "offsets": [ [ 71, 86 ], [ 88, 92 ], [ 98, 117 ], [ 186, 188 ], [ 189, 191 ], [ 192, 202 ] ] }, { "pmid": "23116643", "text": "CCl(4) administration triggered inflammatory response in mice livers by activating nuclear factor-kappaB (NF-κB), which coincided with the induction of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2).", "type": "CHEMICAL", "entities": [ "CCl(4)" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23116643", "text": "RA improved histological and serum markers of liver damage and significantly ameliorated oxidative/nitrosative stress and inflammatory response in liver tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116643", "text": "Additionally, RA prevented transforming growth factor-beta1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) expression, suggesting suppression of profibrotic response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116643", "text": "Furthermore, RA significantly inhibited the CCl(4)-induced apoptosis, which was evident from decreased cleavage of caspase-3.", "type": "CHEMICAL", "entities": [ "CCl(4)" ], "offsets": [ [ 40, 46 ] ] }, { "pmid": "23116643", "text": "The hepatoprotective activity of RA coincided with enhanced NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116643", "text": "The results of this study indicates that RA possesses antioxidant, anti-inflammatory, antiapoptotic and antifibrotic activity against acute liver toxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9399012", "text": "Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine.\n", "type": "CHEMICAL", "entities": [ "zolmitriptan", "Zomig", "formerly", "311C90" ], "offsets": [ [ 29, 41 ], [ 43, 48 ], [ 50, 58 ], [ 59, 65 ] ] }, { "pmid": "9399012", "text": "Zolmitriptan (Zomig; formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D receptor agonist with proven efficacy in the acute treatment of migraine with or without preceding aura.", "type": "CHEMICAL", "entities": [ "Zolmitriptan", "Zomig", "formerly", "311C90", "5-hydroxytryptamine", "5HT" ], "offsets": [ [ 0, 12 ], [ 14, 19 ], [ 21, 29 ], [ 30, 36 ], [ 49, 68 ], [ 70, 73 ] ] }, { "pmid": "9399012", "text": "The drug differs from presently available members of this drug class in that it combines 5HT1B/1D receptor partial agonist activity with robust oral pharmacokinetics and an ability to inhibit trigeminovascular activation centrally as well as peripherally in preclinical studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9399012", "text": "Consistent with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction of various isolated blood vessels, most notably cranial arteries.", "type": "CHEMICAL", "entities": [ "zolmitriptan" ], "offsets": [ [ 56, 68 ] ] }, { "pmid": "9399012", "text": "In anaesthetized animals, these vascular effects manifest as a selective constriction of cranial arterio-venous anastomoses resulting in a redistribution of carotid arterial blood flow.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9399012", "text": "This effect is produced without significant effects on heart rate, blood pressure or blood flow to the brain, heart or lungs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9399012", "text": "Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in the dura of guinea-pigs.", "type": "CHEMICAL", "entities": [ "Zolmitriptan" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "9399012", "text": "These actions are consistent with a pre-junctional inhibition of neuropeptide release from perivascular afferents of the trigeminal nerve, as confirmed by independent studies showing that zolmitriptan blocks elevations of calcitonin-gene-related peptide in jugular venous blood during electrical stimulation of the trigeminal ganglion.", "type": "CHEMICAL", "entities": [ "zolmitriptan" ], "offsets": [ [ 188, 200 ] ] }, { "pmid": "9399012", "text": "In all of these effects, zolmitriptan is three to four times more potent than sumatriptan, but produces the same maximum response.", "type": "CHEMICAL", "entities": [ "zolmitriptan", "sumatriptan" ], "offsets": [ [ 25, 37 ], [ 78, 89 ] ] }, { "pmid": "9399012", "text": "Zolmitriptan crosses the intact blood-brain barrier to inhibit trigeminovascular activation in the brainstem.", "type": "CHEMICAL", "entities": [ "Zolmitriptan" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "9399012", "text": "This was shown initially by the ability of the drug to block a brainstem reflex provoking vasoactive intestinal peptide release from the VIIth cranial (facial) nerve during trigeminal stimulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9399012", "text": "Subsequent ex vivo autoradiography confirmed that intravenously injected [3H]zolmitriptan labels a discrete population of cells in the trigeminal nucleus caudalis (TNC) and nucleus tractus solitarius.", "type": "CHEMICAL", "entities": [ "[3H]zolmitriptan" ], "offsets": [ [ 73, 89 ] ] }, { "pmid": "9399012", "text": "Direct evidence for a central neuromodulatory effect of zolmitriptan was provided by electrophysiological experiments which clearly demonstrated that the drug inhibits the excitability of cells in the TNC after systemic administration.", "type": "CHEMICAL", "entities": [ "zolmitriptan" ], "offsets": [ [ 56, 68 ] ] }, { "pmid": "9399012", "text": "This novel pre-clinical profile not only distinguishes zolmitriptan from sumatriptan, but raises intriguing questions about the clinical relevance of a dual action.", "type": "CHEMICAL", "entities": [ "zolmitriptan", "sumatriptan" ], "offsets": [ [ 55, 67 ], [ 73, 84 ] ] }, { "pmid": "9399012", "text": "Studies to date show that zolmitriptan indeed modulates cranial sensory processing in humans, yet central side-effects are no different from sumatriptan.", "type": "CHEMICAL", "entities": [ "zolmitriptan", "sumatriptan" ], "offsets": [ [ 26, 38 ], [ 141, 152 ] ] }, { "pmid": "9399012", "text": "This property may account for the remarkable consistency in clinical efficacy observed in clinical trials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411272", "text": "Oligomeric procyanidins of lotus seedpod inhibits the formation of advanced glycation end-products by scavenging reactive carbonyls.\n", "type": "CHEMICAL", "entities": [ "procyanidins", "carbonyls" ], "offsets": [ [ 11, 23 ], [ 122, 131 ] ] }, { "pmid": "23411272", "text": "It has been reported that oligomeric procyanidins of lotus seedpod (LSOPC) is effective in the alleviation of Alzheimer's disease and diabetes through its antioxidant and insulin-potentiating activities.", "type": "CHEMICAL", "entities": [ "procyanidins" ], "offsets": [ [ 37, 49 ] ] }, { "pmid": "23411272", "text": "This study investigated the anti-glycative activity of LSOPC in a bovine serum albumin (BSA)-glucose model.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 93, 100 ] ] }, { "pmid": "23411272", "text": "The level of glycation and conformational alterations were assessed by specific fluorescence, Congo red binding assay and circular dichroism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411272", "text": "The results show that LSOPC has a significant anti-glycative activity in vitro and it can also effectively protect the secondary structure of BSA during glycation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411272", "text": "LSOPC or catechin (a major constituent unit of LSOPC), were used to react with methylglyoxal.", "type": "CHEMICAL", "entities": [ "catechin", "methylglyoxal" ], "offsets": [ [ 9, 17 ], [ 79, 92 ] ] }, { "pmid": "23411272", "text": "The structures of their carbonyl adducts were tentatively identified using HPLC-MS(2).", "type": "CHEMICAL", "entities": [ "carbonyl" ], "offsets": [ [ 24, 32 ] ] }, { "pmid": "23411272", "text": "Their capacity to scavenge methylglyoxal suggested carbonyl scavenging as a major mechanism of antiglycation.", "type": "CHEMICAL", "entities": [ "methylglyoxal", "carbonyl" ], "offsets": [ [ 27, 40 ], [ 51, 59 ] ] }, { "pmid": "23411272", "text": "Therefore, LSOPC could be helpful to prevent AGEs-associated diseases, and with the potential to be used as functional food ingredients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion.\n", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 146, 154 ] ] }, { "pmid": "17210712", "text": "Hepatocellular carcinoma (HCC) is believed to be auxotrophic for arginine through the lack of expression of argininosuccinate synthetase (ASS).", "type": "CHEMICAL", "entities": [ "argininosuccinate", "arginine" ], "offsets": [ [ 108, 125 ], [ 65, 73 ] ] }, { "pmid": "17210712", "text": "The successful use of the arginine-depleting enzyme arginine deiminase (ADI) to treat ASS-deficient tumors has opened up new possibilities for effective cancer therapy.", "type": "CHEMICAL", "entities": [ "arginine", "arginine" ], "offsets": [ [ 26, 34 ], [ 52, 60 ] ] }, { "pmid": "17210712", "text": "Nevertheless, many ASS-positive HCC cell lines are found to be resistant to ADI treatment, although most require arginine for proliferation.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 113, 121 ] ] }, { "pmid": "17210712", "text": "Thus far, an arginine-depleting enzyme for killing ASS-positive tumors has not been reported.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "17210712", "text": "Here, we provide direct evidence that recombinant human arginase (rhArg) inhibits ASS-positive HCCs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "All the five human HCC cell lines we used were sensitive to rhArg but ADI had virtually no effect on these cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "They all expressed ASS, but not ornithine transcarbamylase (OTC), the enzyme that converts ornithine, the product of degradation of arginine with rhArg, to citrulline, which is converted back to arginine via ASS.", "type": "CHEMICAL", "entities": [ "ornithine", "ornithine", "arginine", "citrulline", "arginine" ], "offsets": [ [ 32, 41 ], [ 91, 100 ], [ 132, 140 ], [ 156, 166 ], [ 195, 203 ] ] }, { "pmid": "17210712", "text": "Transfection of HCC cells with OTC resulted in resistance to rhArg.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "Thus, OTC expression alone may be sufficient to induce rhArg resistance in ASS-positive HCC cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "This surprising correlation between the lack of OTC expression and sensitivity of ASS-positive HCC cells shows that OTC-deficient HCCs are sensitive to rhArg-mediated arginine depletion.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 167, 175 ] ] }, { "pmid": "17210712", "text": "Therefore, pretreatment tumor gene expression profiling of ASS and OTC could aid in predicting tumor response to arginine depletion with arginine-depleting enzymes.", "type": "CHEMICAL", "entities": [ "arginine", "arginine" ], "offsets": [ [ 113, 121 ], [ 137, 145 ] ] }, { "pmid": "17210712", "text": "We have also shown that the rhArg native enzyme and the pegylated rhArg (rhArg-peg(5,000mw)) gave similar anticancer efficacy in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17210712", "text": "Furthermore, the growth of the OTC-deficient Hep3B tumor cells (ASS-positive and ADI-resistant) in mice was inhibited by treatment with rhArg-peg(5,000mw), which is active alone and is synergistic in combination with 5-fluorouracil.", "type": "CHEMICAL", "entities": [ "5-fluorouracil" ], "offsets": [ [ 217, 231 ] ] }, { "pmid": "17210712", "text": "Thus, our data suggest that rhArg-peg(5,000mw) is a novel agent for effective cancer therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "Visualization and virtual screening of the chemical universe database GDB-17.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "The chemical universe database GDB-17 contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens obeying rules for chemical stability, synthetic feasibility, and medicinal chemistry.", "type": "CHEMICAL", "entities": [ "S", "halogens", "C", "N", "O" ], "offsets": [ [ 101, 102 ], [ 108, 116 ], [ 92, 93 ], [ 95, 96 ], [ 98, 99 ] ] }, { "pmid": "23259841", "text": "GDB-17 was analyzed using 42 integer value descriptors of molecular structure which we term \"Molecular Quantum Numbers\" (MQN).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "Principal component analysis and representation of the (PC1, PC2)-plane provided a graphical overview of the GDB-17 chemical space.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "Rapid ligand-based virtual screening (LBVS) of GDB-17 using the city-block distance CBD(MQN) as a similarity search measure was enabled by a hashed MQN-fingerprint.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "LBVS of the entire GDB-17 and of selected subsets identified shape similar, scaffold hopping analogs (ROCS > 1.6 and T(SF) < 0.5) of 15 drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "Over 97% of these analogs occurred within CBD(MQN) ≤ 12 from each drug, a constraint which might help focus advanced virtual screening.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259841", "text": "An MQN-searchable 50 million subset of GDB-17 is publicly available at www.gdb.unibe.ch .", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10225363", "text": "Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10225363", "text": "A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway.", "type": "CHEMICAL", "entities": [ "sumatriptan" ], "offsets": [ [ 61, 72 ] ] }, { "pmid": "10225363", "text": "Sumatriptan's effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10225363", "text": "To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis.", "type": "CHEMICAL", "entities": [ "sumatriptan", "LY 344864" ], "offsets": [ [ 83, 94 ], [ 146, 155 ] ] }, { "pmid": "10225363", "text": "c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration.", "type": "CHEMICAL", "entities": [ "urethane", "capsaicin" ], "offsets": [ [ 32, 40 ], [ 78, 87 ] ] }, { "pmid": "10225363", "text": "Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)).", "type": "CHEMICAL", "entities": [ "Sumatriptan", "LY 344864", "capsaicin" ], "offsets": [ [ 0, 11 ], [ 16, 25 ], [ 50, 59 ] ] }, { "pmid": "10225363", "text": "The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors.", "type": "CHEMICAL", "entities": [ "sumatriptan", "LY 344864", "SDZ 21-009" ], "offsets": [ [ 14, 25 ], [ 38, 47 ], [ 99, 109 ] ] }, { "pmid": "10225363", "text": "LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors.", "type": "CHEMICAL", "entities": [ "LY 344864", "sumatriptan" ], "offsets": [ [ 0, 9 ], [ 87, 98 ] ] }, { "pmid": "10225363", "text": "The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high fat diet-induced obesity and insulin resistance in mice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α1 subunit of the AMPK complex.", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 82, 85 ] ] }, { "pmid": "23349485", "text": "However, the in vivo role of CRBN was not studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "To elucidate the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyper-phosphorylation, which indicated the constitutive activation of AMPK.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "Since Crbn-deficient mice showed significantly less weight gain when fed a high fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349485", "text": "These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16516814", "text": "Involvement of EP1 and EP2 receptors in the regulation of the Na,K-ATPase by prostaglandins in MDCK cells.\n", "type": "CHEMICAL", "entities": [ "Na", "K", "prostaglandins" ], "offsets": [ [ 62, 64 ], [ 65, 66 ], [ 77, 91 ] ] }, { "pmid": "16516814", "text": "Prostaglandins are key regulators of ion transport in the kidney.", "type": "CHEMICAL", "entities": [ "Prostaglandins" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "16516814", "text": "In MDCK cells, which model distal tubule cells, the transcription of the Na,K-ATPase beta1 subunit is regulated by PGE1 and PGE2.", "type": "CHEMICAL", "entities": [ "Na", "K" ], "offsets": [ [ 73, 75 ], [ 76, 77 ] ] }, { "pmid": "16516814", "text": "To identify the EP receptors that mediate transcriptional regulation, transient transfection studies are conducted using the human beta1promoter/luciferase construct, pHbeta1-1141 Luc.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16516814", "text": "The involvement of EP1 and EP2 receptors is indicated by studies with the EP1 selective agonist 17-phenyl trinor PGE2, and the EP2 selective agonist butaprost (which stimulate), as well as by studies with the antagonists SC-51089 (EP1 specific) and AH 6809 (EP1 and EP2 specific).", "type": "CHEMICAL", "entities": [ "17-phenyl trinor PGE2", "butaprost", "SC-51089", "AH 6809" ], "offsets": [ [ 96, 117 ], [ 149, 158 ], [ 221, 229 ], [ 249, 256 ] ] }, { "pmid": "16516814", "text": "Consistent with the involvement of Gs coupled EP2 receptors, is that the PGE1 stimulation is inhibited by the PKAI expression vector (encoding the protein kinase A (PKA) inhibitory protein), as well as by the myristolated PKA inhibitory peptide PKI.", "type": "CHEMICAL", "entities": [ "PGE1" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "16516814", "text": "In addition to this evidence (for the involvement of EP2 receptors), evidence for the involvement of EP1 receptors in the PGE1 mediated stimulation of Na,K-ATPase beta subunit gene transcription includes the stimulatory effect of 17-phenyl trinor PGE2, as well as the inhibitory effects of SC-51089.", "type": "CHEMICAL", "entities": [ "PGE1", "Na", "K", "17-phenyl trinor PGE2", "SC-51089" ], "offsets": [ [ 122, 126 ], [ 151, 153 ], [ 154, 155 ], [ 230, 251 ], [ 290, 298 ] ] }, { "pmid": "16516814", "text": "Also consistent with the involvement of Gq coupled EP1 receptors, the PGE1 stimulation is inhibited by the PKCI vector (encoding the PKC inhibitory domain), the PKC inhibitor Go 6976, thapsigargin, as well as the calmodulin antagonists W7 and W13.", "type": "CHEMICAL", "entities": [ "PGE1", "Go 6976", "thapsigargin", "W7", "W13" ], "offsets": [ [ 70, 74 ], [ 175, 182 ], [ 184, 196 ], [ 236, 238 ], [ 243, 246 ] ] }, { "pmid": "21272013", "text": "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21272013", "text": "The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21272013", "text": "The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2.", "type": "CHEMICAL", "entities": [ "amphetamine", "AMPH", "cocaine", "COC", "dopamine", "monoamine" ], "offsets": [ [ 15, 26 ], [ 28, 32 ], [ 38, 45 ], [ 47, 50 ], [ 100, 108 ], [ 215, 224 ] ] }, { "pmid": "21272013", "text": "The potential role of DAT as a target for AMPH and COC has been reviewed extensively.", "type": "CHEMICAL", "entities": [ "AMPH", "COC" ], "offsets": [ [ 42, 46 ], [ 51, 54 ] ] }, { "pmid": "21272013", "text": "Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21272013", "text": "The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction.", "type": "CHEMICAL", "entities": [ "AMPH", "COC" ], "offsets": [ [ 184, 188 ], [ 193, 196 ] ] }, { "pmid": "23410798", "text": "Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2'-quinazolines.\n", "type": "CHEMICAL", "entities": [ "Pd", "C", "N-indolylmethyl spiroindoline-3,2'-quinazolines" ], "offsets": [ [ 53, 55 ], [ 56, 57 ], [ 86, 133 ] ] }, { "pmid": "23410798", "text": "Novel N-indolylmethyl substituted spiroindoline-3,2'-quinazolines were designed as potential inhibitiors of SIRT1.", "type": "CHEMICAL", "entities": [ "N-indolylmethyl substituted spiroindoline-3,2'-quinazolines" ], "offsets": [ [ 6, 65 ] ] }, { "pmid": "23410798", "text": "These compounds were synthesized in good yields by using Pd/C-Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione with 2-iodoanilides.", "type": "CHEMICAL", "entities": [ "Pd", "C-Cu", "1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione", "2-iodoanilides" ], "offsets": [ [ 57, 59 ], [ 60, 64 ], [ 144, 212 ], [ 218, 232 ] ] }, { "pmid": "23410798", "text": "Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23410798", "text": "The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues.", "type": "CHEMICAL", "entities": [ "benzene", "1,2,3,4-tetrahydroquinazolin", "NH", "sulfonyl", "H", "amino acid" ], "offsets": [ [ 39, 46 ], [ 55, 83 ], [ 182, 184 ], [ 200, 208 ], [ 238, 239 ], [ 269, 279 ] ] }, { "pmid": "10200320", "text": "Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2.\n", "type": "CHEMICAL", "entities": [ "Cyclopentenone prostaglandins", "15-deoxy-Delta12,14-prostaglandin J2", "nitric-oxide" ], "offsets": [ [ 0, 29 ], [ 118, 154 ], [ 93, 105 ] ] }, { "pmid": "10200320", "text": "Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of activated glia in neurodegeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10200320", "text": "Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions.", "type": "CHEMICAL", "entities": [ "Prostaglandins" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "10200320", "text": "We examined the influence of cyclopentenone prostaglandins and their precursors on activated glia.", "type": "CHEMICAL", "entities": [ "cyclopentenone prostaglandins" ], "offsets": [ [ 29, 58 ] ] }, { "pmid": "10200320", "text": "As models of glial activation, production of inducible nitric-oxide synthase (iNOS) was studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell line BV-2, and IL-1beta-stimulated rat astrocytes.", "type": "CHEMICAL", "entities": [ "nitric-oxide" ], "offsets": [ [ 55, 67 ] ] }, { "pmid": "10200320", "text": "Cyclopentenone prostaglandins were potent inhibitors of iNOS induction and were more effective than their precursors, prostaglandins E2 and D2.", "type": "CHEMICAL", "entities": [ "Cyclopentenone prostaglandins", "prostaglandins E2 and D2" ], "offsets": [ [ 0, 29 ], [ 118, 142 ] ] }, { "pmid": "10200320", "text": "15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) was the most potent prostaglandin among those tested.", "type": "CHEMICAL", "entities": [ "15-Deoxy-Delta12,14-prostaglandin J2", "15d-PGJ2", "prostaglandin" ], "offsets": [ [ 0, 36 ], [ 38, 46 ], [ 68, 81 ] ] }, { "pmid": "10200320", "text": "In activated microglia, 15d-PGJ2 suppressed iNOS promoter activity, iNOS mRNA, and protein levels.", "type": "CHEMICAL", "entities": [ "15d-PGJ2" ], "offsets": [ [ 24, 32 ] ] }, { "pmid": "10200320", "text": "The action of 15d-PGJ2 does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) because troglitazone, a specific ligand of PPARgamma, was unable to inhibit iNOS induction, and neither troglitazone nor 15d-PGJ2 could stimulate the activity of a PPAR-dependent promoter in the absence of cotransfected PPARgamma.", "type": "CHEMICAL", "entities": [ "troglitazone", "troglitazone", "15d-PGJ2", "15d-PGJ2" ], "offsets": [ [ 140, 152 ], [ 236, 248 ], [ 253, 261 ], [ 14, 22 ] ] }, { "pmid": "10200320", "text": "15d-PGJ2 did not block nuclear translocation or DNA-binding activity of the transcription factor NFkappaB, but it did inhibit the activity of an NFkappaB reporter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ2 may involve interference with NFkappaB transcriptional activity in the nucleus.", "type": "CHEMICAL", "entities": [ "15d-PGJ2", "15d-PGJ2" ], "offsets": [ [ 0, 8 ], [ 241, 249 ] ] }, { "pmid": "10200320", "text": "Thus, our data suggest the existence of a novel pathway mediated by cyclopentenone prostaglandins, which may represent part of a feedback mechanism leading to the cessation of inflammatory glial responses in the brain.", "type": "CHEMICAL", "entities": [ "cyclopentenone prostaglandins" ], "offsets": [ [ 68, 97 ] ] }, { "pmid": "3828735", "text": "Mechanism of the haemostatic effect of ethanolamine oleate in the injection sclerotherapy for oesophageal varices.\n", "type": "CHEMICAL", "entities": [ "ethanolamine oleate" ], "offsets": [ [ 39, 58 ] ] }, { "pmid": "3828735", "text": "Changes in coagulation and fibrinolysis were investigated in 20 patients with oesophageal varices, who underwent endoscopic injection sclerotherapy (EIS) with 5 per cent ethanolamine oleate (EO), by means of serial determination of plasma fibrinopeptide A (FPA) and fibrinopeptide B beta 15-42 (B beta 15-42).", "type": "CHEMICAL", "entities": [ "ethanolamine oleate", "EO", "fibrinopeptide B" ], "offsets": [ [ 170, 189 ], [ 191, 193 ], [ 266, 282 ] ] }, { "pmid": "3828735", "text": "One hour after the completion of EIS, the value of FPA was significantly increased to 38.1 +/- 11.1 ng/ml (mean +/- s.e.m.) from a pre-EIS value of 7.1 +/- 1.4 ng/ml (P less than 0.01) and it gradually returned to normal range by 48 h after EIS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3828735", "text": "A very similar change was observed in the value of B beta 15-42 (P less than 0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3828735", "text": "These observations indicated that EIS provokes transient activation of coagulation and fibrinolysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "3828735", "text": "In vitro studies, however, revealed that EO inhibits fibrin clot formation because of the Ca2+-chelating ability of its constituent ethanolamine, although oleate or benzyl alcohol exhibited procoagulant activity in FPA formation in vitro.", "type": "CHEMICAL", "entities": [ "EO", "Ca2+", "ethanolamine", "oleate", "benzyl alcohol" ], "offsets": [ [ 41, 43 ], [ 90, 94 ], [ 132, 144 ], [ 155, 161 ], [ 165, 179 ] ] }, { "pmid": "3828735", "text": "Nevertheless, an external application of EO or oleate over decapsulized kidney of rat resulted in a significant accumulation of 125I-labelled fibrin(ogen).", "type": "CHEMICAL", "entities": [ "EO", "oleate", "125I" ], "offsets": [ [ 41, 43 ], [ 47, 53 ], [ 128, 132 ] ] }, { "pmid": "3828735", "text": "From these results it was suggested that intravascular injection of EO, which exerts an inhibitory effect on coagulation in vitro, activates the local coagulation system.", "type": "CHEMICAL", "entities": [ "EO" ], "offsets": [ [ 68, 70 ] ] }, { "pmid": "3828735", "text": "The activation may be accelerated by an acute inflammatory process provoked by oleate, which is supported by such clinical manifestations as mild fever, retrosternal pain leukocytosis and an increase in plasma fibrinogen level which was observed in all during the period.", "type": "CHEMICAL", "entities": [ "oleate" ], "offsets": [ [ 79, 85 ] ] }, { "pmid": "12093311", "text": "Renal failure associated with the use of celecoxib and rofecoxib.\n", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 41, 50 ], [ 55, 64 ] ] }, { "pmid": "12093311", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "Celecoxib and rofecoxib are two relatively new nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit the cyclo-oxygenase-2 (COX-2) isoenzyme at therapeutic concentrations.", "type": "CHEMICAL", "entities": [ "Celecoxib", "rofecoxib" ], "offsets": [ [ 0, 9 ], [ 14, 23 ] ] }, { "pmid": "12093311", "text": "The nephrotoxic potential of selective COX-2 inhibitors has not been clearly established.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "This study was conducted in order to understand the association between acute renal failure and the two COX-2 inhibitors celecoxib and rofecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 121, 130 ], [ 135, 144 ] ] }, { "pmid": "12093311", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "A search was performed in the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) to identify cases of renal failure submitted to the FDA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "A MEDLINE search of the English language literature was also performed to identify published cases of renal failure associated with celecoxib and rofecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 132, 141 ], [ 146, 155 ] ] }, { "pmid": "12093311", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "One hundred twenty-two and 142 domestic US cases of celecoxib and rofecoxib-associated renal failure, respectively, were identified in the AERS database.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 52, 61 ], [ 66, 75 ] ] }, { "pmid": "12093311", "text": "The literature search identified 19 cases of acute renal impairment in association with celecoxib and rofecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 88, 97 ], [ 102, 111 ] ] }, { "pmid": "12093311", "text": "In addition, drug regulatory authorities in the UK, Canada, and Australia have received about 50 reports of renal failure with celecoxib and rofecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 127, 136 ], [ 141, 150 ] ] }, { "pmid": "12093311", "text": "Descriptive statistics of the AERS cases have been summarised in this report.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "CONCLUSIONS: Data from AERS and published case reports suggest that use of both these drugs is associated with renal effects similar to that of conventional nonselective NSAIDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "Physicians should be aware that serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with celecoxib and rofecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 173, 182 ], [ 187, 196 ] ] }, { "pmid": "12093311", "text": "Patients at greatest risk for renal injury are those with pre-existing renal impairment, heart failure, liver dysfunction, those taking diuretics and/or ACE inhibitors, and the elderly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "Kidney function should be monitored closely for any signs of potential renal injuries soon after initiating treatment with these agents, especially in high-risk populations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "In addition, healthcare practitioners should adequately warn patients of the signs and symptoms of serious renal toxicity, and of the need for them to see their physician promptly if they occur.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12093311", "text": "Celecoxib and rofecoxib are not recommended for use in patients with advanced renal disease.", "type": "CHEMICAL", "entities": [ "Celecoxib", "rofecoxib" ], "offsets": [ [ 0, 9 ], [ 14, 23 ] ] }, { "pmid": "8799556", "text": "Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "The profile of a range of alpha 1 adrenoceptor antagonists was determined in vitro against cloned human alpha 1A, alpha 1B and alpha 1D adrenoceptors and against noradrenaline-mediated contractions of rat aorta and human prostate.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 162, 175 ] ] }, { "pmid": "8799556", "text": "The in vivo profile of compounds was determined in an anaesthetized dog model which allowed the simultaneous assessment of antagonist potency against phenylephrine-mediated increases in blood pressure and prostatic pressure.", "type": "CHEMICAL", "entities": [ "phenylephrine" ], "offsets": [ [ 150, 163 ] ] }, { "pmid": "8799556", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "The quinazoline antagonists, prazosin, doxazosin and alfuzosin displayed high affinity but were non selective for the three cloned human alpha 1 adrenoceptors.", "type": "CHEMICAL", "entities": [ "quinazoline", "prazosin", "doxazosin", "alfuzosin" ], "offsets": [ [ 4, 15 ], [ 29, 37 ], [ 39, 48 ], [ 53, 62 ] ] }, { "pmid": "8799556", "text": "Indoramin and SNAP 1069 showed selectivity for alpha 1A and alpha 1B adrenoceptors relative to the alpha 1D subtype.", "type": "CHEMICAL", "entities": [ "Indoramin", "SNAP 1069" ], "offsets": [ [ 0, 9 ], [ 14, 23 ] ] }, { "pmid": "8799556", "text": "Rec 15/2739, WB 4101, SL 89,0591, (+)- and (-)- tamsulosin showed selectivity for alpha 1A and alpha 1D adrenoceptors relative to the alpha 1B subtype.", "type": "CHEMICAL", "entities": [ "Rec 15/2739", "WB 4101", "SL 89,0591", "(+)- and (-)- tamsulosin" ], "offsets": [ [ 0, 11 ], [ 13, 20 ], [ 22, 32 ], [ 34, 58 ] ] }, { "pmid": "8799556", "text": "RS 17053 showed high affinity and selectivity for alpha 1A adrenoceptors (pKi 8.6) relative to alpha 1B (", "type": "CHEMICAL", "entities": [ "RS 17053" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "8799556", "text": "pKi", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "= 7.3) and alpha 1D (pKi = 7.1) subtypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "3. (+)-Tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069 and RS 17053 appeared to act as competitive antagonists of noradrenaline-mediated contractions of rat aorta yielding pA2 affinity estimates which were similar to binding affinities at cloned human alpha 1D adrenoceptors.", "type": "CHEMICAL", "entities": [ "(+)-Tamsulosin", "(-)-tamsulosin", "SL 89,0591", "Rec 15/2739", "SNAP 1069", "RS 17053", "noradrenaline" ], "offsets": [ [ 3, 17 ], [ 19, 33 ], [ 35, 45 ], [ 47, 58 ], [ 60, 69 ], [ 74, 82 ], [ 129, 142 ] ] }, { "pmid": "8799556", "text": "The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin >", "type": "CHEMICAL", "entities": [ "prazosin", "(-)-tamsulosin", "doxazosin" ], "offsets": [ [ 39, 47 ], [ 50, 64 ], [ 67, 76 ] ] }, { "pmid": "8799556", "text": "SL 89,0591 = (+)-tamsulosin >", "type": "CHEMICAL", "entities": [ "SL 89,0591", "(+)-tamsulosin" ], "offsets": [ [ 0, 10 ], [ 13, 27 ] ] }, { "pmid": "8799556", "text": "Rec 15/2739 >", "type": "CHEMICAL", "entities": [ "Rec 15/2739" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "8799556", "text": "RS 17053 = SNAP 1069.", "type": "CHEMICAL", "entities": [ "RS 17053", "SNAP 1069" ], "offsets": [ [ 0, 8 ], [ 11, 20 ] ] }, { "pmid": "8799556", "text": "4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker.", "type": "CHEMICAL", "entities": [ "(-)-Tamsulosin", "noradrenaline" ], "offsets": [ [ 3, 17 ], [ 66, 79 ] ] }, { "pmid": "8799556", "text": "SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak antagonist on human prostate (pA2 = 6.0) relative to the high affinity (pKi = 8.6) determined at cloned human alpha 1A adrenoceptors.", "type": "CHEMICAL", "entities": [ "prazosin", "RS 17053" ], "offsets": [ [ 26, 34 ], [ 144, 152 ] ] }, { "pmid": "8799556", "text": "5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "In the anaesthetized dog, in vivo pseudo \"pA2' values showed that doxazosin, (+)- and (-)-tamsulosin inhibited phenylephrine-induced increases in prostatic and blood pressure with similar affinity, implying that these agents show little or no selectivity for prostatic responses in this model.", "type": "CHEMICAL", "entities": [ "doxazosin", "(+)- and (-)-tamsulosin", "phenylephrine" ], "offsets": [ [ 66, 75 ], [ 77, 100 ], [ 111, 124 ] ] }, { "pmid": "8799556", "text": "SL 89,0591 and SNAP 1069 were moderately selective (3 and 6 fold respectively) for prostatic pressure relative to blood pressure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8799556", "text": "Rec 15/2739 was a more potent antagonist of phenylephrine-mediated increases in prostatic pressure (\"pA2' = 8.74) compared to blood pressure (\"pA2' = 7.51).", "type": "CHEMICAL", "entities": [ "Rec 15/2739", "phenylephrine" ], "offsets": [ [ 0, 11 ], [ 44, 57 ] ] }, { "pmid": "8799556", "text": "6. Data in this study suggest that the alpha 1 adrenoceptor mediating noradrenaline-induced contractions of human prostate, whilst having some of the characteristics of an alpha 1A adrenoceptor, cannot be satisfactorily aligned with cloned alpha 1A, alpha 1B or alpha 1D adrenoceptors.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 70, 83 ] ] }, { "pmid": "8799556", "text": "In addition, studies in the anaesthetized dog have shown that agents having high affinity and selectivity for prostatic alpha 1 adrenoceptors, particularly over the alpha 1D subtype, appear to inhibit phenylephrine-induced increases in prostatic pressure selectively compared to blood pressure.", "type": "CHEMICAL", "entities": [ "phenylephrine" ], "offsets": [ [ 201, 214 ] ] }, { "pmid": "8925876", "text": "In functional experiments, risperidone is selective, not for the B, but for the A subtype of alpha 1-adrenoceptors.\n", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 27, 38 ] ] }, { "pmid": "8925876", "text": "The potency of the antipsychotic drug, risperidone, to antagonize alpha 1A-adrenoceptor-mediated contraction in rat vas deferens and vasoconstriction in rat perfused kidney, and alpha 1B-adrenoceptor-mediated contractions in spleen from guinea-pig and mouse was evaluated and compared to that of alpha 1-adrenoceptor subtype-discriminating antagonists.", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 39, 50 ] ] }, { "pmid": "8925876", "text": "Prazosin was found to be unselective; 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 5-methyl-urapidil, indoramin and (+)-niguldipine were confirmed as selective for the alpha 1A-adrenoceptor, whereas spiperone was weakly alpha 1B-selective.", "type": "CHEMICAL", "entities": [ "Prazosin", "2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane", "WB 4101", "5-methyl-urapidil", "indoramin", "(+)-niguldipine", "spiperone" ], "offsets": [ [ 0, 8 ], [ 38, 95 ], [ 97, 104 ], [ 107, 124 ], [ 126, 135 ], [ 140, 155 ], [ 223, 232 ] ] }, { "pmid": "8925876", "text": "Risperidone was equipotent to prazosin at alpha 1A-adrenoceptors in rat vas deferens and kidney.", "type": "CHEMICAL", "entities": [ "Risperidone", "prazosin" ], "offsets": [ [ 0, 11 ], [ 30, 38 ] ] }, { "pmid": "8925876", "text": "However, at guinea-pig and mouse splenic alpha 1B-adrenoceptors, the affinity values of risperidone were 10-fold lower than those of prazosin.", "type": "CHEMICAL", "entities": [ "risperidone", "prazosin" ], "offsets": [ [ 88, 99 ], [ 133, 141 ] ] }, { "pmid": "8925876", "text": "Thus, in functional experiments the presumed high selectivity of risperidone for the B subtype of alpha 1-adrenoceptors could not be confirmed, the drug instead appears to be moderately selective (10-fold) for the A subtype.", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 65, 76 ] ] }, { "pmid": "16497876", "text": "New assignments for multitasking signal transduction inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16497876", "text": "An article presented in this issue of Molecular Pharmacology (p. 1527) provides an intriguing example of how tyrosine kinase inhibitors can be put to many uses.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "16497876", "text": "In this article, the action of dasatinib (BMS-354825) is contrasted with that of imatinib, a kinase inhibitor that is currently being used to treat chronic myelogenous leukemia and other disorders.", "type": "CHEMICAL", "entities": [ "dasatinib", "BMS-354825", "imatinib" ], "offsets": [ [ 31, 40 ], [ 42, 52 ], [ 81, 89 ] ] }, { "pmid": "16497876", "text": "Both pharmacologic inhibitors target several tyrosine kinases, including Bcr-Abl and the platelet-derived growth factor receptor (PDGFR).", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 45, 53 ] ] }, { "pmid": "16497876", "text": "Up to this point, the PDGFR has not been a primary therapeutic target for this class of agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16497876", "text": "The work of Chen and colleagues shows that dasatinib is a particularly potent inhibitor of PDGFR and that the compound also targets Src kinase.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "16497876", "text": "The authors suggest that this combination of activities could be useful in the treatment of vascular obstructive diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16497876", "text": "Although a lack of absolute specificity has typically been regarded as a pharmacologic drawback, this study exemplifies how drugs with multiple molecular targets can potentially provide a very beneficial spectrum of therapeutic activities in multiple disease states.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9928259", "text": "Serotonin transporter function in vivo: assessment by chronoamperometry.\n", "type": "CHEMICAL", "entities": [ "Serotonin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "9928259", "text": "Local application of selective serotonin reuptake inhibitors, fluvoxamine and citalopram, prolonged the clearance of exogenously administered serotonin (5-HT) in both the dentate gyrus and CA3 region of the dorsal hippocampus, as measured using in vivo chronoamperometry.", "type": "CHEMICAL", "entities": [ "serotonin", "5-HT", "serotonin", "fluvoxamine", "citalopram" ], "offsets": [ [ 142, 151 ], [ 153, 157 ], [ 31, 40 ], [ 62, 73 ], [ 78, 88 ] ] }, { "pmid": "9928259", "text": "These effects were abolished in rats pretreated with 5,7-dihydroxytryptamine.", "type": "CHEMICAL", "entities": [ "5,7-dihydroxytryptamine" ], "offsets": [ [ 53, 76 ] ] }, { "pmid": "9928259", "text": "The NE uptake inhibitors, desipramine and protriptyline, did not alter the 5-HT signal in the CA3 region, but prolonged the clearance of 5-HT in the dentate gyrus; this effect was absent in rats pretreated with 6-hydroxydopamine.", "type": "CHEMICAL", "entities": [ "NE", "desipramine", "protriptyline", "5-HT", "5-HT", "6-hydroxydopamine" ], "offsets": [ [ 4, 6 ], [ 26, 37 ], [ 42, 55 ], [ 75, 79 ], [ 137, 141 ], [ 211, 228 ] ] }, { "pmid": "9928259", "text": "From these data, it is inferred that both the SERT and NET contribute to the active clearance of exogenously applied 5-HT in the dentate gyrus.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 117, 121 ] ] }, { "pmid": "9928259", "text": "In another experiment, cyanopindolol, an antagonist of the serotonin terminal autoreceptor, also prolonged the clearance of 5-HT from the CA3 region.", "type": "CHEMICAL", "entities": [ "cyanopindolol", "serotonin", "5-HT" ], "offsets": [ [ 23, 36 ], [ 59, 68 ], [ 124, 128 ] ] }, { "pmid": "9928259", "text": "These and other data have generated a working hypothesis that activation of the terminal serotonin autoreceptor enhances the kinetics of 5-HT uptake through an effect on the serotonin transporter.", "type": "CHEMICAL", "entities": [ "5-HT", "serotonin", "serotonin" ], "offsets": [ [ 137, 141 ], [ 174, 183 ], [ 89, 98 ] ] }, { "pmid": "2530096", "text": "Effect of minaprine on cycloheximide-induced amnesia in mice.\n", "type": "CHEMICAL", "entities": [ "minaprine", "cycloheximide" ], "offsets": [ [ 10, 19 ], [ 23, 36 ] ] }, { "pmid": "2530096", "text": "The effects of minaprine on cycloheximide-induced amnesia were investigated in a step-down passive avoidance task in mice.", "type": "CHEMICAL", "entities": [ "minaprine", "cycloheximide" ], "offsets": [ [ 15, 24 ], [ 28, 41 ] ] }, { "pmid": "2530096", "text": "Minaprine significantly improved cycloheximide-induced amnesia.", "type": "CHEMICAL", "entities": [ "Minaprine", "cycloheximide" ], "offsets": [ [ 0, 9 ], [ 33, 46 ] ] }, { "pmid": "2530096", "text": "This effect was inhibited by scopolamine, but was potentiated by physostigmine.", "type": "CHEMICAL", "entities": [ "scopolamine", "physostigmine" ], "offsets": [ [ 29, 40 ], [ 65, 78 ] ] }, { "pmid": "2530096", "text": "The anti-amnesic effect of minaprine on the cycloheximide-induced memory impairment was also antagonized by a serotonin (5-HT) releaser, p-chloroamphetamine, and by a 5-HT precursor, 5-hydroxytryptophan, whereas a 5-HT1A-selective agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, was inactive.", "type": "CHEMICAL", "entities": [ "minaprine", "cycloheximide", "serotonin", "5-HT", "p-chloroamphetamine", "5-HT", "5-hydroxytryptophan", "8-hydroxy-2-(di-n-propylamino)tetralin" ], "offsets": [ [ 27, 36 ], [ 44, 57 ], [ 110, 119 ], [ 121, 125 ], [ 137, 156 ], [ 167, 171 ], [ 183, 202 ], [ 240, 278 ] ] }, { "pmid": "2530096", "text": "The memory-improving effect of minaprine on cycloheximide-induced amnesia was potentiated by a selective 5-HT2 antagonist, ritanserin.", "type": "CHEMICAL", "entities": [ "minaprine", "cycloheximide", "ritanserin" ], "offsets": [ [ 31, 40 ], [ 44, 57 ], [ 123, 133 ] ] }, { "pmid": "2530096", "text": "These results suggest that the beneficial effect of minaprine on cycloheximide-induced amnesia may be related not only to cholinergic but also serotonergic neuronal systems (5-HT2 receptors).", "type": "CHEMICAL", "entities": [ "minaprine", "cycloheximide" ], "offsets": [ [ 52, 61 ], [ 65, 78 ] ] }, { "pmid": "22532505", "text": "Extracts of Scutellaria baicalensis reduced body weight and blood triglyceride in db/db Mice.\nScutellaria baicalensis has been extensively employed for the clinical treatment of hyperlipidemia, atherosclerosis, hypertension, dysentery, inflammatory diseases, and the common cold.", "type": "CHEMICAL", "entities": [ "triglyceride" ], "offsets": [ [ 66, 78 ] ] }, { "pmid": "22532505", "text": "The present study was performed to investigate the anti-obesity and anti-dyslipidemia effect of Scutellaria baicalensis extracts (SBE) in type 2 diabetic db/db mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532505", "text": "Male db/db mice were divided into three groups (n = 5) and orally administrated vehicle (control), SBE 10, and 100 mg/kg body weight/day for 4 weeks everyday.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532505", "text": "Administration of SBE improves weight gain, hypertriglyceridemia, and hyperinsulinemia in db/db mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22532505", "text": "In obese db/db mice, SBE treatment also reduced plasma alanine aminotransferase levels.", "type": "CHEMICAL", "entities": [ "alanine" ], "offsets": [ [ 47, 54 ] ] }, { "pmid": "22532505", "text": "In the livers of db/db mice, SBE promoted 5' AMP-activated protein kinase activity and restored metabolic process and insulin signaling pathways.", "type": "CHEMICAL", "entities": [ "5' AMP" ], "offsets": [ [ 34, 40 ] ] }, { "pmid": "22532505", "text": "Our data demonstrate that SBE exerts potent anti-obesity and anti-hypertriglyceride effects suggesting its useful potential function as adjuvant therapeutic agent for the treatment of weight gain and hypertriglyceridemia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12742526", "text": "Altered methionine metabolism in long living Ames dwarf mice.\n", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 8, 18 ] ] }, { "pmid": "12742526", "text": "Ames dwarf mice (df/df) are deficient in growth hormone, prolactin, and thyroid-stimulating hormone and live significantly longer than their normal siblings.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12742526", "text": "In the current study, we found that the hormone deficiencies affect methionine metabolism.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 68, 78 ] ] }, { "pmid": "12742526", "text": "We previously reported that the dwarf mice exhibit enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12742526", "text": "Moreover, methionine or metabolites of methionine are involved in antioxidative processes.", "type": "CHEMICAL", "entities": [ "methionine", "methionine" ], "offsets": [ [ 10, 20 ], [ 39, 49 ] ] }, { "pmid": "12742526", "text": "Thus, we performed an experiment that compared various parameters of methionine metabolism between 18-month old male dwarf (N=6) and wild type (N=5) mice.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 69, 79 ] ] }, { "pmid": "12742526", "text": "The specific activity of liver methionine adenosyltransferase (MAT) was significantly elevated (205%, p<0.0001) in the dwarf mice, as were cystathionine synthase (50%, p<0.01), cystathionase (83%, p<0.001), and glycine N-methyltransferase (GNMT, 91%, p<0.001) activities.", "type": "CHEMICAL", "entities": [ "methionine", "cystathionine", "glycine", "N" ], "offsets": [ [ 31, 41 ], [ 139, 152 ], [ 211, 218 ], [ 219, 220 ] ] }, { "pmid": "12742526", "text": "Even though the activities of MAT and GNMT were elevated, the concentration of liver S-adenosylmethionine was decreased (24%, p<0.001) and S-adenosylhomocysteine increased (113%, p<0.001) in the dwarf mice.", "type": "CHEMICAL", "entities": [ "S-adenosylmethionine", "S-adenosylhomocysteine" ], "offsets": [ [ 85, 105 ], [ 139, 161 ] ] }, { "pmid": "12742526", "text": "These data indicate that dwarf mice, compared to wild type mice, have a markedly different metabolism of methionine.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 105, 115 ] ] }, { "pmid": "12742526", "text": "Altered methionine metabolism may partially explain earlier reports indicating less oxidative damage to proteins in dwarf mice.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 8, 18 ] ] }, { "pmid": "12742526", "text": "Taken together, the data suggest that methionine metabolism may play a role in oxidative defense in the dwarf mouse and should be studied as a potential mechanism of extended lifespan.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "22705396", "text": "The potential of nicotinic enhancement of cognitive remediation training in schizophrenia.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "Cognitive deficits in schizophrenia are critically important predictors of long-term psychosocial outcome and are not significantly ameliorated by currently available medications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "Cognitive remediation training has shown promise for alleviating cognitive symptoms of schizophrenia, but the clinical significance has often been limited by small effect sizes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "Approaches that achieve larger improvement involve time requirements that can be cost-prohibitive within the current clinical care system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "This mini-review evaluates the theoretical potential of a pharmacological enhancement strategy of cognitive remediation training with nicotinic acetylcholine receptor (nAChR) agonists.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 144, 157 ] ] }, { "pmid": "22705396", "text": "nAChR agonists can facilitate sensory processing, alertness, attention, learning and memory.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "While these effects may be too subtle and short-lasting to be of clinical relevance as a primary treatment of cognitive deficits, they constitute an ideal effects profile for enhancing training benefits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "Several mechanisms are described through which repeated coupling of cognitive training challenges with nAChR stimulation may enhance and accelerate cognitive remediation training effects, advancing such interventions into more effective and practicable treatments of some of the most debilitating symptoms of schizophrenia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22705396", "text": "This article is part of a Special Issue entitled 'Cognitive Enhancers'.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14508322", "text": "Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate.\n", "type": "CHEMICAL", "entities": [ "etomidate" ], "offsets": [ [ 76, 85 ] ] }, { "pmid": "14508322", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14508322", "text": "The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine.", "type": "CHEMICAL", "entities": [ "dexmedetomidine", "etomidate" ], "offsets": [ [ 131, 146 ], [ 27, 36 ] ] }, { "pmid": "14508322", "text": "The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO).", "type": "CHEMICAL", "entities": [ "etomidate" ], "offsets": [ [ 73, 82 ] ] }, { "pmid": "14508322", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14508322", "text": "Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes.", "type": "CHEMICAL", "entities": [ "etomidate", "dexmedetomidine" ], "offsets": [ [ 41, 50 ], [ 75, 90 ] ] }, { "pmid": "14508322", "text": "Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro.", "type": "CHEMICAL", "entities": [ "[3H]RX821002", "etomidate" ], "offsets": [ [ 56, 68 ], [ 104, 113 ] ] }, { "pmid": "14508322", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14508322", "text": "In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype.", "type": "CHEMICAL", "entities": [ "etomidate", "etomidate" ], "offsets": [ [ 108, 117 ], [ 210, 219 ] ] }, { "pmid": "14508322", "text": "Intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg).", "type": "CHEMICAL", "entities": [ "etomidate" ], "offsets": [ [ 25, 34 ] ] }, { "pmid": "14508322", "text": "Etomidate did not affect blood pressure in alpha2B-KO or alpha2AB-KO mice.", "type": "CHEMICAL", "entities": [ "Etomidate" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "14508322", "text": "In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm).", "type": "CHEMICAL", "entities": [ "etomidate", "[3H]RX821002" ], "offsets": [ [ 66, 75 ], [ 120, 132 ] ] }, { "pmid": "14508322", "text": "In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2.", "type": "CHEMICAL", "entities": [ "etomidate" ], "offsets": [ [ 45, 54 ] ] }, { "pmid": "14508322", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14508322", "text": "These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure.", "type": "CHEMICAL", "entities": [ "etomidate" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "14508322", "text": "This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.", "type": "CHEMICAL", "entities": [ "etomidate", "etomidate" ], "offsets": [ [ 15, 24 ], [ 119, 128 ] ] }, { "pmid": "23315277", "text": "Silica nanoparticles-induced cytotoxicity, oxidative stress and apoptosis in cultured A431 and A549 cells.\n", "type": "CHEMICAL", "entities": [ "Silica" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23315277", "text": "In medicine, the use of silica nanoparticles (SiO(2) NPs) offers new perspectives in biosensor, drug delivery and cancer therapy.", "type": "CHEMICAL", "entities": [ "silica", "SiO(2)" ], "offsets": [ [ 24, 30 ], [ 46, 52 ] ] }, { "pmid": "23315277", "text": "However, questions about potential toxic and deleterious effects of SiO(2) NPs have also been raised.", "type": "CHEMICAL", "entities": [ "SiO(2)" ], "offsets": [ [ 68, 74 ] ] }, { "pmid": "23315277", "text": "The aim of this study was to investigate the induction of cytotoxicity, oxidative stress and apoptosis by SiO(2) NPs (size 15 nm) in human skin epithelial (A431) and human lung epithelial (A549) cells.", "type": "CHEMICAL", "entities": [ "SiO(2)" ], "offsets": [ [ 106, 112 ] ] }, { "pmid": "23315277", "text": "SiO(2) NPs (concentration range 25-200 µg/ml) induced dose-dependent cytotoxicity in both types of cells, which was demonstrated by cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) and lactate dehydrogenase leakage assays.", "type": "CHEMICAL", "entities": [ "3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide", "lactate" ], "offsets": [ [ 147, 206 ], [ 212, 219 ] ] }, { "pmid": "23315277", "text": "SiO(2) NPs were also found to induce oxidative stress in a dose-dependent manner, indicated by depletion of glutathione and induction of reactive oxygen species (ROS) generation and lipid peroxidation.", "type": "CHEMICAL", "entities": [ "glutathione", "oxygen" ], "offsets": [ [ 105, 116 ], [ 143, 149 ] ] }, { "pmid": "23315277", "text": "Quantitative real-time polymerase chain reaction analysis showed that following the exposure of cells to SiO(2) NPs, the messenger RNA level of apoptotic genes (caspase-3 and caspase-9) were upregulated in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "SiO(2)" ], "offsets": [ [ 102, 108 ] ] }, { "pmid": "23315277", "text": "Moreover, activities of caspase-3 and caspase-9 enzymes were also significantly higher in both kinds of cells exposed to SiO(2) NPs.", "type": "CHEMICAL", "entities": [ "SiO(2)" ], "offsets": [ [ 118, 124 ] ] }, { "pmid": "23315277", "text": "This study suggested that SiO(2) NPs induce cytotoxicity and apoptosis in A431 and A549 cells, which is likely to be mediated through ROS generation and oxidative stress.", "type": "CHEMICAL", "entities": [ "SiO(2)" ], "offsets": [ [ 23, 29 ] ] }, { "pmid": "23550066", "text": "The CYP2B6*6 Allele Significantly Alters the N-demethylation of Ketamine Enantiomers In Vitro.\n", "type": "CHEMICAL", "entities": [ "Ketamine" ], "offsets": [ [ 64, 72 ] ] }, { "pmid": "23550066", "text": "Ketamine is primarily metabolized to norketamine by hepatic cytochrome P450 (CYP) 2B6 and CYP3A4-mediated N-demethylation.", "type": "CHEMICAL", "entities": [ "Ketamine", "norketamine" ], "offsets": [ [ 0, 8 ], [ 37, 48 ] ] }, { "pmid": "23550066", "text": "However, the relative contribution from each enzyme remains controversial.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550066", "text": "The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism.", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 126, 134 ] ] }, { "pmid": "23550066", "text": "We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell expressed recombinant CYP2B6 and CYP3A4 enzymes and COS-1 cell expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant.", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 46, 54 ] ] }, { "pmid": "23550066", "text": "Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs.", "type": "CHEMICAL", "entities": [ "norketamine" ], "offsets": [ [ 39, 50 ] ] }, { "pmid": "23550066", "text": "The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550066", "text": "The Km value for the high affinity enzyme and the low affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550066", "text": "The intrinsic clearance for both ketamine enantiomers by the high affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype.", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 33, 41 ] ] }, { "pmid": "23550066", "text": "The Vmax and Km values for CYP2B6.1 were approximately 160% and 70% of those for CYP2B6.6, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550066", "text": "ThioTEPA (CYP2B6 inhibitor, 25 μM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 μM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations.", "type": "CHEMICAL", "entities": [ "ThioTEPA", "troleandomycin", "ketamine" ], "offsets": [ [ 0, 8 ], [ 86, 100 ], [ 179, 187 ] ] }, { "pmid": "23550066", "text": "The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (gene-dose P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550066", "text": "These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity.", "type": "CHEMICAL", "entities": [ "ketamine", "ketamine" ], "offsets": [ [ 47, 55 ], [ 139, 147 ] ] }, { "pmid": "23572528", "text": "A Role for Cargo in the Activation of ADP-Ribosylation Factors (Arf) and Adaptor Recruitment.\n", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 38, 41 ] ] }, { "pmid": "23572528", "text": "Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "The recruitment of the adaptors is mediated by activated Arf GTPases and the Arf-adaptor complexes mark sites of carrier formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "However, the nature of the signal(s) that initiate carrier biogenesis remains unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR) and M6PR lacking a C-terminal domain M6PRΔC).", "type": "CHEMICAL", "entities": [ "mannose-6-phosphate", "C" ], "offsets": [ [ 189, 208 ], [ 244, 245 ] ] }, { "pmid": "23572528", "text": "We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "Cargos do not promote adaptor recruitment to all compartments in which they reside and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "We document that within a given compartment different cargos recruit different adaptors suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23572528", "text": "Using temperature block, Brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles.", "type": "CHEMICAL", "entities": [ "Brefeldin A" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "23572528", "text": "These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "Aromatase inhibitors for male infertility.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "Testosterone-to-estradiol ratio levels in infertile men improve during treatment with the aromatase inhibitor, testolactone, and resulting changes in semen parameters.", "type": "CHEMICAL", "entities": [ "testolactone", "estradiol", "Testosterone" ], "offsets": [ [ 111, 123 ], [ 16, 25 ], [ 0, 12 ] ] }, { "pmid": "11792932", "text": "We evaluated the effect of anastrozole, a more selective aromatase inhibitor, on the hormonal and semen profiles of infertile men with abnormal baseline testosterone-to-estradiol ratios.", "type": "CHEMICAL", "entities": [ "anastrozole", "testosterone", "estradiol" ], "offsets": [ [ 27, 38 ], [ 153, 165 ], [ 169, 178 ] ] }, { "pmid": "11792932", "text": "MATERIALS AND METHODS: A total of 140 subfertile men with abnormal testosterone-to-estradiol ratios were treated with 100 to 200 mg.", "type": "CHEMICAL", "entities": [ "testosterone", "estradiol" ], "offsets": [ [ 67, 79 ], [ 83, 92 ] ] }, { "pmid": "11792932", "text": "testolactone daily or 1 mg.", "type": "CHEMICAL", "entities": [ "testolactone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "11792932", "text": "anastrozole daily.", "type": "CHEMICAL", "entities": [ "anastrozole" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11792932", "text": "Changes in testosterone, estradiol, testosterone-to-estradiol ratios and semen parameters were evaluated during therapy.", "type": "CHEMICAL", "entities": [ "testosterone", "estradiol", "testosterone", "estradiol" ], "offsets": [ [ 11, 23 ], [ 25, 34 ], [ 36, 48 ], [ 52, 61 ] ] }, { "pmid": "11792932", "text": "The effect of obesity, diagnosis of the Klinefelter syndrome, and presence of varicocele and/or history of varicocele repair on treatment results was studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "Men treated with testolactone had an increase in testosterone-to-estradiol ratios during therapy (mean plus or minus standard error of the mean 5.3 +/- 0.2 versus 12.4 +/- 1.1, p <0.001).", "type": "CHEMICAL", "entities": [ "testolactone", "testosterone", "estradiol" ], "offsets": [ [ 17, 29 ], [ 49, 61 ], [ 65, 74 ] ] }, { "pmid": "11792932", "text": "This change was confirmed in subgroups of men with the Klinefelter syndrome, a history of varicocele repair and those with varicocele.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "A total of 12 oligospermic men had semen analysis before and during testolactone treatment with an increase in sperm concentration (5.5 versus 11.2 million sperm per ml., p <0.01), motility (14.7% versus 21.0%, p <0.05), morphology (6.5% versus 12.8%, p = 0.05), and motility index (606.3 versus 1685.2 million motile sperm per ejaculate, respectively, p <0.05) appreciated.", "type": "CHEMICAL", "entities": [ "testolactone" ], "offsets": [ [ 68, 80 ] ] }, { "pmid": "11792932", "text": "During anastrozole treatment, similar changes in the testosterone-to-estradiol ratios were seen (7.2 +/- 0.3 versus 18.1 +/- 1.0, respectively, p <0.001).", "type": "CHEMICAL", "entities": [ "anastrozole", "testosterone", "estradiol" ], "offsets": [ [ 7, 18 ], [ 53, 65 ], [ 69, 78 ] ] }, { "pmid": "11792932", "text": "This improvement of hormonal parameters was noted for all subgroups except those patients with the Klinefelter syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11792932", "text": "A total of 25 oligospermic men with semen analysis before and during anastrozole treatment had an increase in semen volume (2.9 versus 3.5 ml., p <0.05), sperm concentration (5.5 versus 15.6 million sperm per ml., p <0.001) and motility index (832.8 versus 2930.8 million motile sperm per ejaculate, respectively, p <0.005).", "type": "CHEMICAL", "entities": [ "anastrozole" ], "offsets": [ [ 69, 80 ] ] }, { "pmid": "11792932", "text": "These changes were similar to those observed in men treated with testolactone.", "type": "CHEMICAL", "entities": [ "testolactone" ], "offsets": [ [ 65, 77 ] ] }, { "pmid": "11792932", "text": "No significant difference in serum testosterone levels during treatment with testolactone and anastrozole was observed.", "type": "CHEMICAL", "entities": [ "testosterone", "testolactone", "anastrozole" ], "offsets": [ [ 35, 47 ], [ 77, 89 ], [ 94, 105 ] ] }, { "pmid": "11792932", "text": "However, the anastrozole treatment group did have a statistically better improvement of serum estradiol concentration and testosterone-to-estradiol ratios (p <0.001).", "type": "CHEMICAL", "entities": [ "anastrozole", "estradiol", "testosterone", "estradiol" ], "offsets": [ [ 13, 24 ], [ 94, 103 ], [ 122, 134 ], [ 138, 147 ] ] }, { "pmid": "11792932", "text": "CONCLUSIONS: Men who are infertile with a low serum testosterone-to-estradiol ratio can be treated with an aromatase inhibitor.", "type": "CHEMICAL", "entities": [ "testosterone", "estradiol" ], "offsets": [ [ 52, 64 ], [ 68, 77 ] ] }, { "pmid": "11792932", "text": "With treatment, an increase in testosterone-to-estradiol ratio occurred in association with increased semen parameters.", "type": "CHEMICAL", "entities": [ "testosterone", "estradiol" ], "offsets": [ [ 31, 43 ], [ 47, 56 ] ] }, { "pmid": "11792932", "text": "Anastrozole and testolactone have similar effects on hormonal profiles and semen analysis.", "type": "CHEMICAL", "entities": [ "Anastrozole", "testolactone" ], "offsets": [ [ 0, 11 ], [ 16, 28 ] ] }, { "pmid": "11792932", "text": "Anastrazole appears to be at least as effective as testolactone for treating men with abnormal testosterone-to-estradiol ratios, except for the subset with the Klinefelter syndrome, who appeared to be more effectively treated with testolactone.", "type": "CHEMICAL", "entities": [ "Anastrazole", "testolactone", "testosterone", "estradiol", "testolactone" ], "offsets": [ [ 0, 11 ], [ 51, 63 ], [ 95, 107 ], [ 111, 120 ], [ 231, 243 ] ] }, { "pmid": "23043184", "text": "Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism.\n", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 64, 69 ] ] }, { "pmid": "23043184", "text": "Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another isoform.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23043184", "text": "In this study, we assessed whether CYP2E1 could influence the catalytic activity of CYP2B4 under steady-state turnover conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23043184", "text": "The results show that CYP2E1 inhibits CYP2B4-mediated metabolism of benzphetamine (BNZ) with a K(i) of 0.04 µM.", "type": "CHEMICAL", "entities": [ "benzphetamine", "BNZ" ], "offsets": [ [ 68, 81 ], [ 83, 86 ] ] }, { "pmid": "23043184", "text": "However, CYP2B4 is not an inhibitor of CYP2E1-mediated p-nitrophenol hydroxylation.", "type": "CHEMICAL", "entities": [ "p-nitrophenol" ], "offsets": [ [ 54, 67 ] ] }, { "pmid": "23043184", "text": "When these inhibition studies were performed with the artificial oxidant tert-butyl hydroperoxide, CYP2E1 did not significantly inhibit CYP2B4 activity.", "type": "CHEMICAL", "entities": [ "tert-butyl hydroperoxide" ], "offsets": [ [ 72, 96 ] ] }, { "pmid": "23043184", "text": "Determinations of the apparent K(M) and k(cat) of CYP2B4 for CPR in the presence of increasing concentrations of CYP2E1 revealed a mixed inhibition of CYP2B4 by CYP2E1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23043184", "text": "At low concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR increased up to 23-fold with virtually no change in the k(cat) for the reaction, however, at higher concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR decreased to levels similar to those observed in the absence of CYP2E1 and the k(cat) also decreased by 11-fold.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23043184", "text": "Additionally, CYP2E1 increased the apparent K(M) of CYP2B4 for BNZ by 8-fold and the apparent K(M) did not decrease to its original value when saturating concentrations of CPR were used.", "type": "CHEMICAL", "entities": [ "BNZ" ], "offsets": [ [ 62, 65 ] ] }, { "pmid": "23043184", "text": "While the individual apparent K(M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K(M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643748", "text": "Prosocial effects of oxytocin in two mouse models of autism spectrum disorders.\n", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 21, 29 ] ] }, { "pmid": "23643748", "text": "Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs).", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 32, 40 ] ] }, { "pmid": "23643748", "text": "However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643748", "text": "In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643748", "text": "This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643748", "text": "Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 59, 67 ] ] }, { "pmid": "23643748", "text": "Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 hours following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test.", "type": "CHEMICAL", "entities": [ "oxytocin", "oxytocin", "oxytocin", "oxytocin", "oxytocin" ], "offsets": [ [ 341, 349 ], [ 6, 14 ], [ 79, 87 ], [ 215, 223 ], [ 270, 278 ] ] }, { "pmid": "23643748", "text": "This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 29, 37 ] ] }, { "pmid": "23643748", "text": "These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 215, 223 ] ] }, { "pmid": "15336276", "text": "Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates.\n", "type": "CHEMICAL", "entities": [ "phenylalkylphosphonamidates" ], "offsets": [ [ 88, 115 ] ] }, { "pmid": "15336276", "text": "To explore for the existence of an auxiliary hydrophobic binding register remote from the active site of PSMA a series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA.", "type": "CHEMICAL", "entities": [ "phenylalkylphosphonamidate", "glutamic acid" ], "offsets": [ [ 122, 148 ], [ 164, 177 ] ] }, { "pmid": "15336276", "text": "Both the phenyl- and benzylphosphonamidates (1a and 1b) exhibited only modest inhibitory potency against.", "type": "CHEMICAL", "entities": [ "phenyl- and benzylphosphonamidates" ], "offsets": [ [ 9, 43 ] ] }, { "pmid": "15336276", "text": "The phenethyl analog 1c was intermediate in inhibitory potency while inhibitors possessing a longer alkyl tether from the phenyl ring, resulted in markedly improved K(i) values.", "type": "CHEMICAL", "entities": [ "phenethyl", "alkyl" ], "offsets": [ [ 4, 13 ], [ 100, 105 ] ] }, { "pmid": "15336276", "text": "The greatest inhibitory potency was obtained for the inhibitors in which the phenyl ring was extended furthest from the central phosphorus (1f, n=5 and 1g, n=6).", "type": "CHEMICAL", "entities": [ "phosphorus" ], "offsets": [ [ 128, 138 ] ] }, { "pmid": "15336276", "text": "The slightly serrated pattern that emerged as the alkyl tether increased from three to six methylene units suggests that inhibitory potency is not simply correlated to increased hydrophobicity imparted by the phenylalkyl chain, but rather that one or more hydrophobic binding registers may exist remote from the substrate recognition architecture in the active site of PSMA.", "type": "CHEMICAL", "entities": [ "alkyl", "phenylalkyl" ], "offsets": [ [ 50, 55 ], [ 209, 220 ] ] }, { "pmid": "23174754", "text": "Deficits in male sexual behavior in adulthood after social instability stress in adolescence in rats.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "There is increasing evidence that exposure to stressors in adolescence has long-lasting effects on emotional and cognitive behavior, but little is known as to whether reproductive functions are affected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "We investigated appetitive and consummatory aspects of sexual behavior in male rats that were exposed to chronic social instability stress (SS, n=24) for 16 days in mid-adolescence compared to control rats (CTL, n=24).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "Over five sexual behavior test sessions with a receptive female, SS rats made fewer ejaculations (p=0.02) and had longer latencies to ejaculation (p=0.03).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "When only data from rats that ejaculated in the fifth session were analyzed, SS rats (n=18) had reduced copulatory efficiency (more mounts and intromissions before ejaculation) compared to CTL rats (n=19) (p=0.004), and CTL rats were twice as likely as SS rats to make more than one ejaculation in the fifth session (p=0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "Further, more CTL (14/24) than SS (5/25) rats ejaculated in four or more sessions (p=0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "SS rats had lower plasma testosterone concentrations than CTL rats (p=0.05), but did not differ in androgen receptor, estrogen receptor alpha, or Fos immunoreactive cell counts in the medial preoptic area.", "type": "CHEMICAL", "entities": [ "testosterone", "androgen", "estrogen" ], "offsets": [ [ 25, 37 ], [ 99, 107 ], [ 118, 126 ] ] }, { "pmid": "23174754", "text": "The groups did not differ in a partner preference test administered between the fourth and fifth sexual behavior session.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23174754", "text": "The results suggest that developmental history contributes to individual differences in reproductive behavior, and that stress exposures in adolescence may be a factor in sexual sluggishness.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551329", "text": "Low-Dose Dexamethasone Treatment Promotes Pro-Survival Signalling Pathway", "type": "CHEMICAL", "entities": [ "Dexamethasone" ], "offsets": [ [ 9, 22 ] ] }, { "pmid": "23551329", "text": "In Adult Rat Prefrontal Cortex.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551329", "text": "Synthetic glucocorticoid dexamethasone (DEX), a highly potent anti-inflammatory and immunosuppressive agent, is widely used in treatments of brain cancer, inflammatory and autoimmune diseases.", "type": "CHEMICAL", "entities": [ "dexamethasone", "DEX" ], "offsets": [ [ 25, 38 ], [ 40, 43 ] ] }, { "pmid": "23551329", "text": "The objective of the current study was to determine whether a low-dose subchronic DEX treatment (100 μg/kg for 8 consecutive days) exerts long-term effects on apoptosis in the adult rat prefrontal cortex (PFC) by examining the expression of cell death-promoting molecules (poly (ADP-ribose) polymerase (PARP), p53, procaspase 3, cleaved caspase 3, Bax) and cell-survival molecules (AKT, Bcl-2).", "type": "CHEMICAL", "entities": [ "DEX", "poly (ADP-ribose)" ], "offsets": [ [ 82, 85 ], [ 273, 290 ] ] }, { "pmid": "23551329", "text": "Our results revealed that body, thymus and adrenal weight as well corticosterone level in the serum and PFC were reduced a day following last DEX injection.", "type": "CHEMICAL", "entities": [ "corticosterone", "DEX" ], "offsets": [ [ 65, 79 ], [ 141, 144 ] ] }, { "pmid": "23551329", "text": "In PFC, DEX caused activation of AKT, augmentation of pro-survival Bcl-2 protein and enhanced Bcl-2/Bax protein ratio, as well Bcl-2 translocation to mitochondria.", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 7, 10 ] ] }, { "pmid": "23551329", "text": "The unaltered profile in the protein expression of apoptotic molecules PARP, procaspase 3 and Bax was detected, while the p53 protein was decreased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551329", "text": "Results of RT-PCR analysis showed decrease of p53 mRNA level and no significant difference in Bcl-2 and Bax mRNA expressions in DEX-treated rats.", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 127, 130 ] ] }, { "pmid": "23551329", "text": "Finally, the DNA fragmentation assay and Fluoro-Jade staining demonstrated no considerable changes in the apoptosis in rat PFC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23551329", "text": "Our findings support the concept that a low-dose DEX creates the hypocorticoid state in the brain and indicate that subchronic DEX treatment activates pro-survival signalling pathway but does not change apoptotic markers in rat PFC.", "type": "CHEMICAL", "entities": [ "DEX", "DEX" ], "offsets": [ [ 48, 51 ], [ 126, 129 ] ] }, { "pmid": "23551329", "text": "This mechanism might be relevant for DEX-induced apoptosis resistance observed during and after chemotherapy of patients with brain tumours.", "type": "CHEMICAL", "entities": [ "DEX" ], "offsets": [ [ 36, 39 ] ] }, { "pmid": "23551329", "text": "© 2013 British Society for Neuroendocrinology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16477002", "text": "The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.", "type": "CHEMICAL", "entities": [ "hydrogen" ], "offsets": [ [ 87, 95 ] ] }, { "pmid": "17205056", "text": "Antitumor activity of sorafenib in FLT3-driven leukemic cells.\n", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "17205056", "text": "Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 96, 104 ] ] }, { "pmid": "17205056", "text": "We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities.", "type": "CHEMICAL", "entities": [ "sorafenib", "BAY 43-9006", "Nexavar" ], "offsets": [ [ 13, 22 ], [ 24, 35 ], [ 37, 44 ] ] }, { "pmid": "17205056", "text": "In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation.", "type": "CHEMICAL", "entities": [ "sorafenib", "tyrosine" ], "offsets": [ [ 61, 70 ], [ 120, 128 ] ] }, { "pmid": "17205056", "text": "In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "17205056", "text": "The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 81, 90 ] ] }, { "pmid": "17205056", "text": "Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 79, 88 ] ] }, { "pmid": "17205056", "text": "The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "17205056", "text": "Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17205056", "text": "The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "23041257", "text": "Apoptosis induced neurotoxicity of Di-n-butyl-di-(4-chlorobenzohydroxamato)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23041257", "text": "Tin (IV) via mitochondria-mediated pathway in PC12 cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23041257", "text": "The severe toxicity of antitumor organotin (IV) compounds limits their application in clinic, however, the toxic mechanism is still unclear.", "type": "CHEMICAL", "entities": [ "organotin (IV)" ], "offsets": [ [ 33, 47 ] ] }, { "pmid": "23041257", "text": "Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) (DBDCT), an antitumor agent with high activity and obvious neurotoxicity was chosen as a typical diorganotin (IV) compound to investigate its neurotoxic mechanism using PC12 cells and comprehensive methods.", "type": "CHEMICAL", "entities": [ "Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV)", "DBDCT", "diorganotin (IV)" ], "offsets": [ [ 0, 49 ], [ 51, 56 ], [ 147, 163 ] ] }, { "pmid": "23041257", "text": "Treatment with DBDCT resulted in a dose- and time-dependent growth inhibition of PC12 cells.", "type": "CHEMICAL", "entities": [ "DBDCT" ], "offsets": [ [ 15, 20 ] ] }, { "pmid": "23041257", "text": "The changes in cell morphology were observed using light microscopy, fluorescence microscopy and transmission electron microscopy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23041257", "text": "PC12 cell apoptosis induced by DBDCT was confirmed by annexin V/propidium iodide staining, and characterized by cleavage of caspase-9 and caspase-3 proteins.", "type": "CHEMICAL", "entities": [ "DBDCT", "propidium iodide" ], "offsets": [ [ 31, 36 ], [ 64, 80 ] ] }, { "pmid": "23041257", "text": "DBDCT induced the release of cytochrome c from the mitochondria to the cytosol and the generation of reactive oxygen species.", "type": "CHEMICAL", "entities": [ "DBDCT", "oxygen" ], "offsets": [ [ 0, 5 ], [ 110, 116 ] ] }, { "pmid": "23041257", "text": "DBDCT up-regulated the expression of Bax, down-regulated the expression of Bcl-2, and significantly increased the ratio of Bax/Bcl-2.", "type": "CHEMICAL", "entities": [ "DBDCT" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23041257", "text": "DBDCT also caused the phosphorylation of JNK and p38(MAPK).", "type": "CHEMICAL", "entities": [ "DBDCT" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23041257", "text": "In rats exposed to DBDCT, apoptosis was also observed in brain, as shown by the detection of cleaved caspase-9 and caspase-3 proteins and increased TUNEL positive staining.", "type": "CHEMICAL", "entities": [ "DBDCT" ], "offsets": [ [ 19, 24 ] ] }, { "pmid": "23041257", "text": "In conclusion, the results demonstrated that DBDCT caused the neurotoxicity by inducing apoptosis via mitochondria-mediated pathway.", "type": "CHEMICAL", "entities": [ "DBDCT" ], "offsets": [ [ 45, 50 ] ] }, { "pmid": "12927775", "text": "Structure-based design of aliskiren, a novel orally effective renin inhibitor.\n", "type": "CHEMICAL", "entities": [ "aliskiren" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "12927775", "text": "Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12927775", "text": "Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension.", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "12927775", "text": "As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12927775", "text": "Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12927775", "text": "We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12927775", "text": "This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients.", "type": "CHEMICAL", "entities": [ "aliskiren", "aliskiren", "sodium" ], "offsets": [ [ 29, 38 ], [ 143, 152 ], [ 195, 201 ] ] }, { "pmid": "12927775", "text": "Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.", "type": "CHEMICAL", "entities": [ "Aliskiren" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16774921", "text": "Functional divergence of a unique C-terminal domain of leucyl-tRNA synthetase to accommodate its splicing and aminoacylation roles.\n", "type": "CHEMICAL", "entities": [ "C", "leucyl" ], "offsets": [ [ 34, 35 ], [ 55, 61 ] ] }, { "pmid": "16774921", "text": "Leucyl-tRNA synthetase (LeuRS) performs dual essential roles in group I intron RNA splicing as well as protein synthesis within the yeast mitochondria.", "type": "CHEMICAL", "entities": [ "Leucyl" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "16774921", "text": "Deletions of the C terminus differentially impact the two functions of the enzyme in splicing and aminoacylation in vivo.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 17, 18 ] ] }, { "pmid": "16774921", "text": "Herein, we determined that a fiveamino acid C-terminal deletion of LeuRS, which does not complement a null strain, can form a ternary complex with the bI4 intron and its maturase splicing partner.", "type": "CHEMICAL", "entities": [ "fiveamino acid", "C" ], "offsets": [ [ 29, 43 ], [ 44, 45 ] ] }, { "pmid": "16774921", "text": "However, the complex fails to stimulate splicing activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16774921", "text": "The x-ray co-crystal structure of LeuRS showed that a C-terminal extension of about 60 amino acids forms a discrete domain, which is unique among the LeuRSs and interacts with the corner of the L-shaped tRNALeu.", "type": "CHEMICAL", "entities": [ "C", "amino acids" ], "offsets": [ [ 54, 55 ], [ 87, 98 ] ] }, { "pmid": "16774921", "text": "Interestingly, deletion of the entire yeast mitochondrial LeuRS C-terminal domain enhanced its aminoacylation and amino acid editing activities.", "type": "CHEMICAL", "entities": [ "C", "amino acid" ], "offsets": [ [ 64, 65 ], [ 114, 124 ] ] }, { "pmid": "16774921", "text": "In striking contrast, deletion of the corresponding C-terminal domain of Escherichia coli LeuRS abolished aminoacylation of tRNALeu and also amino acid editing of mischarged tRNA molecules.", "type": "CHEMICAL", "entities": [ "amino acid", "C" ], "offsets": [ [ 141, 151 ], [ 52, 53 ] ] }, { "pmid": "16774921", "text": "These results suggest that the role of the leucine-specific C-terminal domain in tRNA recognition for aminoacylation and amino acid editing has adapted differentially and with surprisingly opposite effects.", "type": "CHEMICAL", "entities": [ "leucine", "C", "amino acid" ], "offsets": [ [ 43, 50 ], [ 60, 61 ], [ 121, 131 ] ] }, { "pmid": "16774921", "text": "We propose that the secondary role of yeast mitochondrial LeuRS in RNA splicing has impacted the functional evolution of this critical C-terminal domain.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 135, 136 ] ] }, { "pmid": "20531964", "text": "Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib.\n", "type": "CHEMICAL", "entities": [ "Everolimus", "sorafenib", "sunitinib" ], "offsets": [ [ 0, 10 ], [ 107, 116 ], [ 90, 99 ] ] }, { "pmid": "20531964", "text": "Everolimus (RAD001, Afinitor((R))", "type": "CHEMICAL", "entities": [ "Everolimus", "RAD001" ], "offsets": [ [ 0, 10 ], [ 12, 18 ] ] }, { "pmid": "20531964", "text": "Novartis) is the first oral inhibitor of mTOR (mammalian target of rapamycin) to reach the oncology clinic.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "20531964", "text": "Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients.", "type": "CHEMICAL", "entities": [ "Everolimus" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "20531964", "text": "A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib.", "type": "CHEMICAL", "entities": [ "everolimus", "tyrosine", "sunitinib", "sorafenib" ], "offsets": [ [ 75, 85 ], [ 187, 195 ], [ 214, 223 ], [ 231, 240 ] ] }, { "pmid": "20531964", "text": "The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001) and 25% were still progression-free after 10 months of everolimus therapy.", "type": "CHEMICAL", "entities": [ "everolimus" ], "offsets": [ [ 180, 190 ] ] }, { "pmid": "20531964", "text": "There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20531964", "text": "In 2009, everolimus was approved in the US and Europe as the only validated option for this indication.", "type": "CHEMICAL", "entities": [ "everolimus" ], "offsets": [ [ 9, 19 ] ] }, { "pmid": "20531964", "text": "Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20531964", "text": "Opportunistic infections and non-infectious pneumonitis are seen as a class effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20531964", "text": "Management of common practical management issues are discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20531964", "text": "Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.", "type": "CHEMICAL", "entities": [ "everolimus" ], "offsets": [ [ 64, 74 ] ] }, { "pmid": "23361587", "text": "Anti-aging molecule, Sirt1: a novel therapeutic target for diabetic nephropathy.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "Caloric restriction prolongs the lifespan of many species.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "Therefore, investigators have researched the usefulness of caloric restriction for healthy lifespan extension.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "Sirt1, an NAD(+)-dependent deacetylase, was identified as a molecule necessary for caloric restriction-related anti-aging strategies.", "type": "CHEMICAL", "entities": [ "NAD(+)" ], "offsets": [ [ 10, 16 ] ] }, { "pmid": "23361587", "text": "Sirt1 functions as an intracellular energy sensor to detect the concentration of NAD(+), and controls in vivo metabolic changes under caloric restriction and starvation through its deacetylase activity to many targets including histones, nuclear transcriptional factors, and enzymes.", "type": "CHEMICAL", "entities": [ "NAD(+)" ], "offsets": [ [ 81, 87 ] ] }, { "pmid": "23361587", "text": "During the past decade, investigators have reported the relationship between disturbance of Sirt1 activation and the onset of aging- and obesity-associated diseases such as diabetes, cardiovascular disease and neurodegenerative disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "Consequently, a calorie restriction-mimetic action of Sirt1 is now expected as a new therapy for these diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "In addition, recent studies have gradually clarified the role of Sirt1 in the onset of kidney disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "Its activation may also become a new target of treatment in the patients with chronic kidney disease including diabetic nephropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23361587", "text": "In this article, we would like to review the role of Sirt1 in the onset of kidney disease based on previous studies, and discuss its possibility as the target of treatment in diabetic nephropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7948825", "text": "Sucralfate: the Bangkok review.\n", "type": "CHEMICAL", "entities": [ "Sucralfate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "7948825", "text": "Sucralfate is a site-protective ulcer healing drug with a remarkable range of mechanisms of action.", "type": "CHEMICAL", "entities": [ "Sucralfate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "7948825", "text": "Recent studies highlight the capacity of sucralfate to bind basic fibroblast growth factor (bFGF) and deliver it in high concentration to the ulcer.", "type": "CHEMICAL", "entities": [ "sucralfate" ], "offsets": [ [ 41, 51 ] ] }, { "pmid": "7948825", "text": "Basic fibroblast growth factor stimulates the production of granulation tissue, angiogenesis and re-epithelization, thus improving the quality of ulcer healing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7948825", "text": "The effect of sucralfate in reducing parietal cell sensitivity may be another factor important in the lower relapse rate demonstrated after duodenal ulcer healing.", "type": "CHEMICAL", "entities": [ "sucralfate" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "7948825", "text": "Sucralfate has been demonstrated to be efficacious in healing both duodenal and gastric ulcers together with mild oesophagitis, and it is safe for both short-term use and maintenance.", "type": "CHEMICAL", "entities": [ "Sucralfate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "7948825", "text": "In stress ulcer prophylaxis it is as effective as acid suppression or neutralization and has the advantage of lesser rates of nosocomial pneumonia than are demonstrated with antacids or H2 antagonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7948825", "text": "The potential advantages of sucralfate lie in the better quality of ulcer healing associated with longer duration of remission.", "type": "CHEMICAL", "entities": [ "sucralfate" ], "offsets": [ [ 28, 38 ] ] }, { "pmid": "23535327", "text": "Synthesis and structure-activity relationship of pyripyropene", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535327", "text": "A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: Part 2.\n", "type": "CHEMICAL", "entities": [ "acyl-CoA", "cholesterol" ], "offsets": [ [ 38, 46 ], [ 47, 58 ] ] }, { "pmid": "23535327", "text": "Synthesis and structure-activity relationships of 7-O-p-cyanobenzoyl pyripyropene A derivatives with modification at C1 and 11 are described.", "type": "CHEMICAL", "entities": [ "7-O-p-cyanobenzoyl pyripyropene A" ], "offsets": [ [ 50, 83 ] ] }, { "pmid": "23535327", "text": "Regioselective mono-deprotection of di-tert-butylsilylene acetal was critical in their synthesis.", "type": "CHEMICAL", "entities": [ "di-tert-butylsilylene acetal" ], "offsets": [ [ 36, 64 ] ] }, { "pmid": "1680855", "text": "Involvement of pertussis toxin-sensitive G-proteins in the hormonal inhibition of dihydropyridine-sensitive Ca2+ currents in an insulin-secreting cell line (RINm5F).\n", "type": "CHEMICAL", "entities": [ "Ca2+", "dihydropyridine" ], "offsets": [ [ 108, 112 ], [ 82, 97 ] ] }, { "pmid": "1680855", "text": "Adrenaline inhibits insulin secretion via pertussis toxin-sensitive mechanisms.", "type": "CHEMICAL", "entities": [ "Adrenaline" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "1680855", "text": "Since voltage-dependent Ca2+ currents play a key role in insulin secretion, we examined whether adrenaline modulates voltage-dependent Ca2+ currents of the rat insulinoma cell line, RINm5F. In the whole-cell configuration of the patch-clamp technique, dihydropyridine- but not omega-conotoxin-sensitive Ca2+ currents were identified.", "type": "CHEMICAL", "entities": [ "Ca2+", "adrenaline", "Ca2+", "dihydropyridine", "Ca2+" ], "offsets": [ [ 24, 28 ], [ 96, 106 ], [ 135, 139 ], [ 252, 267 ], [ 303, 307 ] ] }, { "pmid": "1680855", "text": "Adrenaline via alpha 2-adrenoceptors inhibited the Ca2+ currents by about 50%.", "type": "CHEMICAL", "entities": [ "Adrenaline", "Ca2+" ], "offsets": [ [ 0, 10 ], [ 51, 55 ] ] }, { "pmid": "1680855", "text": "Somatostatin which also inhibits insulin secretion was less efficient (inhibition by 20%).", "type": "CHEMICAL", "entities": [ "Somatostatin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "1680855", "text": "The hormonal inhibition of Ca2+ currents was not affected by intracellularly applied cAMP but blocked by the intracellularly applied GDP analog guanosine 5'-O-(2-thiodiphosphate) and by pretreatment of cells with pertussis toxin.", "type": "CHEMICAL", "entities": [ "Ca2+", "cAMP", "GDP", "guanosine 5'-O-(2-thiodiphosphate)" ], "offsets": [ [ 27, 31 ], [ 85, 89 ], [ 133, 136 ], [ 144, 178 ] ] }, { "pmid": "1680855", "text": "In contrast to adrenaline and somatostatin, galanin, another inhibitor of insulin secretion, reduced Ca2+ currents by about 40% in a pertussis toxin-insensitive manner.", "type": "CHEMICAL", "entities": [ "adrenaline", "somatostatin", "Ca2+" ], "offsets": [ [ 15, 25 ], [ 30, 42 ], [ 101, 105 ] ] }, { "pmid": "1680855", "text": "Immunoblot experiments performed with antibodies generated against synthetic peptides revealed that membranes of RINm5F cells possess four pertussis toxin-sensitive G-proteins including Gi1, Gi2, Go2, and another Go subtype, most likely representing Go1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1680855", "text": "In membranes of control but not of pertussis toxin-treated cells, adrenaline via alpha 2-adrenoceptors stimulated incorporation of the photo-reactive GTP analog [alpha-32P]GTP azidoanilide into pertussis toxin substrates comigrating with the alpha-subunits of Gi2, Go2, and the not further identified Go subtype.", "type": "CHEMICAL", "entities": [ "adrenaline", "GTP", "[alpha-32P]GTP azidoanilide" ], "offsets": [ [ 66, 76 ], [ 150, 153 ], [ 161, 188 ] ] }, { "pmid": "1680855", "text": "The present findings indicate that activated alpha 2-adrenoceptors of RINm5F cells interact with multiple G-proteins, i.e. two forms of Go and with Gi2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1680855", "text": "These G-proteins are likely to be involved in the adrenaline-induced inhibition of dihydropyridine-sensitive Ca2+ currents and in other signal transduction pathways contributing to the adrenaline-induced inhibition of insulin secretion.", "type": "CHEMICAL", "entities": [ "adrenaline", "dihydropyridine", "Ca2+", "adrenaline" ], "offsets": [ [ 50, 60 ], [ 83, 98 ], [ 109, 113 ], [ 185, 195 ] ] }, { "pmid": "23532918", "text": "Synthesis and in Vitro Characterisation of Ifenprodil-Based Fluorescein Conjugates as GluN1/GluN2B N-Methyl-D-aspartate Receptor Antagonists.\nGluN2B-containing NMDA receptors are involved in many important physiological functions and play a pivotal role in mediating pain as well as in several neurodegenerative disorders.", "type": "CHEMICAL", "entities": [ "NMDA", "Ifenprodil", "Fluorescein", "N-Methyl-D-aspartate" ], "offsets": [ [ 160, 164 ], [ 43, 53 ], [ 60, 71 ], [ 99, 119 ] ] }, { "pmid": "23532918", "text": "We aimed to develop fluorescent probes to target the GluN2B subunit selectively in order to allow better understanding of the relationships between receptor localisation and physiological importance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23532918", "text": "Ifenprodil, known as the GluNR2B antagonist of reference, was chosen as the template for the elaboration of probes.", "type": "CHEMICAL", "entities": [ "Ifenprodil" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23532918", "text": "We had previously reported a fluorescein conjugate that was shown (by confocal microscopy imaging of DS-red-labelled cortical neurons) to bind specifically to GluN2B. To elaborate this probe, we explored the influence of both the nature and the attachment point of the spacer between the fluorophore and the parent compound, ifenprodil.", "type": "CHEMICAL", "entities": [ "fluorescein", "ifenprodil" ], "offsets": [ [ 29, 40 ], [ 325, 335 ] ] }, { "pmid": "23532918", "text": "We performed chemical modifications of ifenprodil at the benzylic position and on the phenol ring by introducing secondary amine or amide functions and evaluated alkyl chains from two to 20 bonds either including or not including secondary amide functions as spacers.", "type": "CHEMICAL", "entities": [ "secondary amide", "ifenprodil", "benzylic", "phenol", "secondary amine or amide" ], "offsets": [ [ 230, 245 ], [ 39, 49 ], [ 57, 65 ], [ 86, 92 ], [ 113, 137 ] ] }, { "pmid": "23532918", "text": "The previously developed probe was found to display the greatest activity in the inhibition of NMDA-induced Ca(2+) influx by calcium imaging experiments on HEK293 cells transfected with the cDNA encoding for GluN1-1A and GluN2B. Further investigations revealed that this probe had a neuroprotective effect equivalent to that of ifenprodil in a standard test for neurotoxicity.", "type": "CHEMICAL", "entities": [ "NMDA", "Ca(2+)", "calcium", "ifenprodil" ], "offsets": [ [ 95, 99 ], [ 108, 114 ], [ 125, 132 ], [ 328, 338 ] ] }, { "pmid": "23532918", "text": "Despite effects of lesser amplitude with these probes relative to ifenprodil, we demonstrated that they displaced [(3) H]ifenprodil in mouse brain slices in a similar manner.", "type": "CHEMICAL", "entities": [ "ifenprodil", "[(3) H]ifenprodil" ], "offsets": [ [ 66, 76 ], [ 114, 131 ] ] }, { "pmid": "11034389", "text": "Conformational epitopes on the diabetes autoantigen GAD65 identified by peptide phage display and molecular modeling.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034389", "text": "The major diabetes autoantigen, glutamic acid decarboxylase (GAD65), contains a region of sequence similarity, including six identical residues PEVKEK, to the P2C protein of coxsackie B virus, suggesting that cross-reactivity between coxsackie B virus and GAD65 can initiate autoimmune diabetes.", "type": "CHEMICAL", "entities": [ "PEVKEK", "glutamic acid" ], "offsets": [ [ 144, 150 ], [ 32, 45 ] ] }, { "pmid": "11034389", "text": "We used the human islet cell mAbs MICA3 and MICA4 to identify the Ab epitopes of GAD65 by screening phage-displayed random peptide libraries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034389", "text": "The identified peptide sequences could be mapped to a homology model of the pyridoxal phosphate (PLP) binding domain of GAD65.", "type": "CHEMICAL", "entities": [ "pyridoxal phosphate", "PLP" ], "offsets": [ [ 76, 95 ], [ 97, 100 ] ] }, { "pmid": "11034389", "text": "For MICA3, a surface loop containing the sequence PEVKEK and two adjacent exposed helixes were identified in the PLP binding domain as well as a region of the C terminus of GAD65 that has previously been identified as critical for MICA3 binding.", "type": "CHEMICAL", "entities": [ "PEVKEK", "PLP", "C" ], "offsets": [ [ 50, 56 ], [ 113, 116 ], [ 159, 160 ] ] }, { "pmid": "11034389", "text": "To confirm that the loop containing the PEVKEK sequence contributes to the MICA3 epitope, this loop was deleted by mutagenesis.", "type": "CHEMICAL", "entities": [ "PEVKEK" ], "offsets": [ [ 40, 46 ] ] }, { "pmid": "11034389", "text": "This reduced binding of MICA3 by 70%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034389", "text": "Peptide sequences selected using MICA4 were rich in basic or hydroxyl-containing amino acids, and the surface of the GAD65 PLP-binding domain surrounding Lys358, which is known to be critical for MICA4 binding, was likewise rich in these amino acids.", "type": "CHEMICAL", "entities": [ "hydroxyl", "amino acids", "PLP", "amino acids" ], "offsets": [ [ 61, 69 ], [ 81, 92 ], [ 123, 126 ], [ 238, 249 ] ] }, { "pmid": "11034389", "text": "Also, the two phage most reactive with MICA4 encoded the motif VALxG, and the reverse of this sequence, LAV, was located in this same region.", "type": "CHEMICAL", "entities": [ "LAV" ], "offsets": [ [ 104, 107 ] ] }, { "pmid": "11034389", "text": "Thus, we have defined the MICA3 and MICA4 epitopes on GAD65 using the combination of phage display, molecular modeling, and mutagenesis and have provided compelling evidence for the involvement of the PEVKEK loop in the MICA3 epitope.", "type": "CHEMICAL", "entities": [ "PEVKEK" ], "offsets": [ [ 201, 207 ] ] }, { "pmid": "17434872", "text": "Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib.\n", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 75, 86 ] ] }, { "pmid": "17434872", "text": "Lumiracoxib is the first example of a marketed COX-2 inhibitor of the arylacetic acid class, and it is reported to be the most selective COXIB in vivo.", "type": "CHEMICAL", "entities": [ "Lumiracoxib", "arylacetic acid" ], "offsets": [ [ 0, 11 ], [ 70, 85 ] ] }, { "pmid": "17434872", "text": "However, the molecular basis of its COX-2 inhibition has not been completely defined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17434872", "text": "Using standard assays, lumiracoxib was found to be a poor inhibitor of purified ovine COX-1 and a relatively weak inhibitor of purified human COX-2.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "17434872", "text": "The extent of COX-2 inhibition plateaued at around 50% and suggested that the inhibitor may be reversibly bound to the enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17434872", "text": "Kinetic studies with lumiracoxib demonstrated that it was a time-dependent and slowly reversible inhibitor of human COX-2 that exhibited at least two binding steps during inhibition.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "17434872", "text": "Derivatives of lumiracoxib were synthesized with or without the methyl group on the phenylacetic acid ring and with various substitutions on the lower aniline ring.", "type": "CHEMICAL", "entities": [ "lumiracoxib", "methyl", "phenylacetic acid", "aniline" ], "offsets": [ [ 15, 26 ], [ 64, 70 ], [ 84, 101 ], [ 151, 158 ] ] }, { "pmid": "17434872", "text": "Inhibition studies demonstrated that the methyl group on the phenylacetic acid ring is required for COX-2 selectivity.", "type": "CHEMICAL", "entities": [ "methyl", "phenylacetic acid" ], "offsets": [ [ 41, 47 ], [ 61, 78 ] ] }, { "pmid": "17434872", "text": "The chemical identity and position of the substituents on the lower aniline ring were important in determining the potency and extent of COX inhibition as well as COX-2 selectivity.", "type": "CHEMICAL", "entities": [ "aniline" ], "offsets": [ [ 68, 75 ] ] }, { "pmid": "17434872", "text": "Mutation of Ser-530 to Ala or Val-349 to Ala or Leu abolished the potent inhibition observed with wild-type human COX-2 and key lumiracoxib analogs.", "type": "CHEMICAL", "entities": [ "Ser", "Ala", "Val", "Ala", "Leu", "lumiracoxib" ], "offsets": [ [ 12, 15 ], [ 23, 26 ], [ 30, 33 ], [ 41, 44 ], [ 48, 51 ], [ 128, 139 ] ] }, { "pmid": "17434872", "text": "Interestingly, a Val-349 to Ile mutant was inhibited with equal potency to human COX-2 with 2,6-dichloro-, 2,6-dimethyl-, or 2-chloro-6-methyl-substituted inhibitors and, in the case of lumiracoxib, actually showed an increase in potency.", "type": "CHEMICAL", "entities": [ "Val", "2,6-dichloro", "2,6-dimethyl", "2-chloro-6-methyl", "lumiracoxib" ], "offsets": [ [ 17, 20 ], [ 92, 104 ], [ 107, 119 ], [ 125, 142 ], [ 186, 197 ] ] }, { "pmid": "17434872", "text": "Taken together with a recent crystal structure of a lumiracoxib-COX-2 complex, the kinetic analyses presented herein of the inhibition of mutant COX-2s by lumiracoxib allows the definition of the molecular basis of COX-2 inhibition.", "type": "CHEMICAL", "entities": [ "lumiracoxib", "lumiracoxib" ], "offsets": [ [ 52, 63 ], [ 155, 166 ] ] }, { "pmid": "15358979", "text": "Cerebral D2 and 5-HT2 receptor occupancy in Schizophrenic patients treated with olanzapine or clozapine.\n", "type": "CHEMICAL", "entities": [ "olanzapine", "clozapine" ], "offsets": [ [ 80, 90 ], [ 94, 103 ] ] }, { "pmid": "15358979", "text": "We report the results of a double-blind, randomized prospective trial on D2 and 5-HT2 receptor occupancy and the clinical effects of olanzapine versus clozapine in a sample of neuroleptic-refractory schizophrenic patients.", "type": "CHEMICAL", "entities": [ "olanzapine", "clozapine" ], "offsets": [ [ 133, 143 ], [ 151, 160 ] ] }, { "pmid": "15358979", "text": "Receptor occupancy was evaluated in different cortical areas and in basal ganglia using [18F] fluoro-ethyl-spiperone ([18F] FESP) and positron emission tomography (PET).", "type": "CHEMICAL", "entities": [ "[18F] fluoro-ethyl-spiperone", "[18F] FESP" ], "offsets": [ [ 88, 116 ], [ 118, 128 ] ] }, { "pmid": "15358979", "text": "A total of 15 neuroleptic-free patients completed the study undergoing a baseline and a post-treatment PET scan (olanzapine, nine patients, one female; clozapine, six patients, three female) 8 weeks after starting treatment.", "type": "CHEMICAL", "entities": [ "olanzapine", "clozapine" ], "offsets": [ [ 113, 123 ], [ 152, 161 ] ] }, { "pmid": "15358979", "text": "PET data were analysed both by regions of interest and on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM96).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15358979", "text": "Olanzapine and clozapine induced a similar and significant inhibition of [18F] FESP binding index in the cortex.", "type": "CHEMICAL", "entities": [ "Olanzapine", "clozapine", "[18F] FESP" ], "offsets": [ [ 0, 10 ], [ 15, 24 ], [ 73, 83 ] ] }, { "pmid": "15358979", "text": "In the basal ganglia, receptor occupancy was significantly higher with olanzapine than with clozapine (p=0.0018).", "type": "CHEMICAL", "entities": [ "olanzapine", "clozapine" ], "offsets": [ [ 71, 81 ], [ 92, 101 ] ] }, { "pmid": "15358979", "text": "By contrast, no differences in receptor occupancy were detected at the level of the pituitary gland.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15358979", "text": "Clinical outcomes, in particular a full extra pyramidal tolerability, were similar.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15358979", "text": "In this sample of neuroleptic-refractory schizophrenic patients, olanzapine and clozapine showed a different pattern of occupancy of D2-like receptor despite a common lack of extrapyramidal side-effects.", "type": "CHEMICAL", "entities": [ "olanzapine", "clozapine" ], "offsets": [ [ 65, 75 ], [ 80, 89 ] ] }, { "pmid": "19429089", "text": "Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2.\n", "type": "CHEMICAL", "entities": [ "serotonin", "monoamine" ], "offsets": [ [ 31, 40 ], [ 78, 87 ] ] }, { "pmid": "19429089", "text": "The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA).", "type": "CHEMICAL", "entities": [ "methamphetamine", "3,4-methylenedioxymethamphetamine", "MDMA", "monoamine" ], "offsets": [ [ 120, 135 ], [ 140, 173 ], [ 175, 179 ], [ 23, 32 ] ] }, { "pmid": "19429089", "text": "The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum.", "type": "CHEMICAL", "entities": [ "serotonin", "adenosine triphosphate", "[(3)H]dopamine" ], "offsets": [ [ 76, 85 ], [ 146, 168 ], [ 179, 193 ] ] }, { "pmid": "19429089", "text": "SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular", "type": "CHEMICAL", "entities": [ "fluoxetine", "paroxetine", "fluvoxamine" ], "offsets": [ [ 7, 17 ], [ 19, 29 ], [ 35, 46 ] ] }, { "pmid": "19429089", "text": "[(3)H]dopamine uptake in vitro.", "type": "CHEMICAL", "entities": [ "[(3)H]dopamine" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "19429089", "text": "The rank order of potency was reserpine>>fluoxetine, paroxetine>fluvoxamine, methamphetamine>MDMA.", "type": "CHEMICAL", "entities": [ "reserpine", "fluoxetine", "paroxetine", "fluvoxamine", "methamphetamine", "MDMA" ], "offsets": [ [ 30, 39 ], [ 41, 51 ], [ 53, 63 ], [ 64, 75 ], [ 77, 92 ], [ 93, 97 ] ] }, { "pmid": "19429089", "text": "Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine.", "type": "CHEMICAL", "entities": [ "reserpine", "dopamine" ], "offsets": [ [ 55, 64 ], [ 157, 165 ] ] }, { "pmid": "19429089", "text": "Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine.", "type": "CHEMICAL", "entities": [ "fluoxetine", "dopamine" ], "offsets": [ [ 14, 24 ], [ 82, 90 ] ] }, { "pmid": "19429089", "text": "These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.", "type": "CHEMICAL", "entities": [ "reserpine", "fluoxetine" ], "offsets": [ [ 108, 117 ], [ 27, 37 ] ] }, { "pmid": "23411171", "text": "Anti-inflammatory effects of an aqueous extract of Welsh onion green leaves in mice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411171", "text": "The anti-inflammatory effects of an aqueous extract of Welsh onion green leaves (WOE) in mice was investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411171", "text": "Administration of WOE, in the range of 0.25-1g/kg, showed a concentration dependent inhibition on paw edema development after carrageenan treatment in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411171", "text": "The anti-inflammatory effects of WOE were closely attributed to decreased levels of tissue NO and tumor necrosis factor-α (TNF-α).", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 91, 93 ] ] }, { "pmid": "23411171", "text": "Further evidence for WOE's protection is shown in the reduction of lipid oxidation and the increase of antioxidant enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) in vivo.", "type": "CHEMICAL", "entities": [ "superoxide", "glutathione" ], "offsets": [ [ 158, 168 ], [ 190, 201 ] ] }, { "pmid": "23411171", "text": "Further, WOE also decreased the number of acetic acid-induced writhing responses and formalin-induced pain in the late phase in mice.", "type": "CHEMICAL", "entities": [ "acetic acid", "formalin" ], "offsets": [ [ 40, 51 ], [ 83, 91 ] ] }, { "pmid": "23411171", "text": "Overall, the results showed that WOE might serve as a natural source of anti-inflammatory compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Application of the bradford hill criteria to assess the causality of cisapride-induced arrhythmia: a model for assessing causal association in pharmacovigilance.\n", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "17408310", "text": "INTRODUCTION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "The Bradford Hill criteria are a widely used, useful tool for the assessment of biomedical causation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "We have examined their application to pharmacovigilance using the example of cisapride-induced QTc interval prolongation/arrhythmia.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 77, 86 ] ] }, { "pmid": "17408310", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "A literature search was conducted using MEDLINE, EMBASE, Reactions Weekly and regulatory websites to identify evidence for the association between cisapride and QTc interval prolongation/arrhythmia that had been published in the English language.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 147, 156 ] ] }, { "pmid": "17408310", "text": "Two hundred and five publications were identified as being potentially suitable for the study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "After excluding irrelevant articles, studies on high-risk populations and review articles, 70 publications were assessed using the Bradford Hill criteria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "These included 24 case reports, case series or spontaneous report summaries; eight epidemiological studies; 22 clinical studies; and 16 experimental (in vivo and in vitro) publications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "The most compelling evidence for an association between cisapride use and QTc interval prolongation/arrhythmia came from case/spontaneous reports and biological plausibility.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 56, 65 ] ] }, { "pmid": "17408310", "text": "Considering the rare incidence of serious cardiac events, these criteria formed the basis for the strength of the association.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "The number of reports from different populations showed consistency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Specificity was supported by clinical and cardiographic characterisation of the events.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "There were temporal relationships between the events and the initiation of cisapride treatment, increases in the dosage and the receipt of interacting medications.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 75, 84 ] ] }, { "pmid": "17408310", "text": "The relationships between the adverse events and the latter two factors exhibited biological gradients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Experimental evidence could be found from biological models, as well as reports of positive dechallenge and/or rechallenge found in individual patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Cisapride was found to bind the human ether-a-go-go-related gene (HERG) potassium channel, which provides a plausible mechanism for QTc interval prolongation/arrhythmia.", "type": "CHEMICAL", "entities": [ "Cisapride", "potassium" ], "offsets": [ [ 0, 9 ], [ 72, 81 ] ] }, { "pmid": "17408310", "text": "Other QTc interval-prolonging/arrhythmic drugs that also bind to HERG provided an analogy for cisapride causing QTc interval prolongation/arrhythmia via this mechanism.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 94, 103 ] ] }, { "pmid": "17408310", "text": "The evidence provided by clinical studies was inconsistent, and epidemiological studies failed to demonstrate an association.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Nevertheless, this did not prevent the assessment of causation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "DISCUSSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "This study showed how different types of evidence found in pharmacovigilance can be evaluated using the Bradford Hill criteria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17408310", "text": "Further work is required to examine how the criteria can be applied to different types of adverse events and how they may be applied to pharmacovigilance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10864881", "text": "Betaxolol, a beta(1)-adrenoceptor antagonist, reduces Na(+) influx into cortical synaptosomes by direct interaction with Na(+) channels: comparison with other beta-adrenoceptor antagonists.\n", "type": "CHEMICAL", "entities": [ "Betaxolol", "Na(+)", "Na(+)" ], "offsets": [ [ 0, 9 ], [ 121, 126 ], [ 54, 59 ] ] }, { "pmid": "10864881", "text": "Betaxolol, a beta(1)-adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity.", "type": "CHEMICAL", "entities": [ "Betaxolol" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10864881", "text": "In this study, we examined whether betaxolol and other beta-adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage-sensitive sodium channel (Na(+) channel) in rat cerebrocortical synaptosomes.", "type": "CHEMICAL", "entities": [ "betaxolol", "sodium", "Na(+)" ], "offsets": [ [ 35, 44 ], [ 169, 175 ], [ 185, 190 ] ] }, { "pmid": "10864881", "text": "Betaxolol inhibited specific [(3)H]-batrachotoxinin-A 20-alpha-benzoate ([(3)H]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC(50) value of 9.8 microM. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol approximately levobetaxolol>levobunolol approximately carteolol>/=timolol>atenolol.", "type": "CHEMICAL", "entities": [ "Betaxolol", "[(3)H]-batrachotoxinin-A 20-alpha-benzoate", "[(3)H]-BTX-B", "propranolol", "betaxolol", "levobetaxolol", "levobunolol", "carteolol", "timolol", "atenolol" ], "offsets": [ [ 0, 9 ], [ 29, 71 ], [ 73, 85 ], [ 275, 286 ], [ 287, 296 ], [ 311, 324 ], [ 325, 336 ], [ 351, 360 ], [ 363, 370 ], [ 371, 379 ] ] }, { "pmid": "10864881", "text": "None of the drugs caused a significant inhibition of [(3)H]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 microM. Saturation experiments showed that betaxolol increased the K(D) of [(3)H]-BTX-B binding but had no effect on the B(max).", "type": "CHEMICAL", "entities": [ "[(3)H]-saxitoxin", "betaxolol", "[(3)H]-BTX-B" ], "offsets": [ [ 53, 69 ], [ 190, 199 ], [ 222, 234 ] ] }, { "pmid": "10864881", "text": "The association kinetics of [(3)H]-BTX-B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand.", "type": "CHEMICAL", "entities": [ "[(3)H]-BTX-B", "betaxolol" ], "offsets": [ [ 28, 40 ], [ 60, 69 ] ] }, { "pmid": "10864881", "text": "These findings argue for a competitive, indirect, allosteric mode of inhibition of [(3)H]-BTX-B binding by betaxolol.", "type": "CHEMICAL", "entities": [ "[(3)H]-BTX-B", "betaxolol" ], "offsets": [ [ 83, 95 ], [ 107, 116 ] ] }, { "pmid": "10864881", "text": "Betaxolol inhibited veratridine-stimulated Na(+) influx in rat cortical synaptosomes with an IC(50) value of 28.", "type": "CHEMICAL", "entities": [ "Betaxolol", "veratridine", "Na(+)" ], "offsets": [ [ 0, 9 ], [ 20, 31 ], [ 43, 48 ] ] }, { "pmid": "10864881", "text": "3 microM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na(+) influx.", "type": "CHEMICAL", "entities": [ "Carteolol", "levobunolol", "timolol", "atenolol", "betaxolol", "veratridine", "Na(+)" ], "offsets": [ [ 10, 19 ], [ 21, 32 ], [ 34, 41 ], [ 46, 54 ], [ 94, 103 ], [ 116, 127 ], [ 135, 140 ] ] }, { "pmid": "10864881", "text": "The ability of betaxolol to interact with neurotoxin site 2 of the Na(+) channel and inhibit Na(+) influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma.", "type": "CHEMICAL", "entities": [ "betaxolol", "Na(+)", "Na(+)" ], "offsets": [ [ 15, 24 ], [ 67, 72 ], [ 93, 98 ] ] }, { "pmid": "23567953", "text": "Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents.\n", "type": "CHEMICAL", "entities": [ "1,3,4-trisubstituted pyrazoles" ], "offsets": [ [ 19, 49 ] ] }, { "pmid": "23567953", "text": "Some novel 1,3,4-trisubstituted pyrazoles were synthesized and screened for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability.", "type": "CHEMICAL", "entities": [ "1,3,4-trisubstituted pyrazoles" ], "offsets": [ [ 11, 41 ] ] }, { "pmid": "23567953", "text": "They showed anti-inflammatory and analgesic activities with better GIT tolerance than the standard drug phenylbutazone.", "type": "CHEMICAL", "entities": [ "phenylbutazone" ], "offsets": [ [ 104, 118 ] ] }, { "pmid": "23567953", "text": "In addition, IC50 values for 5e and 8e were recorded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567953", "text": "Compound 5e was found to be the most active one as anti-inflammatory and analgesic agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23567953", "text": "On the other hand, COX-1/COX-2 isozyme selectivity was also done which showed equal inhibition to both isoforms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22982445", "text": "Leukotriene D4 induces cognitive impairment through enhancement of CysLT₁ R-mediated amyloid-β generation in mice.\n", "type": "CHEMICAL", "entities": [ "Leukotriene D4" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "22982445", "text": "Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimer's disease (AD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22982445", "text": "In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice.", "type": "CHEMICAL", "entities": [ "leukotriene D4", "LTD4" ], "offsets": [ [ 125, 139 ], [ 141, 145 ] ] }, { "pmid": "22982445", "text": "The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of Aβ1-40 and Aβ1-42 in the hippocampus and cortex through increased activity of β- and γ-secretases accompanied with increased expression of amyloid precursor protein (APP).", "type": "CHEMICAL", "entities": [ "LTD4", "LTD4" ], "offsets": [ [ 52, 56 ], [ 365, 369 ] ] }, { "pmid": "22982445", "text": "LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT(1)R) and NF-κB p65 in the hippocampus and cortex.", "type": "CHEMICAL", "entities": [ "cysteinyl leukotriene" ], "offsets": [ [ 23, 44 ] ] }, { "pmid": "22982445", "text": "Pretreatment with pranlukast (1.5 ng/mouse, intracerebroventricularly), a CysLT(1)R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits.", "type": "CHEMICAL", "entities": [ "pranlukast", "LTD4" ], "offsets": [ [ 8, 18 ], [ 94, 98 ] ] }, { "pmid": "22982445", "text": "Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro.", "type": "CHEMICAL", "entities": [ "LTD4" ], "offsets": [ [ 25, 29 ] ] }, { "pmid": "22982445", "text": "Moreover, LTD4-induced increases in CysLT(1)R and NF-κB p65 in the brain were also attenuated by pranlukast.", "type": "CHEMICAL", "entities": [ "pranlukast" ], "offsets": [ [ 86, 96 ] ] }, { "pmid": "22982445", "text": "These results suggest that LTD4 increases Aβ peptide burden via activation of CysLT(1)R, which further affects APP levels and activity of β- and γ-secretases via the NF-κB pathway.", "type": "CHEMICAL", "entities": [ "LTD4" ], "offsets": [ [ 15, 19 ] ] }, { "pmid": "22982445", "text": "Our findings identify CysLT(1)R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT(1)R in neuroinflammatory diseases such as AD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20566645", "text": "Predicting cardiomyopathic phenotypes by altering Ca2+ affinity of cardiac troponin C.\nCardiac diseases associated with mutations in troponin subunits include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM).", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 50, 54 ] ] }, { "pmid": "20566645", "text": "Altered calcium handling in these diseases is evidenced by changes in the Ca(2+) sensitivity of contraction.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 74, 80 ] ] }, { "pmid": "20566645", "text": "Mutations in the Ca(2+) sensor, troponin C (TnC), were generated to increase/decrease the Ca(2+) sensitivity of cardiac skinned fibers to create the characteristic effects of DCM, HCM, and RCM.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 17, 23 ], [ 90, 96 ] ] }, { "pmid": "20566645", "text": "We also used a reconstituted assay to determine the mutation effects on ATPase activation and inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20566645", "text": "One mutant (A23Q) was found with HCM-like properties (increased Ca(2+) sensitivity of force and normal levels of ATPase inhibition).", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 64, 70 ] ] }, { "pmid": "20566645", "text": "Three mutants (S37G, V44Q, and L48Q) were identified with RCM-like properties (a large increase in Ca(2+) sensitivity, partial loss of ATPase inhibition, and increased basal force).", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 99, 105 ] ] }, { "pmid": "20566645", "text": "Two mutations were identified (E40A and I61Q) with DCM properties (decreased Ca(2+) sensitivity, maximal force recovery, and activation of the ATPase at high [Ca(2+)]).", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 159, 165 ], [ 77, 83 ] ] }, { "pmid": "20566645", "text": "Steady-state fluorescence was utilized to assess Ca(2+) affinity in isolated cardiac (c)TnCs containing F27W and did not necessarily mirror the fiber Ca(2+) sensitivity.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 49, 55 ], [ 150, 156 ] ] }, { "pmid": "20566645", "text": "Circular dichroism of mutant cTnCs revealed a trend where increased alpha-helical content correlated with increased Ca(2+) sensitivity in skinned fibers and vice versa.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 116, 122 ] ] }, { "pmid": "20566645", "text": "The main findings from this study were as follows: 1) cTnC mutants demonstrated distinct functional phenotypes reminiscent of bona fide HCM, RCM, and DCM mutations; 2) a region in cTnC associated with increased Ca(2+) sensitivity in skinned fibers was identified; and 3) the F27W reporter mutation affected Ca(2+) sensitivity, maximal force, and ATPase activation of some mutants.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 211, 217 ], [ 307, 313 ] ] }, { "pmid": "23033256", "text": "DNA methylation and histone modification profiles of mouse organic anion transporting polypeptides.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transportation of a wide range of endogenous and exogenous compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "Multiple mouse Oatp1 isoforms are closely located on chromosome 6, where each isoform shows distinct tissue distribution; Oatp1b2, Oatp1a6, and Oatp1c1 are expressed exclusively in the liver, kidney, and cerebrum, respectively; Oatp1a1 in the liver and kidney; and Oatp1a4 in the liver and cerebrum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "We have identified tissue-dependent differentially methylated region (T-DMR) around the transcriptional start site (TSS) of Oatp1b2, which correlates with its liver-specific expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "Bisulfite sequencing also demonstrated the presence of T-DMRs around the TSS in other Oatp1 genes: CpG dinucleotides at +149 relative to the TSS for Oatp1c1; -48, +101, and +356 for Oatp1a4; -572 and -550 for Oatp1a1; and -122 and +216 for Oatp1a6 were differentially methylated among the liver, kidney, and cerebrum.", "type": "CHEMICAL", "entities": [ "Bisulfite" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23033256", "text": "These methylation profiles were largely consistent with the tissue distribution of Oatp1 mRNAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "Chromatin immunoprecipitation assay revealed that the mRNA expression of Oatp1 genes was accompanied by acetylated histone H3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "Human OATP1B1 and OATP1B3 are located on chromosome 12p12 in the OATP1 cluster; both show predominant expression in the liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "These genes also contained T-DMRs that were hypomethylated in the liver, compared with kidney cortex: -511, -411, and +92 relative to the TSS for OATP1B1 and -331, +70, and +73 for OATP1B3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23033256", "text": "These results suggest that the difference in epigenetic profiles comprising DNA methylation and histone acetylation determines the distinct tissue distribution of Oatp/OATP mRNAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12387707", "text": "Escitalopram.\n", "type": "CHEMICAL", "entities": [ "Escitalopram" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "12387707", "text": "Escitalopram oxalate (S-citalopram, Lexapro), a selective serotonin re-uptake inhibitor antidepressant which is the S-enantiomer of citalopram, is in clinical development worldwide for the treatment of depression and anxiety disorders.", "type": "CHEMICAL", "entities": [ "Escitalopram oxalate", "S-enantiomer of citalopram", "S-citalopram", "Lexapro", "serotonin" ], "offsets": [ [ 0, 20 ], [ 116, 142 ], [ 22, 34 ], [ 36, 43 ], [ 58, 67 ] ] }, { "pmid": "12387707", "text": "Preclinical studies demonstrate that the therapeutic activity of citalopram resides in the S-isomer and that escitalopram binds with high affinity to the human serotonin transporter.", "type": "CHEMICAL", "entities": [ "citalopram", "escitalopram", "serotonin" ], "offsets": [ [ 65, 75 ], [ 109, 121 ], [ 160, 169 ] ] }, { "pmid": "12387707", "text": "Conversely, R-citalopram is approximately 30-fold less potent than escitalopram at this transporter.", "type": "CHEMICAL", "entities": [ "R-citalopram", "escitalopram" ], "offsets": [ [ 12, 24 ], [ 67, 79 ] ] }, { "pmid": "12387707", "text": "Escitalopram has linear pharmacokinetics, so that plasma levels increase proportionately and predictably with increased doses and its half-life of 27 - 32 h is consistent with once-daily dosing.", "type": "CHEMICAL", "entities": [ "Escitalopram" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "12387707", "text": "In addition, escitalopram has negligible effects on cytochrome P450 drug-metabolising enzymes in vitro, suggesting a low potential for drug-drug interactions.", "type": "CHEMICAL", "entities": [ "escitalopram" ], "offsets": [ [ 13, 25 ] ] }, { "pmid": "12387707", "text": "The efficacy of escitalopram in patients with major depressive disorder has been demonstrated in multiple short-term, placebo-controlled clinical trials, three of which included citalopram as an active control, as well as in a 36-week study evaluating efficacy in the prevention of depression relapse.", "type": "CHEMICAL", "entities": [ "citalopram", "escitalopram" ], "offsets": [ [ 178, 188 ], [ 16, 28 ] ] }, { "pmid": "12387707", "text": "In these studies, escitalopram was shown to have robust efficacy in the treatment of depression and associated symptoms of anxiety relative to placebo.", "type": "CHEMICAL", "entities": [ "escitalopram" ], "offsets": [ [ 18, 30 ] ] }, { "pmid": "12387707", "text": "Efficacy has also been shown in treating generalised anxiety disorder, panic disorder and social anxiety disorder.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12387707", "text": "Results also suggest that, at comparable doses, escitalopram demonstrates clinically relevant and statistically significant superiority to placebo treatment earlier than citalopram.", "type": "CHEMICAL", "entities": [ "escitalopram", "citalopram" ], "offsets": [ [ 48, 60 ], [ 170, 180 ] ] }, { "pmid": "12387707", "text": "Analysis of the safety database shows a low rate of discontinuation due to adverse events, and there was no statistically significant difference between escitalopram 10 mg/day and placebo in the proportion of patients who discontinued treatment early because of adverse events.", "type": "CHEMICAL", "entities": [ "escitalopram" ], "offsets": [ [ 153, 165 ] ] }, { "pmid": "12387707", "text": "The most common adverse events associated with escitalopram which occurred at a rate greater than placebo include nausea, insomnia, ejaculation disorder, diarrhoea, dry mouth and somnolence.", "type": "CHEMICAL", "entities": [ "escitalopram" ], "offsets": [ [ 47, 59 ] ] }, { "pmid": "12387707", "text": "Only nausea occurred in > 10% of escitalopram-treated patients.", "type": "CHEMICAL", "entities": [ "escitalopram" ], "offsets": [ [ 33, 45 ] ] }, { "pmid": "18381445", "text": "Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.\n", "type": "CHEMICAL", "entities": [ "Statins" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "18381445", "text": "Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia.", "type": "CHEMICAL", "entities": [ "Statins", "3-hydroxy-3-methylglutaryl-CoA" ], "offsets": [ [ 0, 7 ], [ 12, 42 ] ] }, { "pmid": "18381445", "text": "Recently, they are reported to have beneficial effects on certain cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18381445", "text": "In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18381445", "text": "Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2.", "type": "CHEMICAL", "entities": [ "carboxylic acid" ], "offsets": [ [ 60, 75 ] ] }, { "pmid": "18381445", "text": "In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a K(i) value of 31.6 micromol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays.", "type": "CHEMICAL", "entities": [ "lovastatin" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "18381445", "text": "DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18381445", "text": "In vitro cell proliferation and in vivo tumor growth were both inhibited by statins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18381445", "text": "These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18381445", "text": "Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17049513", "text": "Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity.\n", "type": "CHEMICAL", "entities": [ "Imatinib mesylate", "Gleevec" ], "offsets": [ [ 0, 17 ], [ 19, 26 ] ] }, { "pmid": "17049513", "text": "Recent studies have reported that imatinib mesylate, a kinase inhibitor that targets the intracellular tyrosine kinase BCR-ABL and the platelet derived growth factor (PDGF) receptor, is an effective inhibitor of the macrophage colony stimulating factor (M-CSF) receptor, c-FMS.", "type": "CHEMICAL", "entities": [ "tyrosine", "imatinib mesylate" ], "offsets": [ [ 103, 111 ], [ 34, 51 ] ] }, { "pmid": "17049513", "text": "Given that M-CSF signalling through c-FMS plays an important role in osteoclast biology, we speculated that blocking such a pathway with imatinib may modulate osteoclast activity.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 137, 145 ] ] }, { "pmid": "17049513", "text": "Using a cell model of mature rabbit osteoclasts, we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 84, 92 ] ] }, { "pmid": "17049513", "text": "Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis, a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fmk.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "17049513", "text": "The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "17049513", "text": "Imatinib was also found to inhibit M-CSF-induced osteoclast survival as well as M-CSF-induced osteoclast bone resorbing activity, but was without effect on interleukin 1alpha (IL-1alpha) and receptor activator of nuclear factor kappa B ligand (RANKL)-induced inhibition of osteoclasts apoptosis, further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c-FMS.", "type": "CHEMICAL", "entities": [ "imatinib", "Imatinib" ], "offsets": [ [ 335, 343 ], [ 0, 8 ] ] }, { "pmid": "17049513", "text": "Taken together, these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive M-CSF production such as osteoporosis, inflammatory-and tumor-induced osteolysis.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 43, 51 ] ] }, { "pmid": "10493852", "text": "Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain.\n", "type": "CHEMICAL", "entities": [ "lovastatin" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "10493852", "text": "The lymphocyte function-associated antigen (LFA-1) belongs to the family of beta2-integrins and plays an important role in T-cell activation and leukocyte migration to sites of inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10493852", "text": "We report here that lovastatin, a drug clinically used for lowering cholesterol levels, inhibits the interaction of human LFA-1 with its counter-receptor intercellular adhesion molecule-1.", "type": "CHEMICAL", "entities": [ "lovastatin", "cholesterol" ], "offsets": [ [ 20, 30 ], [ 68, 79 ] ] }, { "pmid": "10493852", "text": "Using nuclear magnetic resonance spectroscopy and X-ray crystallography we show that the inhibitor binds to a highly conserved domain of the LFA-1 alpha-chain called the I-domain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10493852", "text": "The first three-dimensional structure of an integrin inhibitor bound to its receptor reveals atomic details for a hitherto unknown mode of LFA-1 inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10493852", "text": "It also sheds light into possible mechanisms of LFA-1 mediated signalling and will support the design of novel anti-adhesive and immunosuppressive drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate hypertension-induced cardiovascular alterations.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23316965", "text": "Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed.", "type": "CHEMICAL", "entities": [ "doxycycline" ], "offsets": [ [ 29, 40 ] ] }, { "pmid": "23339625", "text": "Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats.\n", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 105, 118 ] ] }, { "pmid": "23339625", "text": "Abstract 1. We investigated the effects of the dose of and the number of times an inducer was administered and the duration of induction of hepatic and intestinal cytochrome P450 3A (CYP3A) in rats using dexamethasone 21-phosphate (DEX-P) and midazolam (MDZ) as an inducer and a substrate to CYP3A, respectively.", "type": "CHEMICAL", "entities": [ "dexamethasone 21-phosphate", "DEX-P", "midazolam", "MDZ" ], "offsets": [ [ 204, 230 ], [ 232, 237 ], [ 243, 252 ], [ 254, 257 ] ] }, { "pmid": "23339625", "text": "2. The number of times DEX-P was administered was not a significant factor in the induction of either hepatic or intestinal CYP3A; however, administration of DEX-P multiple times markedly decreased the bioavailability of DEX-P by self-induction of CYP3A.", "type": "CHEMICAL", "entities": [ "DEX-P", "DEX-P", "DEX-P" ], "offsets": [ [ 21, 26 ], [ 156, 161 ], [ 219, 224 ] ] }, { "pmid": "23339625", "text": "3. CYP3A induction in the liver increased depending on the dose of DEX-P, whereas that in intestine showed a mild increase, but the induction level was almost constant regardless of the dose of DEX-P. 4. Administration of a single dose of DEX-P showed a temporal increase in CYP3A activity in both tissues and the induction ratios reached maximum values at 12 h after DEX-P administration.", "type": "CHEMICAL", "entities": [ "DEX-P", "DEX-P", "DEX-P", "DEX-P" ], "offsets": [ [ 63, 68 ], [ 190, 195 ], [ 235, 240 ], [ 364, 369 ] ] }, { "pmid": "23339625", "text": "On the other hand, a mild increase of CYP3A activity, which lasted for at least 48 h, was observed in both tissues after administration of multiple doses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23339625", "text": "5. Some physiological compounds such as cytokines might be involved in decreasing the CYP3A activity to maintain homeostasis of the body.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20226815", "text": "Autoradiographic study of serotonin transporter during memory formation.\n", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "20226815", "text": "Serotonin transporter (SERT) has been associated with drugs of abuse like d-methamphetamine (METH).", "type": "CHEMICAL", "entities": [ "Serotonin", "d-methamphetamine", "METH" ], "offsets": [ [ 0, 9 ], [ 74, 91 ], [ 93, 97 ] ] }, { "pmid": "20226815", "text": "METH is well known to produce effects on the monoamine systems but it is unclear how METH affects SERT and memory.", "type": "CHEMICAL", "entities": [ "METH", "monoamine", "METH" ], "offsets": [ [ 0, 4 ], [ 45, 54 ], [ 85, 89 ] ] }, { "pmid": "20226815", "text": "Here the effects of METH and the serotonin reuptake inhibitor fluoxetine (FLX) on autoshaping and novel object recognition (NOR) were investigated.", "type": "CHEMICAL", "entities": [ "METH", "serotonin", "fluoxetine", "FLX" ], "offsets": [ [ 20, 24 ], [ 33, 42 ], [ 62, 72 ], [ 74, 77 ] ] }, { "pmid": "20226815", "text": "Notably, both memory tasks recruit different behavioral, neural and cognitive demand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20226815", "text": "In autoshaping task a dose-response curve for METH was determined.", "type": "CHEMICAL", "entities": [ "METH" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "20226815", "text": "METH (1.0mg/kg) impaired short-term memory (STM; lasting less of 90min) in NOR and impaired both STM and long-term memory (LTM; lasting 24 and 48h) in autoshaping, indicating that METH had long-lasting effects in the latter task.", "type": "CHEMICAL", "entities": [ "METH", "METH" ], "offsets": [ [ 0, 4 ], [ 180, 184 ] ] }, { "pmid": "20226815", "text": "A comparative autoradiography study of the relationship between the binding pattern of SERT in autoshaping new untrained vs. trained treated (METH, FLX, or both) animals was made.", "type": "CHEMICAL", "entities": [ "METH", "FLX" ], "offsets": [ [ 142, 146 ], [ 148, 151 ] ] }, { "pmid": "20226815", "text": "Considering that hemispheric dominance is important for LTM, hence right vs. left hemisphere of the brain was compared.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20226815", "text": "Results showed that trained animals decreased cortical SERT binding relative to untrained ones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20226815", "text": "In untrained and trained treated animals with the amnesic dose (1.0mg/kg) of METH SERT binding in several areas including hippocampus and cortex decreased, more remarkably in the trained animals.", "type": "CHEMICAL", "entities": [ "METH" ], "offsets": [ [ 77, 81 ] ] }, { "pmid": "20226815", "text": "In contrast, FLX improved memory, increased SERT binding, prevented the METH amnesic effect and re-established the SERT binding.", "type": "CHEMICAL", "entities": [ "METH" ], "offsets": [ [ 72, 76 ] ] }, { "pmid": "20226815", "text": "In general, memory and amnesia seemed to make SERT more vulnerable to drugs effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "Hypoxia and lactate production in trophoblast cells.\n", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 12, 19 ] ] }, { "pmid": "17275903", "text": "The etiology of preeclampsia is unknown but is thought to be related to hypoxia in the placenta.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "We previously reported that the enzyme lactate dehydrogenase (LDH) has increased activity and gene expression in placentas from preeclamptic pregnancies [Tsoi SCM, Zheng J, Xu F, Kay HH.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 39, 46 ] ] }, { "pmid": "17275903", "text": "Differential expression of lactate dehydrogenase isozymes (LDH) in human placenta with high expression of LDH-A(4) isozyme in the endothelial cells of pre-eclampsia villi.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 27, 34 ] ] }, { "pmid": "17275903", "text": "Placenta 2001;22:317-22].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "LDH is responsible for pyruvate conversion to lactate through glycolysis.", "type": "CHEMICAL", "entities": [ "pyruvate", "lactate" ], "offsets": [ [ 23, 31 ], [ 46, 53 ] ] }, { "pmid": "17275903", "text": "In this study, we further investigated the role of hypoxia in primary trophoblast cells and a cultured cell line, JEG3 cells, to obtain a better understanding of how it affects the activities of lactate dehydrogenase, lactate production and regulatory genes, as a possible model for preeclampsia.", "type": "CHEMICAL", "entities": [ "lactate", "lactate" ], "offsets": [ [ 195, 202 ], [ 218, 225 ] ] }, { "pmid": "17275903", "text": "Primary trophoblast cells and JEG3 cells were cultured under 1% oxygen.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 64, 70 ] ] }, { "pmid": "17275903", "text": "At 6, 12 and 24h, cells were analyzed for LDHA and LDHB isozyme activities, mRNA and protein expression compared to standard culture conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "Lactate was measured from cell medium.", "type": "CHEMICAL", "entities": [ "Lactate" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "17275903", "text": "The hypoxia inducible transcription factor (HIF-1alpha) protein expression was confirmed by western blot.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "Two lactate transporters (MCT1 and MCT4) mRNA and protein expression were also studied under hypoxia.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 4, 11 ] ] }, { "pmid": "17275903", "text": "Finally, lactate was measured in plasma obtained from patients with severe preeclampsia.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 9, 16 ] ] }, { "pmid": "17275903", "text": "Under hypoxic conditions, LDHA mRNA is increased in primary trophoblast cells and JEG3 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "The HIF-1alpha protein expression is higher in hypoxia-treated JEG3 cells than control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "LDHA isozyme activity and its protein expression are increased most significantly at 24h of culture under hypoxia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "However, LDHB protein is unchanged while its mRNA is decreased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "Lactate secretion from JEG3 cells under hypoxia is increased, as is the lactate levels in the plasma from preeclampsia patients.", "type": "CHEMICAL", "entities": [ "Lactate", "lactate" ], "offsets": [ [ 0, 7 ], [ 72, 79 ] ] }, { "pmid": "17275903", "text": "Of the two lactate transporters studied, MCT4 mRNA and protein level are increased under hypoxia.", "type": "CHEMICAL", "entities": [ "lactate" ], "offsets": [ [ 11, 18 ] ] }, { "pmid": "17275903", "text": "Our findings support the role of hypoxia in inducing HIF-1alpha activity in trophoblasts and increasing LDH transcription as well as its activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17275903", "text": "Higher levels of lactate are produced and secreted which may contribute to the higher lactate levels in plasma of preeclamptic patients.", "type": "CHEMICAL", "entities": [ "lactate", "lactate" ], "offsets": [ [ 17, 24 ], [ 86, 93 ] ] }, { "pmid": "17275903", "text": "These mechanisms may be important in the pathophysiology of preeclampsia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL.\n", "type": "CHEMICAL", "entities": [ "dasatinib", "BMS-354825" ], "offsets": [ [ 56, 65 ], [ 67, 77 ] ] }, { "pmid": "17429625", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Dasatinib (BMS-354825), a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL, has recently been approved for the treatment of chronic myelogenous leukaemia (CML) in imatinib-acquired resistance and intolerance.", "type": "CHEMICAL", "entities": [ "imatinib", "BMS-354825", "Dasatinib" ], "offsets": [ [ 182, 190 ], [ 11, 21 ], [ 0, 9 ] ] }, { "pmid": "17429625", "text": "In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism of dasatinib in mouse, rat, dog, and monkey.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 99, 108 ] ] }, { "pmid": "17429625", "text": "Possible mechanisms contributing to the incomplete oral bioavailability of dasatinib in animals were investigated.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 75, 84 ] ] }, { "pmid": "17429625", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Metabolic stability of dasatinib was measured after incubation with liver microsomes (either NADPH- or UDPGA-fortified) and isolated hepatocytes obtained from mouse, rat, dog, monkey, and human.", "type": "CHEMICAL", "entities": [ "dasatinib", "NADPH", "UDPGA" ], "offsets": [ [ 23, 32 ], [ 93, 98 ], [ 103, 108 ] ] }, { "pmid": "17429625", "text": "In all cases, substrate depletion over time was measured, and appropriate scaling factors were used to predict in vivo clearance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Pharmacokinetics of dasatinib were determined in mice, rats, dogs, and monkeys after administration of single intravenous or oral doses.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "17429625", "text": "In addition, the routes of excretion were investigated after administration of dasatinib to bile duct cannulated (BDC) rats.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 79, 88 ] ] }, { "pmid": "17429625", "text": "Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability using various in vitro and in vivo models like Caco-2 cells, P-glycoprotein (P-gp) knockout mice, and intra-portal dosing in rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "In vivo systemic plasma clearance values of dasatinib were 62, 26, 25, and 34 ml/min/kg in mouse, rat, dog, and monkey, respectively.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 44, 53 ] ] }, { "pmid": "17429625", "text": "Scaling of in vitro hepatocyte and liver microsomal data gave reasonably good predictions of in vivo clearances across all species.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Percent distribution in blood cells ranged from 43% in mouse to 57% in dog.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Dasatinib showed high volumes of distribution (>3 l/kg) and high serum protein binding values (>90%) in all four species tested.", "type": "CHEMICAL", "entities": [ "Dasatinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17429625", "text": "Oral bioavailability of dasatinib ranged from 14% in the mouse to 34% in the dog.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "17429625", "text": "In rats, bioavailability after an intraportal dose was comparable to that after intra-arterial administration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "In BDC rats, less than 15% of an intravenous dose was excreted unchanged in urine, bile, and the gastrointestinal tract, suggesting that dasatinib is cleared primarily via metabolism.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 137, 146 ] ] }, { "pmid": "17429625", "text": "Dasatinib has high intrinsic permeability in Caco-2 cells, however, the efflux ratio was approximately two-fold indicating that it may be a substrate for an intestinal efflux transporter.", "type": "CHEMICAL", "entities": [ "Dasatinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17429625", "text": "However, in vivo studies in P-gp knockout mice versus wild-type mice showed no difference in the amount of dasatinib remaining unabsorbed in the gastrointestinal tract, suggesting that P-gp may not be responsible for the incomplete bioavailability.", "type": "CHEMICAL", "entities": [ "dasatinib" ], "offsets": [ [ 107, 116 ] ] }, { "pmid": "17429625", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "Dasatinib shows intermediate clearance in mouse, rat, dog, and monkey, and distributes extensively in those species.", "type": "CHEMICAL", "entities": [ "Dasatinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17429625", "text": "Oxidative metabolism appears to be the predominant clearance pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "The incomplete oral bioavailability may be due to both incomplete absorption and high first-pass metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17429625", "text": "However, the efflux transporter, P-glycoprotein does not appear to be limiting oral absorption.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "Genetic linkage of Fc gamma RIIa and Fc gamma RIIIa and implications for their use in predicting clinical responses to CD20-directed monoclonal antibody therapy.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "BACKGROUND: Polymorphisms in FcgammaRIIa and FcgammaRIIIa receptors are associated with responses to the CD20-directed immunoglobulin G1 (IgG1) monoclonal antibody rituximab among patients with indolent lymphoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "At odds with the aforementioned clinical observations has been the finding that IgG1 binding is impacted by polymorphisms in FcgammaRIIIa but not FcgammaRIIa.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "One possibility for this discrepancy might involve linkage of polymorphisms between FcgammaRIIa and FcgammaRIIIa.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "MATERIALS AND METHODS: As such, we performed allelespecific polymerase chain reaction and directed sequencing of the genomic DNA coding region of FcgammaRIIA and FcgammaRIIIA for 52 healthy individuals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "Two common polymorphisms were observed for FcgammaRIIA (at positions 27 and 131) and FcgammaRIIIA (at positions 48 and 158).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "Importantly, we observed linkage among polymorphisms within and between FcgammaRIIa and FcgammaRIIIa, including the expression of histidine at FcgammaRIIa-131 and valine at FcgammaRIIIa, both of which are associated with enhanced responses to rituximab.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "The results of these studies demonstrate that there is wide linkage within and between polymorphisms in FcgammaRIIa and FcgammaRIIIa and might provide an explanation for why polymorphisms at FcgammaRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17324336", "text": "Knowledge of such linkages could facilitate the development of diagnostic tests aimed at identifying patients who might be more suitable for treatment with rituximab and possibly other therapeutic antibodies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7582530", "text": "Characterization of an alpha 1D-adrenoceptor mediating the contractile response of rat aorta to noradrenaline.\n", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 96, 109 ] ] }, { "pmid": "7582530", "text": "1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7582530", "text": "The affinities of a number of alpha 1-adrenoceptor antagonists were determined by displacement of [3H]-prazosin binding from cloned human alpha 1A-adrenoceptors (previously designated cloned alpha 1c subtype), alpha 1B alpha 1D and rat alpha 1D-adrenoceptors, stably expressed in rat-1 fibroblasts.", "type": "CHEMICAL", "entities": [ "[3H]-prazosin" ], "offsets": [ [ 98, 111 ] ] }, { "pmid": "7582530", "text": "Functional affinity estimates for these compounds were also determined from noradrenaline-mediated contractions of rat aorta.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 76, 89 ] ] }, { "pmid": "7582530", "text": "2. BMY 7378 displayed high affinity for cloned human alpha 1D-adrenoceptors (pKi = 8.2 +/- 0.10) and was selective over alpha 1A (pKi = 6.2 +/- 0.10) and alpha 1B subtypes (6.7 +/- 0.11).", "type": "CHEMICAL", "entities": [ "BMY 7378" ], "offsets": [ [ 3, 11 ] ] }, { "pmid": "7582530", "text": "WB 4101, benoxathian and phentolamine displayed high affinity for alpha 1A and alpha 1D adrenoceptors compared to the alpha 1B subtype.", "type": "CHEMICAL", "entities": [ "benoxathian", "phentolamine" ], "offsets": [ [ 9, 20 ], [ 25, 37 ] ] }, { "pmid": "7582530", "text": "Spiperone displayed high affinity and selectivity for alpha 1B adrenoceptors (pKi 8.8 +/- 0.16).", "type": "CHEMICAL", "entities": [ "Spiperone" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "7582530", "text": "5-Methyl-urapidil was selective for cloned alpha 1A adrenoceptors.", "type": "CHEMICAL", "entities": [ "5-Methyl-urapidil" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "7582530", "text": "3. Comparative binding affinities (pKi) for compounds at cloned human and rat1D adrenoceptors were almost identical (r = 0.99, slope = 1.08).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7582530", "text": "4. Prazosin, doxazosin and 5-methyl-urapidil were potent, competitive antagonists of noradrenaline-mediated contractions of rat aorta (pA2 values of 9.8, 8.8 and 7.8 respectively).", "type": "CHEMICAL", "entities": [ "Prazosin", "doxazosin", "5-methyl-urapidil", "noradrenaline" ], "offsets": [ [ 3, 11 ], [ 13, 22 ], [ 27, 44 ], [ 85, 98 ] ] }, { "pmid": "7582530", "text": "The selective alpha 1D antagonist BMY 7378 was also a potent antagonist on rat aorta (pKB = 8.3 +/- 0.1) but the interaction of this compound was not consistent with competitive antagonism at a single population of receptors.", "type": "CHEMICAL", "entities": [ "BMY 7378" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "7582530", "text": "5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7582530", "text": "Functional affinities for compounds determined against noradrenaline-mediated contractions of rat aorta correlated well with binding affinities at cloned alpha 1D-adrenoceptors (r = 0.96), but not with alpha 1A (r = 0.61) or alpha 1B (r = 0.46) subtypes.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 55, 68 ] ] }, { "pmid": "7582530", "text": "6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7582530", "text": "Noradrenaline-mediated contractions of rat aorta were sensitive to the alkylating effects of chlorethylclonidine (CEC).", "type": "CHEMICAL", "entities": [ "Noradrenaline", "chlorethylclonidine", "CEC" ], "offsets": [ [ 0, 13 ], [ 93, 112 ], [ 114, 117 ] ] }, { "pmid": "7582530", "text": "CEC (10 microM) caused a small rightward shift in the noradrenaline concentration-response curve.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 54, 67 ] ] }, { "pmid": "7582530", "text": "CEC at 100 microM caused a further shift and suppression of the maximum response to noradrenaline.7.", "type": "CHEMICAL", "entities": [ "CEC", "noradrenaline" ], "offsets": [ [ 0, 3 ], [ 84, 97 ] ] }, { "pmid": "7582530", "text": "The results of this study suggest that noradrenaline predominantly, but not exclusively, mediates contraction of rat aorta through the activation of an alphalD-adrenoceptor.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 39, 52 ] ] }, { "pmid": "23276150", "text": "Display of amino groups on substrate surfaces by simple dip-coating of methacrylate-based polymers and its application to DNA immobilization.\n", "type": "CHEMICAL", "entities": [ "amino", "methacrylate" ], "offsets": [ [ 11, 16 ], [ 71, 83 ] ] }, { "pmid": "23276150", "text": "The implementation of a reactive functional group onto a material surface is of great importance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23276150", "text": "Reactive functional groups (e.g., an amino group and a hydroxyl group) are usually hydrophilic, which makes it difficult to display them on a dry polymer surface.", "type": "CHEMICAL", "entities": [ "amino", "hydroxyl" ], "offsets": [ [ 37, 42 ], [ 55, 63 ] ] }, { "pmid": "23276150", "text": "We here propose a novel method for displaying amino groups on the surfaces of polymeric substrates through dip-coating of a methacrylate-based copolymer.", "type": "CHEMICAL", "entities": [ "amino", "methacrylate" ], "offsets": [ [ 46, 51 ], [ 124, 136 ] ] }, { "pmid": "23276150", "text": "We synthesized copolymers composed of methyl methacrylate and 2-aminoethyl methacrylate with different protecting groups or ion-complexes on their amino groups, then dip-coated the copolymers onto a poly(methyl methacrylate) (PMMA) substrate.", "type": "CHEMICAL", "entities": [ "methyl methacrylate", "2-aminoethyl methacrylate", "amino", "poly(methyl methacrylate)", "PMMA" ], "offsets": [ [ 38, 57 ], [ 62, 87 ], [ 147, 152 ], [ 199, 224 ], [ 226, 230 ] ] }, { "pmid": "23276150", "text": "Evaluation using a cleavable fluorescent compound, which was synthesized in the present study to quantify a small amount (pmol/cm(2)) of amino groups on a solid surface, revealed that the protection of amino groups affected their surface segregation in the copolymer coating.", "type": "CHEMICAL", "entities": [ "amino", "amino" ], "offsets": [ [ 137, 142 ], [ 202, 207 ] ] }, { "pmid": "23276150", "text": "p-Toluenesulfonate ion-complex and tert-butoxycarbonyl (Boc) protection of amino groups were found to effectively display amino groups on the surface (more than 70 pmol/cm(2)).", "type": "CHEMICAL", "entities": [ "amino", "amino", "p-Toluenesulfonate", "tert-butoxycarbonyl", "Boc" ], "offsets": [ [ 75, 80 ], [ 122, 127 ], [ 0, 18 ], [ 35, 54 ], [ 56, 59 ] ] }, { "pmid": "23276150", "text": "The density of amino groups displayed on a surface can be easily controlled by mixing the copolymer and PMMA before dip-coating.", "type": "CHEMICAL", "entities": [ "amino", "PMMA" ], "offsets": [ [ 15, 20 ], [ 104, 108 ] ] }, { "pmid": "23276150", "text": "Dip-coating of the copolymer with Boc protection on various polymeric substrates also successfully displayed amino groups on their surfaces.", "type": "CHEMICAL", "entities": [ "Boc", "amino" ], "offsets": [ [ 34, 37 ], [ 109, 114 ] ] }, { "pmid": "23276150", "text": "Finally, we demonstrated that the amino groups displayed can be utilized for the immobilization of a DNA oligonucleotide on a substrate surface.", "type": "CHEMICAL", "entities": [ "amino" ], "offsets": [ [ 34, 39 ] ] }, { "pmid": "23123646", "text": "Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia.\n", "type": "CHEMICAL", "entities": [ "ATP", "potassium" ], "offsets": [ [ 24, 27 ], [ 38, 47 ] ] }, { "pmid": "23123646", "text": "ATP-sensitive potassium (K(ATP))", "type": "CHEMICAL", "entities": [ "ATP", "potassium", "K", "ATP" ], "offsets": [ [ 0, 3 ], [ 14, 23 ], [ 25, 26 ], [ 27, 30 ] ] }, { "pmid": "23123646", "text": "channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123646", "text": "An increase in the ADP/ATP ratio opens K(ATP) channels, leading to membrane hyperpolarization.", "type": "CHEMICAL", "entities": [ "ADP", "ATP", "K", "ATP" ], "offsets": [ [ 19, 22 ], [ 23, 26 ], [ 39, 40 ], [ 41, 44 ] ] }, { "pmid": "23123646", "text": "K(ATP) channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 0, 1 ], [ 2, 5 ] ] }, { "pmid": "23123646", "text": "Brief hypoxia triggers membrane hyperpolarization in these central neurons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123646", "text": "In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K(ATP) channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 77, 78 ], [ 79, 82 ] ] }, { "pmid": "23123646", "text": "These findings provide the basis for a practical strategy whereby activation of endogenous K(ATP) channels reduces cellular damage resulting from cerebral ischemic stroke.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 91, 92 ], [ 93, 96 ] ] }, { "pmid": "23123646", "text": "K(ATP) channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 0, 1 ], [ 2, 5 ] ] }, { "pmid": "10693877", "text": "Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial.", "type": "CHEMICAL", "entities": [ "rofecoxib", "ibuprofen" ], "offsets": [ [ 28, 37 ], [ 70, 79 ] ] }, { "pmid": "10693877", "text": "The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group.\n", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "10693877", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "This randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design).", "type": "CHEMICAL", "entities": [ "ibuprofen", "rofecoxib" ], "offsets": [ [ 171, 180 ], [ 63, 72 ] ] }, { "pmid": "10693877", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "Seven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 83, 92 ] ] }, { "pmid": "10693877", "text": "Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "Ulcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively).", "type": "CHEMICAL", "entities": [ "rofecoxib", "ibuprofen" ], "offsets": [ [ 75, 84 ], [ 112, 121 ] ] }, { "pmid": "10693877", "text": "In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 65, 74 ] ] }, { "pmid": "10693877", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10693877", "text": "At 2-4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen.", "type": "CHEMICAL", "entities": [ "rofecoxib", "ibuprofen" ], "offsets": [ [ 49, 58 ], [ 112, 121 ] ] }, { "pmid": "10693877", "text": "Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Understanding potential health risks is a significant challenge due to large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phase I and II of the U.S. EPA's ToxCast™ project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical-assay pairs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Some of the most commonly affected assays were CYPs (CYP2C9, CYP2C19), transporters (mitochondrial TSPO, norepinephrine, dopaminergic), and GPCRs (aminergic).", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 103, 117 ] ] }, { "pmid": "23611293", "text": "Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous, but distinctly different patterns of activity whereas many of the pharma compounds showed promiscuous activity across GPCRs.", "type": "CHEMICAL", "entities": [ "dithiocarbamate" ], "offsets": [ [ 29, 44 ] ] }, { "pmid": "23611293", "text": "Literature analysis confirmed >50% of the activities for the most potent chemical-assay pairs (56), but also revealed 10 missed interactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "In many cases, novel findings for previously unreported chemical-target combinations clustered with known chemical-target interactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "Results from this large inventory of chemical-biological interactions can inform read-across methods as well as to link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23611293", "text": "This abstract does not necessarily reflect U.S. EPA policy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123250", "text": "A combination of [+] and [-]-Huperzine A improves protection against soman toxicity compared to [+]-Huperzine A in guinea pigs.\n", "type": "CHEMICAL", "entities": [ "[+] and [-]-Huperzine A", "[+]-Huperzine A" ], "offsets": [ [ 17, 40 ], [ 96, 111 ] ] }, { "pmid": "23123250", "text": "The neuropathologic mechanisms after exposure to lethal doses of nerve agent are complex and involve multiple biochemical pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123250", "text": "Effective treatment requires drugs that can simultaneously protect by reversible binding to the acetylcholinesterase (AChE) and blocking cascades of seizure related brain damage, inflammation, neuronal degeneration as well as promoting induction of neuroregeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123250", "text": "[-]-Huperzine A ([-]-Hup A), is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier.", "type": "CHEMICAL", "entities": [ "[-]-Huperzine A", "[-]-Hup A" ], "offsets": [ [ 0, 15 ], [ 17, 26 ] ] }, { "pmid": "23123250", "text": "It also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123250", "text": "Toxicities at higher doses restrict the neuroporotective ability of [-]-Hup A for treatment.", "type": "CHEMICAL", "entities": [ "[-]-Hup A" ], "offsets": [ [ 68, 77 ] ] }, { "pmid": "23123250", "text": "The synthetic stereoisomer, [+]-Hup A, is less toxic due to poor AChE inhibition and is suitable for both pre-/post-exposure treatments of nerve agent toxicity.", "type": "CHEMICAL", "entities": [ "[+]-Hup A" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "23123250", "text": "[+]-Hup A block the N-methyl-d-aspartate (NMDA)-induced seizure in rats, reduce excitatory amino acid induced neurotoxicity and also prevent soman induced toxicity with minimum performance decrement.", "type": "CHEMICAL", "entities": [ "N-methyl-d-aspartate", "NMDA", "amino acid", "[+]-Hup A" ], "offsets": [ [ 20, 40 ], [ 42, 46 ], [ 91, 101 ], [ 0, 9 ] ] }, { "pmid": "23123250", "text": "Unique combinations of two stereo-isomers of Hup A may provide an excellent pre/post-treatment drug for the nerve agent induced seizure/status epilepticus.", "type": "CHEMICAL", "entities": [ "Hup A" ], "offsets": [ [ 45, 50 ] ] }, { "pmid": "23123250", "text": "We investigated a combination of [+]-Hup A with a small dose of [-]-Hup A ([+] and [-]-Hup A) against soman toxicity.", "type": "CHEMICAL", "entities": [ "[+]-Hup A", "[-]-Hup A", "[+] and [-]-Hup A", "soman" ], "offsets": [ [ 33, 42 ], [ 64, 73 ], [ 75, 92 ], [ 102, 107 ] ] }, { "pmid": "23123250", "text": "Our data showed that pretreatment with a combination [+] and [-]-Hup A significantly increased the survival rate and reduced behavioral abnormalities after exposure to 1.2×LD50 soman compared to [+]-Hup A in guinea pigs.", "type": "CHEMICAL", "entities": [ "[+] and [-]-Hup A", "[+]-Hup A" ], "offsets": [ [ 53, 70 ], [ 195, 204 ] ] }, { "pmid": "23123250", "text": "In addition, [+] and [-]-Hup A pretreatment inhibited the development of high power of EEG better than [+]-Hup A pretreatment alone.", "type": "CHEMICAL", "entities": [ "[+] and [-]-Hup A", "[+]-Hup A" ], "offsets": [ [ 12, 29 ], [ 102, 111 ] ] }, { "pmid": "23123250", "text": "These data suggest that a combination of [+] and [-]-Hup A offers better protection than [+]-Hup A and serves as a potent medical countermeasure against lethal dose nerve agent toxicity in guinea pigs.", "type": "CHEMICAL", "entities": [ "[+] and [-]-Hup A", "[+]-Hup A" ], "offsets": [ [ 40, 57 ], [ 88, 97 ] ] }, { "pmid": "23564313", "text": "Vinblastine-induced apoptosis of melanoma cells is mediated by Ras homologous A protein (Rho A) via mitochondrial and non-mitochondrial-dependent mechanisms.\n", "type": "CHEMICAL", "entities": [ "Vinblastine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23564313", "text": "Despite the availability of melanoma treatment at the primary site, the recurrence of local melanoma can metastasize to any distant organ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23564313", "text": "Currently, the available therapies for the treatment of metastatic melanoma are of limited benefit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23564313", "text": "Thus, the functional analysis of conventional therapies may help to improve their efficiency in the treatment of metastatic melanoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23564313", "text": "In the present study, the exposure of melanoma cells to vinblastine was found to trigger apoptosis as evidenced by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis inducing factor, activation of caspase-9 and 3, and cleavage of Poly (ADP-ribose)-Polymerase.", "type": "CHEMICAL", "entities": [ "vinblastine", "Poly (ADP-ribose)" ], "offsets": [ [ 56, 67 ], [ 272, 289 ] ] }, { "pmid": "23564313", "text": "Also, vinblastine enhances the phosphorylation of Ras homologous protein A, the accumulation of reactive oxygen species, the release of intracellular Ca(2+), as well as the activation of apoptosis signal-regulating kinase 1, c-jun-N-terminal kinase, p38, inhibitor of kappaBα (IκBα) kinase, and inositol requiring enzyme 1α. In addition, vinblastine induces the DNA-binding activities of the transcription factor NF-κB, HSF1, AP-1, and ATF-2, together with the expression of HSP70 and Bax proteins.", "type": "CHEMICAL", "entities": [ "vinblastine", "vinblastine", "oxygen", "Ca(2+)", "N", "inositol" ], "offsets": [ [ 338, 349 ], [ 6, 17 ], [ 105, 111 ], [ 150, 156 ], [ 231, 232 ], [ 295, 303 ] ] }, { "pmid": "23564313", "text": "Moreover, inhibitory experiments addressed a central role for Rho A in the regulation of vinblastine-induced apoptosis of melanoma cells via mitochondrial and non-mitochondrial-dependent mechanisms.", "type": "CHEMICAL", "entities": [ "vinblastine" ], "offsets": [ [ 84, 95 ] ] }, { "pmid": "23564313", "text": "In conclusion, the present study addresses for the first time a central role for Rho A in the modulation of vinblastine-induced apoptosis of melanoma cells and thereby provides an insight into the molecular action of vinblastine in melanoma treatment.", "type": "CHEMICAL", "entities": [ "vinblastine", "vinblastine" ], "offsets": [ [ 103, 114 ], [ 212, 223 ] ] }, { "pmid": "10373451", "text": "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A).\n", "type": "CHEMICAL", "entities": [ "cAMP", "cGMP" ], "offsets": [ [ 85, 89 ], [ 94, 98 ] ] }, { "pmid": "10373451", "text": "cDNA encoding a novel phosphodiesterase (PDE) was isolated from a human fetal lung cDNA library and designated PDE10A. The deduced amino acid sequence contains 779 amino acids, including a putative cGMP binding sequence in the amino-terminal portion of the molecule and a catalytic domain that is 16-47% identical in amino acid sequence to those of other PDE families.", "type": "CHEMICAL", "entities": [ "amino acid", "amino acids", "cGMP", "amino", "amino acid" ], "offsets": [ [ 131, 141 ], [ 164, 175 ], [ 198, 202 ], [ 227, 232 ], [ 317, 327 ] ] }, { "pmid": "10373451", "text": "Recombinant PDE10A transfected and expressed in COS-7 cells hydrolyzed cAMP and cGMP with Km values of 0.26 and 7.2 microM, respectively, and Vmax with cGMP was almost twice that with cAMP.", "type": "CHEMICAL", "entities": [ "cAMP", "cGMP", "cGMP", "cAMP" ], "offsets": [ [ 71, 75 ], [ 80, 84 ], [ 152, 156 ], [ 184, 188 ] ] }, { "pmid": "10373451", "text": "Of the PDE inhibitors tested, dipyridamole was most effective, with IC50 values of 1.2 and 0.45 microM for inhibition of cAMP and cGMP hydrolysis, respectively.", "type": "CHEMICAL", "entities": [ "dipyridamole", "cAMP", "cGMP" ], "offsets": [ [ 30, 42 ], [ 121, 125 ], [ 130, 134 ] ] }, { "pmid": "10373451", "text": "cGMP inhibited hydrolysis of cAMP, and cAMP inhibited cGMP hydrolysis with IC50 values of 14 and 0.39 microM, respectively.", "type": "CHEMICAL", "entities": [ "cGMP", "cAMP", "cAMP", "cGMP" ], "offsets": [ [ 0, 4 ], [ 29, 33 ], [ 39, 43 ], [ 54, 58 ] ] }, { "pmid": "10373451", "text": "Thus, PDE10A exhibited properties of a cAMP PDE and a cAMP-inhibited cGMP PDE.", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP", "cGMP" ], "offsets": [ [ 39, 43 ], [ 54, 58 ], [ 69, 73 ] ] }, { "pmid": "10373451", "text": "PDE10A transcripts were particularly abundant in the putamen and caudate nucleus regions of brain and in thyroid and testis, and in much lower amounts in other tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10373451", "text": "The PDE10A gene was located on chromosome 6q26 by fluorescent in situ hybridization analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10373451", "text": "PDE10A represents a new member of the PDE superfamily, exhibiting unique kinetic properties and inhibitor sensitivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease.\n", "type": "CHEMICAL", "entities": [ "5-aza-2'-deoxycytidine" ], "offsets": [ [ 11, 33 ] ] }, { "pmid": "12907443", "text": "Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Silencing of the gamma-globin (HbF) gene is associated with DNA methylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "The cytosine analog 5-aza-2'-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase.", "type": "CHEMICAL", "entities": [ "cytosine", "5-aza-2'-deoxycytidine", "decitabine" ], "offsets": [ [ 4, 12 ], [ 20, 42 ], [ 44, 54 ] ] }, { "pmid": "12907443", "text": "We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity.", "type": "CHEMICAL", "entities": [ "decitabine" ], "offsets": [ [ 28, 38 ] ] }, { "pmid": "12907443", "text": "Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration.", "type": "CHEMICAL", "entities": [ "hydroxyurea", "decitabine" ], "offsets": [ [ 82, 93 ], [ 103, 113 ] ] }, { "pmid": "12907443", "text": "Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P <.0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P <.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "gamma-Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action.", "type": "CHEMICAL", "entities": [ "decitabine" ], "offsets": [ [ 20, 30 ] ] }, { "pmid": "12907443", "text": "Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12907443", "text": "Further studies in SSD and thalassemia are indicated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583257", "text": "Quinone compounds regulate the level of ROS production by the NADPH oxidase Nox4.\n", "type": "CHEMICAL", "entities": [ "Quinone", "NADPH" ], "offsets": [ [ 0, 7 ], [ 62, 67 ] ] }, { "pmid": "23583257", "text": "NADPH oxidase Nox4 is expressed in a wide range of tissues and plays a role in cellular signaling by providing reactive oxygen species (ROS) as intracellular messengers.", "type": "CHEMICAL", "entities": [ "NADPH", "oxygen" ], "offsets": [ [ 0, 5 ], [ 120, 126 ] ] }, { "pmid": "23583257", "text": "Nox4 oxidase activity is thought to be constitutive and regulated at the transcriptional level; however, we challenge this point of view and suggest that specific quinone derivatives could modulate this activity.", "type": "CHEMICAL", "entities": [ "quinone" ], "offsets": [ [ 163, 170 ] ] }, { "pmid": "23583257", "text": "In fact, we demonstrated a significant stimulation of Nox4 activity by 4 quinone derivatives (AA-861, tBuBHQ, tBuBQ, and duroquinone) observed in 3 different cellular models, HEK293E, T-REx™, and chondrocyte cell lines.", "type": "CHEMICAL", "entities": [ "quinone", "AA-861", "tBuBHQ", "tBuBQ", "duroquinone" ], "offsets": [ [ 73, 80 ], [ 94, 100 ], [ 102, 108 ], [ 110, 115 ], [ 121, 132 ] ] }, { "pmid": "23583257", "text": "Our results indicate that the effect is specific toward Nox4 versus Nox2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583257", "text": "Furthermore, we showed that NAD(P)H:quinone oxidoreductase (NQO1) may participate in this stimulation.", "type": "CHEMICAL", "entities": [ "NAD(P)H", "quinone" ], "offsets": [ [ 26, 33 ], [ 34, 41 ] ] }, { "pmid": "23583257", "text": "Interestingly, Nox4 activity is also stimulated by reducing agents that possibly act by reducing the disulfide bridge (Cys226, Cys270) located in the extracellular E-loop of Nox4.", "type": "CHEMICAL", "entities": [ "disulfide", "Cys", "Cys" ], "offsets": [ [ 99, 108 ], [ 117, 120 ], [ 125, 128 ] ] }, { "pmid": "23583257", "text": "Such model of Nox4 activity regulation could provide new insight into the understanding of the molecular mechanism of the electron transfer through the enzyme, i.e., its potential redox regulation, and could also define new therapeutic targets in diseases in which quinones and Nox4 are implicated.", "type": "CHEMICAL", "entities": [ "quinones" ], "offsets": [ [ 263, 271 ] ] }, { "pmid": "21475861", "text": "Does aspirin acetylate multiple cellular proteins?", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 5, 12 ] ] }, { "pmid": "21475861", "text": "(Review).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21475861", "text": "Aspirin is a salicylate drug that is extensively used for its anti-inflammatory, antipyretic, analgesic and anti-thrombotic effects.", "type": "CHEMICAL", "entities": [ "Aspirin", "salicylate" ], "offsets": [ [ 0, 7 ], [ 13, 23 ] ] }, { "pmid": "21475861", "text": "More recently, it has been shown to decrease the incidence of cancers of epithelial origin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21475861", "text": "In most cases, aspirin is relatively safe.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "21475861", "text": "However, it does cause a host of adverse effects and toxicities, including gastrointestinal bleeding, ulcerations, nephrotoxicity and hypersensitivity reactions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21475861", "text": "Although the inhibition of cyclooxygenases by aspirin, which leads to its anti-inflammatory/analgesic properties, has been well studied, the mechanisms involved in its chemopreventive effects as well as some of its adverse effects are as yet ill-defined.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "21475861", "text": "Studies over the past decades suggest that, besides cyclooxygenases, aspirin acetylates other cellular proteins.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 69, 76 ] ] }, { "pmid": "21475861", "text": "These studies used radiolabeled 3H or 14C aspirin, the only approach used to date for the detection of proteins acetylated by aspirin.", "type": "CHEMICAL", "entities": [ "3H", "14C", "aspirin", "aspirin" ], "offsets": [ [ 32, 34 ], [ 38, 41 ], [ 42, 49 ], [ 126, 133 ] ] }, { "pmid": "21475861", "text": "In a recent study using protein-specific anti-acetyl lysine antibodies and immunological methods, we demonstrated the ability of aspirin to acetylate the tumor suppressor protein p53.", "type": "CHEMICAL", "entities": [ "aspirin", "lysine" ], "offsets": [ [ 129, 136 ], [ 53, 59 ] ] }, { "pmid": "21475861", "text": "In this review, we present current research from the literature on the aspirin-induced acetylation of proteins.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 71, 78 ] ] }, { "pmid": "21475861", "text": "We also describe an immunological approach to detecting acetylated proteins in aspirin-treated cells, and demonstrate that multiple proteins are acetylated.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 79, 86 ] ] }, { "pmid": "21475861", "text": "Since post-translational modification of proteins, such as acetylation, may lead to the alteration of their function, it is possible that some of the hitherto unexplained beneficial or adverse effects of aspirin could occur as a result of these modifications.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 204, 211 ] ] }, { "pmid": "21475861", "text": "The identification of these novel acetylation targets of aspirin represents a new area for investigation.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "23344961", "text": "Topoisomerase IIβ deficiency enhances camptothecin-induced apoptosis.\n", "type": "CHEMICAL", "entities": [ "camptothecin" ], "offsets": [ [ 38, 50 ] ] }, { "pmid": "23344961", "text": "Camptothecin (CPT), a topoisomerase (Top) I-targeting drug that stabilizes Top1-DNA covalent adducts, can induce S-phase-specific cytotoxicity due to the arrest of progressing replication forks.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23344961", "text": "However, CPT-induced non-S-phase cytotoxicity is less well characterized.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 8, 11 ] ] }, { "pmid": "23344961", "text": "In this study, we have identified topoisomerase IIβ (Top2β) as a specific determinant for CPT sensitivity, but not for many other cytotoxic agents, in non-S-phase cells.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 89, 92 ] ] }, { "pmid": "23344961", "text": "First, quiescent mouse embryonic fibroblasts (MEFs) lacking Top2β were shown to be hypersensitive to CPT with prominent induction of apoptosis.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 98, 101 ] ] }, { "pmid": "23344961", "text": "Second, ICRF-187, a Top2 catalytic inhibitor known to deplete Top2β, specifically sensitized MEFs to CPT.", "type": "CHEMICAL", "entities": [ "ICRF-187", "CPT" ], "offsets": [ [ 4, 12 ], [ 97, 100 ] ] }, { "pmid": "23344961", "text": "To explore the molecular basis for CPT hypersensitivity in Top2β-deficient cells, we found that upon CPT exposure, the RNA polymerase II large subunit (RNAP LS) became progressively depleted, followed by recovery to nearly the original level in wild-type MEFs, whereas RNAP LS remained depleted without recovery in Top2β-deficient cells.", "type": "CHEMICAL", "entities": [ "CPT", "CPT" ], "offsets": [ [ 30, 33 ], [ 96, 99 ] ] }, { "pmid": "23344961", "text": "Concomitant with the reduction of the RNAP LS level, the p53 protein level was greatly induced.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344961", "text": "Interestingly, RNAP LS depletion has been well documented to lead to p53-dependent apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344961", "text": "Altogether, our findings support a model in which Top2β deficiency promotes CPT-induced apoptosis in quiescent non-S-phase cells, possibly due to RNAP LS depletion and p53 accumulation.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 69, 72 ] ] }, { "pmid": "2833901", "text": "Effects of felodipine (a dihydropyridine calcium channel blocker) and analogues on calmodulin-dependent enzymes.\n", "type": "CHEMICAL", "entities": [ "felodipine", "dihydropyridine", "calcium" ], "offsets": [ [ 11, 21 ], [ 25, 40 ], [ 41, 48 ] ] }, { "pmid": "2833901", "text": "We have examined the effects on the activities of three calmodulin-dependent enzymes (cAMP phosphodiesterase, caldesmon kinase and myosin light chain kinase) of the dihydropyridine Ca2+ channel blocker felodipine and three analogues (p-chloro, oxidized and t-butyl) exhibiting different pharmacological potencies.", "type": "CHEMICAL", "entities": [ "dihydropyridine", "Ca2+", "felodipine", "p-chloro", "t-butyl", "cAMP" ], "offsets": [ [ 165, 180 ], [ 181, 185 ], [ 202, 212 ], [ 234, 242 ], [ 257, 264 ], [ 86, 90 ] ] }, { "pmid": "2833901", "text": "The cAMP phosphodiesterase was inhibited completely by felodipine and the p-chloro analogue with IC50 values of 3.7 and 1.5 microM respectively.", "type": "CHEMICAL", "entities": [ "cAMP", "felodipine", "p-chloro" ], "offsets": [ [ 4, 8 ], [ 55, 65 ], [ 74, 82 ] ] }, { "pmid": "2833901", "text": "The oxidized and t-butyl analogues were relatively ineffective in inhibiting cAMP phosphodiesterase.", "type": "CHEMICAL", "entities": [ "t-butyl", "cAMP" ], "offsets": [ [ 17, 24 ], [ 77, 81 ] ] }, { "pmid": "2833901", "text": "Felodipine and the p-chloro analogue inhibited the basal (Ca2+/calmodulin-independent) activity of cAMP phosphodiesterase as well as the calmodulin-stimulated activity.", "type": "CHEMICAL", "entities": [ "Felodipine", "p-chloro", "Ca2+", "cAMP" ], "offsets": [ [ 0, 10 ], [ 19, 27 ], [ 58, 62 ], [ 99, 103 ] ] }, { "pmid": "2833901", "text": "Calmodulin was relatively ineffective in preventing inhibition of cAMP phosphodiesterase by felodipine and the p-chloro analogue.", "type": "CHEMICAL", "entities": [ "cAMP", "felodipine", "p-chloro" ], "offsets": [ [ 66, 70 ], [ 92, 102 ], [ 111, 119 ] ] }, { "pmid": "2833901", "text": "These observations suggest that felodipine may act directly on the phosphodiesterase as well as through calmodulin.", "type": "CHEMICAL", "entities": [ "felodipine" ], "offsets": [ [ 32, 42 ] ] }, { "pmid": "2833901", "text": "Felodipine and the p-chloro analogue inhibited Ca2+/calmodulin-dependent caldesmon kinase with similar potencies (IC50 = 17.4 microM), whereas the oxidized and t-butyl analogues caused no inhibition.", "type": "CHEMICAL", "entities": [ "Ca2+", "t-butyl", "Felodipine", "p-chloro" ], "offsets": [ [ 47, 51 ], [ 160, 167 ], [ 0, 10 ], [ 19, 27 ] ] }, { "pmid": "2833901", "text": "Similarly, felodipine and the p-chloro analogue inhibited myosin light chain kinase activity whether the isolated 20 kD light chain (IC50 = 12.6 microM) or intact myosin (IC50 = 11.0 microM) was used as substrate.", "type": "CHEMICAL", "entities": [ "felodipine", "p-chloro" ], "offsets": [ [ 11, 21 ], [ 30, 38 ] ] }, { "pmid": "2833901", "text": "Inhibition in each case was prevented by excess calmodulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2833901", "text": "The oxidized and t-butyl derivatives caused little or no inhibition.", "type": "CHEMICAL", "entities": [ "t-butyl" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "2833901", "text": "Finally, the effects of felodipine and the three analogues on two processes which are dependent on myosin phosphorylation were examined, namely the actin-activated Mg2+-ATPase activity of myosin and the assembly of myosin filaments.", "type": "CHEMICAL", "entities": [ "felodipine", "Mg2+" ], "offsets": [ [ 24, 34 ], [ 164, 168 ] ] }, { "pmid": "2833901", "text": "Felodipine and the p-chloro analogue inhibited the actin-activated Mg2+-ATPase activity of smooth muscle myosin (IC50 = 25.1 microM).", "type": "CHEMICAL", "entities": [ "Felodipine", "p-chloro", "Mg2+" ], "offsets": [ [ 0, 10 ], [ 19, 27 ], [ 67, 71 ] ] }, { "pmid": "2833901", "text": "The oxidized and t-butyl analogues exhibited no inhibition.", "type": "CHEMICAL", "entities": [ "t-butyl" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "2833901", "text": "Similarly, felodipine and the p-chloro analogue blocked myosin filament assembly induced by low concentrations of calmodulin, whereas the oxidized and t-butyl analogues did not.", "type": "CHEMICAL", "entities": [ "felodipine", "p-chloro", "t-butyl" ], "offsets": [ [ 11, 21 ], [ 30, 38 ], [ 151, 158 ] ] }, { "pmid": "2833901", "text": "Again, inhibition of the actin-activated myosin Mg2+-ATPase and myosin filament assembly by felodipine and the p-chloro analogue could be reversed by raising the calmodulin concentration.", "type": "CHEMICAL", "entities": [ "Mg2+", "felodipine", "p-chloro" ], "offsets": [ [ 48, 52 ], [ 92, 102 ], [ 111, 119 ] ] }, { "pmid": "2833901", "text": "These observations suggest that some of the pharmacological actions of felodipine on smooth muscle may involve inhibition of calmodulin-dependent enzymes which are functionally involved in the regulation of smooth muscle contraction.", "type": "CHEMICAL", "entities": [ "felodipine" ], "offsets": [ [ 71, 81 ] ] }, { "pmid": "23541637", "text": "Aldosterone-induced ENaC and basal Na(+)/K(+)-ATPase trafficking via protein kinase D1-phosphatidylinositol 4-kinaseIIIβ trans Golgi signalling in M1 cortical collecting duct cells.\n", "type": "CHEMICAL", "entities": [ "Aldosterone", "Na(+)", "K(+)", "phosphatidylinositol" ], "offsets": [ [ 0, 11 ], [ 35, 40 ], [ 41, 45 ], [ 87, 107 ] ] }, { "pmid": "23541637", "text": "Aldosterone regulates Na(+) transport in the distal nephron through multiple mechanisms that include the transcriptional control of epithelial sodium channel (ENaC) and Na(+)/K(+)-ATPase subunits.", "type": "CHEMICAL", "entities": [ "Na(+)", "K(+)", "Na(+)" ], "offsets": [ [ 168, 173 ], [ 174, 178 ], [ 21, 26 ] ] }, { "pmid": "23541637", "text": "Aldosterone also induces the rapid phosphorylation of Protein Kinase D1 (PKD1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541637", "text": "PKD isoforms regulate protein trafficking, by the control of vesicle fission from the trans Golgi network (TGN) through activation of phosphatidylinositol 4-kinaseIIIβ (PI4KIIIβ).", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 133, 153 ] ] }, { "pmid": "23541637", "text": "We report rapid ENaCγ translocation to the plasma membrane after 30min aldosterone treatment in polarized M1 cortical collecting duct cells, which was significantly impaired in PKD1 shRNA-mediated knockdown cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541637", "text": "In PKD1-deficient cells, the ouabain-sensitive current was significantly reduced and Na(+)/K(+)-ATPase α and β subunits showed aberrant localization.", "type": "CHEMICAL", "entities": [ "ouabain", "Na(+)", "K(+)" ], "offsets": [ [ 25, 32 ], [ 81, 86 ], [ 87, 91 ] ] }, { "pmid": "23541637", "text": "PKD1 and PI4KIIIβ localize to the TGN, and aldosterone induced an interaction between PKD1 and PI4KIIIβ following aldosterone treatment.", "type": "CHEMICAL", "entities": [ "aldosterone", "aldosterone" ], "offsets": [ [ 37, 48 ], [ 108, 119 ] ] }, { "pmid": "23541637", "text": "This study reveals a novel mechanism for rapid regulation of ENaC and the Na(+)/K(+)-ATPase, via directed trafficking through PKD1-PI4KIIIβ signalling at the level of the TGN.", "type": "CHEMICAL", "entities": [ "Na(+)", "K(+)" ], "offsets": [ [ 66, 71 ], [ 72, 76 ] ] }, { "pmid": "10727715", "text": "The role of 5-HT(1A) and 5-HT(1B/1D) receptors on the modulation of acute fluoxetine-induced changes in extracellular 5-HT: the mechanism of action of (+/-)pindolol.\n", "type": "CHEMICAL", "entities": [ "5-HT", "(+/-)pindolol", "fluoxetine" ], "offsets": [ [ 118, 122 ], [ 151, 164 ], [ 74, 84 ] ] }, { "pmid": "10727715", "text": "Some clinical evidence has suggested that (+/-)pindolol can be effective at producing a shortened time to onset of antidepressant activity when co-administered with a serotonin specific reuptake inhibitor (SSRI).", "type": "CHEMICAL", "entities": [ "serotonin", "(+/-)pindolol" ], "offsets": [ [ 167, 176 ], [ 42, 55 ] ] }, { "pmid": "10727715", "text": "This effect has been attributed to the antagonist effects of pindolol at the 5-HT(1A) receptor.", "type": "CHEMICAL", "entities": [ "pindolol" ], "offsets": [ [ 61, 69 ] ] }, { "pmid": "10727715", "text": "In the present study, we compared the pharmacology of (+/-)pindolol, WAY-100635 (a 5-HT(1A) antagonist), GR127935 (a 5-HT(1B/1D) antagonist), and isamoltane (a 5-HT(1B) antagonist), when given acutely in combination with fluoxetine, using in vivo microdialysis in the frontal cortex of the freely moving rat.", "type": "CHEMICAL", "entities": [ "(+/-)pindolol", "WAY-100635", "GR127935", "isamoltane", "fluoxetine" ], "offsets": [ [ 54, 67 ], [ 69, 79 ], [ 105, 113 ], [ 146, 156 ], [ 221, 231 ] ] }, { "pmid": "10727715", "text": "We have determined that the acute fluoxetine-induced increases in extracellular 5-HT can be augmented by (+/-)pindolol, WAY100635, GR127935 and isamoltane with maximum increases of 216+/-32%, 235+/-49%, 240+/-18% and 171+/-47% of preinjection control levels, respectively.", "type": "CHEMICAL", "entities": [ "fluoxetine", "5-HT", "(+/-)pindolol", "WAY100635", "GR127935", "isamoltane" ], "offsets": [ [ 34, 44 ], [ 80, 84 ], [ 105, 118 ], [ 120, 129 ], [ 131, 139 ], [ 144, 154 ] ] }, { "pmid": "10727715", "text": "Combination of both 5-HT(1A) and 5-HT(1B/1D) autoreceptor antagonists with fluoxetine produced additive increases in extracellular 5-HT (i.e. WAY100635+GR127935+fluoxetine and WAY100635+isamoltane+fluoxetine produced a four- and five-fold potentiation, respectively), suggesting that this strategy may be useful in further augmenting the action of a SSRI in the treatment of depression.", "type": "CHEMICAL", "entities": [ "5-HT", "WAY100635", "GR127935", "fluoxetine", "WAY100635", "isamoltane", "fluoxetine", "fluoxetine" ], "offsets": [ [ 131, 135 ], [ 142, 151 ], [ 152, 160 ], [ 161, 171 ], [ 176, 185 ], [ 186, 196 ], [ 197, 207 ], [ 75, 85 ] ] }, { "pmid": "10727715", "text": "In addition, by comparing the combined administration of (+/-)pindolol with either WAY100635, GR127935 or isamoltane, we have determined that (+/-)pindolol produces much of its acute potentiation of fluoxetine-induced increases in extracellular 5-HT via its action at the 5-HT(1B/D) receptor in addition to any activity it has at the presynaptic 5-HT(1A) receptor.", "type": "CHEMICAL", "entities": [ "(+/-)pindolol", "WAY100635", "GR127935", "isamoltane", "(+/-)pindolol", "fluoxetine", "5-HT" ], "offsets": [ [ 57, 70 ], [ 83, 92 ], [ 94, 102 ], [ 106, 116 ], [ 142, 155 ], [ 199, 209 ], [ 245, 249 ] ] }, { "pmid": "23353748", "text": "Design, synthesis and biological evaluation of novel hybrid compounds of imidazole scaffold-based 2-benzylbenzofuran as potent anticancer agents.\n", "type": "CHEMICAL", "entities": [ "imidazole", "2-benzylbenzofuran" ], "offsets": [ [ 73, 82 ], [ 98, 116 ] ] }, { "pmid": "23353748", "text": "A series of novel hybrid compounds between 2-benzylbenzofuran and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines.", "type": "CHEMICAL", "entities": [ "2-benzylbenzofuran", "imidazole" ], "offsets": [ [ 43, 61 ], [ 66, 75 ] ] }, { "pmid": "23353748", "text": "The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-methoxyphenacyl group were vital for modulating cytotoxic activity.", "type": "CHEMICAL", "entities": [ "benzimidazole", "imidazolyl", "naphthylacyl", "4-methoxyphenacyl" ], "offsets": [ [ 41, 54 ], [ 84, 94 ], [ 113, 125 ], [ 129, 146 ] ] }, { "pmid": "23353748", "text": "In particular, hybrid compounds 46 and 47 were found to be the most potent derivatives against 5 strains human tumor cell lines and more active than cisplatin (DDP), and exhibited cytotoxic activities selectively against breast carcinoma (MCF-7) and myeloid liver carcinoma (SMMC-7721), respectively.", "type": "CHEMICAL", "entities": [ "cisplatin", "DDP" ], "offsets": [ [ 148, 157 ], [ 159, 162 ] ] }, { "pmid": "23636303", "text": "Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain.\n", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin" ], "offsets": [ [ 15, 24 ], [ 92, 101 ] ] }, { "pmid": "23636303", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23636303", "text": "Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23636303", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23636303", "text": "This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 109, 118 ] ] }, { "pmid": "23636303", "text": "METHODS: Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23636303", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23636303", "text": "Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max = 141 ± 13 %) and simultaneously decreased NA in the PFC (Emax = -46 ± 7 %).", "type": "CHEMICAL", "entities": [ "citalopram", "noradrenaline" ], "offsets": [ [ 9, 19 ], [ 47, 60 ] ] }, { "pmid": "23636303", "text": "In the local presence into the LC of the α2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (Emax = 157 ± 25 %) and PFC (Emax = 175 ± 24 %).", "type": "CHEMICAL", "entities": [ "RS79948", "citalopram", "citalopram" ], "offsets": [ [ 47, 54 ], [ 72, 82 ], [ 161, 171 ] ] }, { "pmid": "23636303", "text": "Local citalopram (0.1-100 μM) into the LC induced NA increase in the LC (Emax = 210 ± 25 %) and decrease in the PFC (Emax = -38 ± 9 %).", "type": "CHEMICAL", "entities": [ "citalopram" ], "offsets": [ [ 101, 111 ] ] }, { "pmid": "23636303", "text": "Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 μM) but not the 5-HT1/2 receptor antagonist methiothepin (1 μM).", "type": "CHEMICAL", "entities": [ "MDL72222", "methiothepin", "citalopram", "MDL72222" ], "offsets": [ [ 23, 31 ], [ 79, 91 ], [ 109, 119 ], [ 142, 150 ] ] }, { "pmid": "23636303", "text": "Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax = 158 ± 26 %).", "type": "CHEMICAL", "entities": [ "citalopram" ], "offsets": [ [ 64, 74 ] ] }, { "pmid": "23636303", "text": "Local citalopram into the PFC enhanced NA (Emax = 376 ± 18 %) in the area, which was prevented by MDL72222.", "type": "CHEMICAL", "entities": [ "MDL72222", "citalopram" ], "offsets": [ [ 18, 26 ], [ 50, 60 ] ] }, { "pmid": "23636303", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23636303", "text": "The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "23636303", "text": "Therefore, 5-HT3 receptors and somatodendritic α2-adrenoceptors in the LC play an important role in the global effect of SSRIs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "Expressions and mechanical functions of alpha1-adrenoceptor subtypes in hamster ureter.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "We characterized the alpha(1)-adrenoceptor subtypes in hamster ureters according to gene and protein expressions and contractile function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "Real-time quantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis were performed to determine mRNA levels and receptor protein expressions respectively, for alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptors in hamster ureteral smooth muscle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "alpha(1)-Adrenoceptor antagonists were tested against the phenylephrine (alpha(1)-adrenoceptor agonist)-induced contraction in isolated hamster ureteral preparations using a functional experimental approach.", "type": "CHEMICAL", "entities": [ "phenylephrine" ], "offsets": [ [ 58, 71 ] ] }, { "pmid": "17658513", "text": "In the smooth muscle, relative mRNA expression levels for alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptors were 10.7%, 1.2% and 88.1%, respectively, and protein expressions were identified for alpha(1A)- and alpha(1D)-adrenoceptors immunohistochemically.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "Noradrenaline and phenylephrine (alpha(1)-adrenoceptor agonist) each produced a concentration-dependent tonic contraction, their pD(2) values being 6.87+/-0.08 and 6.10+/-0.05, respectively.", "type": "CHEMICAL", "entities": [ "Noradrenaline", "phenylephrine" ], "offsets": [ [ 0, 13 ], [ 18, 31 ] ] }, { "pmid": "17658513", "text": "Prazosin (nonselective alpha(1)-adrenoceptor antagonist), silodosin (selective alpha(1A)-adrenoceptor antagonist) and BMY-7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride) (selective alpha(1D)-adrenoceptor antagonist) competitively antagonized the phenylephrine-induced contraction (pA(2) values, 8.60+/-0.07, 9.44+/-0.06 and 5.75+/-0.07, respectively).", "type": "CHEMICAL", "entities": [ "Prazosin", "silodosin", "BMY-7378", "8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride", "phenylephrine" ], "offsets": [ [ 0, 8 ], [ 58, 67 ], [ 118, 126 ], [ 128, 222 ], [ 300, 313 ] ] }, { "pmid": "17658513", "text": "Chloroethylclonidine (3x10(-6) mol/L or more) produced a rightward shift in the concentration-response curve for phenylephrine.", "type": "CHEMICAL", "entities": [ "Chloroethylclonidine", "phenylephrine" ], "offsets": [ [ 0, 20 ], [ 113, 126 ] ] }, { "pmid": "17658513", "text": "Thus, in hamster ureters, alpha(1A)- and alpha(1D)-adrenoceptors were more prevalent than the alpha(1B)-adrenoceptor, with contraction being mediated mainly via alpha(1A)-adrenoceptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17658513", "text": "If these findings hold true for humans, alpha(1A)-adrenoceptor antagonists could become useful medication for stone passage in urolithiasis patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "Amylin receptors: molecular composition and pharmacology.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "Several receptors which bind the hormone AMY (amylin) with high affinity have now been identified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "The minimum binding unit is composed of the CT (calcitonin) receptor at its core, plus a RAMP (receptor activity modifying protein).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "The receptors have been named AMY(1(a)), AMY(2(a)) and AMY(3(a))", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "in accordance with the association of the CT receptor (CT((a)))", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "with RAMP1, RAMP2 and RAMP3 respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "The challenge is now to determine the localization and pharmacological nature of each of these receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15494035", "text": "Recent attempts to achieve these aims will be briefly discussed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "The association between osteoporosis and cardiovascular diseases has been demonstrated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "Higher cardiovascular risk has also been correlated with vertebral fractures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age- and sex-matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "Both groups were followed-up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan-Meier and Cox regression analyses.", "type": "CHEMICAL", "entities": [ "aspirin", "nitrates" ], "offsets": [ [ 237, 244 ], [ 270, 278 ] ] }, { "pmid": "22836881", "text": "The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% confidence interval [CI], 27.5-51.2) was significantly higher than in the comparison group (14.0 per 1000 person-years; 95% CI, 12.0-16.4, p < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89-3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22836881", "text": "In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21262851", "text": "Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors.\n", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 47, 54 ] ] }, { "pmid": "21262851", "text": "Benzodiazepines (BDZs) depress neuronal excitability via positive allosteric modulation of inhibitory GABA(A) receptors (GABA(A)R).", "type": "CHEMICAL", "entities": [ "Benzodiazepines", "BDZs" ], "offsets": [ [ 0, 15 ], [ 17, 21 ] ] }, { "pmid": "21262851", "text": "BDZs and other positive GABA(A)R modulators, including barbiturates, ethanol, and neurosteroids, can also inhibit L-type voltage-gated calcium channels (L-VGCCs), which could contribute to reduced neuronal excitability.", "type": "CHEMICAL", "entities": [ "BDZs", "barbiturates", "ethanol", "neurosteroids", "calcium" ], "offsets": [ [ 0, 4 ], [ 55, 67 ], [ 69, 76 ], [ 82, 95 ], [ 135, 142 ] ] }, { "pmid": "21262851", "text": "Because neuronal L-VGCC function is up-regulated after long-term GABA(A)R modulator exposure, an interaction with L-VGCCs may also play a role in physical dependence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21262851", "text": "The current studies assessed the effects of BDZs (diazepam, flurazepam, and desalkylflurazepam), allopregnanolone, pentobarbital, and ethanol on whole-cell Ba(2+) currents through recombinant neuronal Ca(v)1.2 and Ca(v)1.3 L-VGCCs expressed with beta(3) and alpha(2)delta-1", "type": "CHEMICAL", "entities": [ "BDZs", "diazepam", "flurazepam", "desalkylflurazepam", "allopregnanolone", "pentobarbital", "ethanol", "Ba(2+)" ], "offsets": [ [ 44, 48 ], [ 50, 58 ], [ 60, 70 ], [ 76, 94 ], [ 97, 113 ], [ 115, 128 ], [ 134, 141 ], [ 156, 162 ] ] }, { "pmid": "21262851", "text": "in HEK293T cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21262851", "text": "Allopregnanolone was the most potent inhibitor (IC(50), approximately 10 muM), followed by BDZs (IC(50), approximately 50 muM), pentobarbital (IC(50), 0.3-1 mM), and ethanol (IC(50), approximately 300 mM).", "type": "CHEMICAL", "entities": [ "Allopregnanolone", "BDZs", "pentobarbital", "ethanol" ], "offsets": [ [ 0, 16 ], [ 91, 95 ], [ 128, 141 ], [ 166, 173 ] ] }, { "pmid": "21262851", "text": "Ca(v)1.3 channels were less sensitive to pentobarbital inhibition than Ca(v)1.2 channels, similar to dihydropyridine (DHP) L-VGCC antagonists.", "type": "CHEMICAL", "entities": [ "pentobarbital", "dihydropyridine", "DHP" ], "offsets": [ [ 41, 54 ], [ 101, 116 ], [ 118, 121 ] ] }, { "pmid": "21262851", "text": "All GABA(A)R modulators induced a negative shift in the steady-state inactivation curve of Ca(v)1.3 channels, but only BDZs and pentobarbital induced a negative shift in Ca(v)1.2 channel inactivation.", "type": "CHEMICAL", "entities": [ "BDZs", "pentobarbital" ], "offsets": [ [ 119, 123 ], [ 128, 141 ] ] }, { "pmid": "21262851", "text": "Mutation of the high-affinity DHP binding site (T1039Y and Q1043M) in Ca(v)1.2 channels reduced pentobarbital potency.", "type": "CHEMICAL", "entities": [ "DHP", "pentobarbital" ], "offsets": [ [ 30, 33 ], [ 96, 109 ] ] }, { "pmid": "21262851", "text": "Despite the structural similarity between benzothiazepines and BDZs, mutation of an amino acid important for diltiazem potency (I1150A) did not affect diazepam potency.", "type": "CHEMICAL", "entities": [ "benzothiazepines", "BDZs", "amino acid", "diltiazem", "diazepam" ], "offsets": [ [ 42, 58 ], [ 63, 67 ], [ 84, 94 ], [ 109, 118 ], [ 151, 159 ] ] }, { "pmid": "21262851", "text": "Although L-VGCC inhibition by BDZs occurred at concentrations that are possibly too high to be clinically relevant and is not likely to play a role in the up-regulation of L-VGCCs during long-term treatment, pentobarbital and ethanol inhibited L-VGCCs at clinically relevant concentrations.", "type": "CHEMICAL", "entities": [ "BDZs", "pentobarbital" ], "offsets": [ [ 30, 34 ], [ 208, 221 ] ] }, { "pmid": "23542513", "text": "5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharide-stimulated BV2 microglia via NF-κB suppression and Nrf-2-dependent heme oxygenase-1 induction.\n", "type": "CHEMICAL", "entities": [ "5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone", "nitric oxide" ], "offsets": [ [ 0, 41 ], [ 51, 63 ] ] }, { "pmid": "23542513", "text": "In this study, we found that 5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone (5HHMF) from Hizikia fusiforme considerably inhibits lipopolysaccharide (LPS)-stimulated NO production by suppressing the expression of inducible NO synthase (iNOS) in BV2 microglia.", "type": "CHEMICAL", "entities": [ "NO", "NO", "5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone", "5HHMF" ], "offsets": [ [ 159, 161 ], [ 216, 218 ], [ 28, 69 ], [ 71, 76 ] ] }, { "pmid": "23542513", "text": "In addition, 5HHMF blocked LPS-induced phosphorylation of IκB, resulting in suppression of the nuclear translocation of nuclear factor-κB (NF-κB) subunits, namely p65 and p50, which are important molecules involved in the regulation of iNOS expression.", "type": "CHEMICAL", "entities": [ "5HHMF" ], "offsets": [ [ 12, 17 ] ] }, { "pmid": "23542513", "text": "Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor, along with 20S proteasome inhibitor (PSI) significantly inhibited LPS-induced iNOS expression, which indirectly suggested that 5HHMF downregulated iNOS expression by suppressing NF-κB activity.", "type": "CHEMICAL", "entities": [ "PDTC", "5HHMF" ], "offsets": [ [ 25, 29 ], [ 187, 192 ] ] }, { "pmid": "23542513", "text": "Thus, we found that 5HHMF enhances heme oxygenase-1 (HO-1) expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation.", "type": "CHEMICAL", "entities": [ "5HHMF" ], "offsets": [ [ 14, 19 ] ] }, { "pmid": "23542513", "text": "In addition, cobalt protoporphyrin (CoPP), a specific HO-1 inducer, predominantly suppressed LPS-induced NO production.", "type": "CHEMICAL", "entities": [ "NO", "cobalt protoporphyrin", "CoPP" ], "offsets": [ [ 99, 101 ], [ 7, 28 ], [ 30, 34 ] ] }, { "pmid": "23542513", "text": "In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, showed a partial suppressive effect of 5HHMF on LPS-induced NO production.", "type": "CHEMICAL", "entities": [ "zinc protoporphyrin", "ZnPP", "5HHMF", "NO" ], "offsets": [ [ 7, 26 ], [ 28, 32 ], [ 101, 106 ], [ 122, 124 ] ] }, { "pmid": "23542513", "text": "Further, 5HHMF increased specific DNA-binding activity of Nrf2, and transient knockdown with Nrf2 siRNA subsequently reversed 5HHMF-induced NO inhibition, which was followed by suppression of HO-1 activity.", "type": "CHEMICAL", "entities": [ "5HHMF", "5HHMF", "NO" ], "offsets": [ [ 3, 8 ], [ 120, 125 ], [ 134, 136 ] ] }, { "pmid": "23542513", "text": "Taken together, our findings indicate that 5HHMF suppresses NO production through modulation of iNOS, consequently suppressing NF-κB activity and induction of Nrf2-dependent HO-1 activity.", "type": "CHEMICAL", "entities": [ "5HHMF", "NO" ], "offsets": [ [ 37, 42 ], [ 54, 56 ] ] }, { "pmid": "23582273", "text": "Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors.\n", "type": "CHEMICAL", "entities": [ "methionine", "1,3,4-oxadiazole", "1,4-benzodioxan" ], "offsets": [ [ 114, 124 ], [ 36, 52 ], [ 64, 79 ] ] }, { "pmid": "23582273", "text": "A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity.", "type": "CHEMICAL", "entities": [ "1,3,4-oxadiazole", "1,4-benzodioxan" ], "offsets": [ [ 12, 28 ], [ 52, 67 ] ] }, { "pmid": "23582273", "text": "Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23582273", "text": "Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23582273", "text": "The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway.", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 123, 126 ] ] }, { "pmid": "23582273", "text": "Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 61, 64 ] ] }, { "pmid": "23131798", "text": "Discovery of novel cannabinoid receptor ligands by a virtual screening approach: further development of 2,4,6-trisubstituted 1,3,5-triazines as CB2 agonists.\n", "type": "CHEMICAL", "entities": [ "2,4,6-trisubstituted 1,3,5-triazines" ], "offsets": [ [ 104, 140 ] ] }, { "pmid": "23131798", "text": "3D ligand-based virtual screening was employed to identify novel scaffolds for cannabinoid receptor ligand development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23131798", "text": "A total of 112 compounds with diverse structures were purchased from commercial vendors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23131798", "text": "12 CB1 receptor antagonists/inverse agonists and 10 CB2 receptor agonists were identified in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23131798", "text": "One of the CB2 agonists, N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine (19, -logEC(50)=7.5, E(max)=255%) was selected for further development.", "type": "CHEMICAL", "entities": [ "N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine" ], "offsets": [ [ 25, 96 ] ] }, { "pmid": "23131798", "text": "As far as we are aware, the compound's 1,3,5-triazine scaffold represents a new core structure for CB2 agonists.", "type": "CHEMICAL", "entities": [ "1,3,5-triazine" ], "offsets": [ [ 39, 53 ] ] }, { "pmid": "23131798", "text": "A library of fifty-seven 2,4,6-trisubstituted-1,3,5-triazines was created to clarify the structure-activity relationship study of the analogs.", "type": "CHEMICAL", "entities": [ "2,4,6-trisubstituted-1,3,5-triazines" ], "offsets": [ [ 25, 61 ] ] }, { "pmid": "17397529", "text": "Inborn errors in the metabolism of glutathione.\n", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "17397529", "text": "Glutathione is a tripeptide composed of glutamate, cysteine and glycine.", "type": "CHEMICAL", "entities": [ "Glutathione", "tripeptide", "glutamate", "cysteine", "glycine" ], "offsets": [ [ 0, 11 ], [ 17, 27 ], [ 40, 49 ], [ 51, 59 ], [ 64, 71 ] ] }, { "pmid": "17397529", "text": "Glutathione is present in millimolar concentrations in most mammalian cells and it is involved in several fundamental biological functions, including free radical scavenging, detoxification of xenobiotics and carcinogens, redox reactions, biosynthesis of DNA, proteins and leukotrienes, as well as neurotransmission/neuromodulation.", "type": "CHEMICAL", "entities": [ "leukotrienes", "Glutathione" ], "offsets": [ [ 273, 285 ], [ 0, 11 ] ] }, { "pmid": "17397529", "text": "Glutathione is metabolised via the gamma-glutamyl cycle, which is catalyzed by six enzymes.", "type": "CHEMICAL", "entities": [ "Glutathione", "gamma-glutamyl" ], "offsets": [ [ 0, 11 ], [ 35, 49 ] ] }, { "pmid": "17397529", "text": "In man, hereditary deficiencies have been found in five of the six enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "Glutathione synthetase deficiency is the most frequently recognized disorder and, in its severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system (CNS) damage and recurrent bacterial infections.", "type": "CHEMICAL", "entities": [ "Glutathione" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17397529", "text": "Gamma-glutamylcysteine synthetase deficiency is also associated with hemolytic anemia, and some patients with this disorder show defects of neuromuscular function and generalized aminoaciduria.", "type": "CHEMICAL", "entities": [ "Gamma-glutamylcysteine" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "17397529", "text": "Gamma-glutamyl transpeptidase deficiency has been found in patients with CNS involvement and glutathionuria.", "type": "CHEMICAL", "entities": [ "Gamma-glutamyl" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "17397529", "text": "5-Oxoprolinase deficiency is associated with 5-oxoprolinuria but without a clear association with other symptoms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "Dipeptidase deficiency has been described in one patient.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "All disorders are very rare and inherited in an autosomal recessive manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "Most of the mutations are leaky so that many patients have residual enzyme activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "Diagnosis is made by measuring the concentration of different metabolites in the gamma-glutamyl cycle, enzyme activity and in glutathione synthetase and gamma-glutamylcysteine synthetase deficiency, also by mutation analysis.", "type": "CHEMICAL", "entities": [ "gamma-glutamyl", "glutathione", "gamma-glutamylcysteine" ], "offsets": [ [ 81, 95 ], [ 126, 137 ], [ 153, 175 ] ] }, { "pmid": "17397529", "text": "Prenatal diagnosis has been preformed in glutathione synthetase deficiency.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "17397529", "text": "The prognosis is difficult to predict, as few patients are known, but seems to vary significantly between different patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17397529", "text": "The aims of the treatment of glutathione synthesis defects are to avoid hemolytic crises and to increase the defense against reactive oxygen species.", "type": "CHEMICAL", "entities": [ "glutathione", "oxygen" ], "offsets": [ [ 29, 40 ], [ 134, 140 ] ] }, { "pmid": "17397529", "text": "No treatment has been recommended for gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase deficiency.", "type": "CHEMICAL", "entities": [ "gamma-glutamyl" ], "offsets": [ [ 38, 52 ] ] }, { "pmid": "12727196", "text": "Properties of purified recombinant human polyamine oxidase, PAOh1/SMO.\n", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "12727196", "text": "The discovery of an inducible oxidase whose apparent substrate preference is spermine indicates that polyamine catabolism is more complex than that originally proposed.", "type": "CHEMICAL", "entities": [ "polyamine", "spermine" ], "offsets": [ [ 101, 110 ], [ 77, 85 ] ] }, { "pmid": "12727196", "text": "To facilitate the study of this enzyme, the purification and characterization of the recombinant human PAOh1/SMO polyamine oxidase are reported.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 113, 122 ] ] }, { "pmid": "12727196", "text": "Purified PAOh1/SMO oxidizes both spermine (K(m)=1.6 microM) and N(1)-acetylspermine (K(m)=51 microM), but does not oxidize spermidine.", "type": "CHEMICAL", "entities": [ "spermine", "N(1)-acetylspermine", "spermidine" ], "offsets": [ [ 33, 41 ], [ 64, 83 ], [ 123, 133 ] ] }, { "pmid": "12727196", "text": "The purified human enzyme also does not oxidize eight representative antitumor polyamine analogues; however, specific oligamine analogues were found to be potent inhibitors of the oxidation of spermine by PAOh1/SMO.", "type": "CHEMICAL", "entities": [ "polyamine", "spermine" ], "offsets": [ [ 79, 88 ], [ 193, 201 ] ] }, { "pmid": "12727196", "text": "The results of these studies are consistent with the hypothesis that PAOh1/SMO represents a new addition to the polyamine metabolic pathway that may represent a new target for antineoplastic drug development.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "12650833", "text": "Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice.\n", "type": "CHEMICAL", "entities": [ "serine", "threonine", "morphine" ], "offsets": [ [ 11, 17 ], [ 18, 27 ], [ 62, 70 ] ] }, { "pmid": "12650833", "text": "The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction.", "type": "CHEMICAL", "entities": [ "morphine", "[3H]naloxone", "serine", "threonine" ], "offsets": [ [ 109, 117 ], [ 181, 193 ], [ 53, 59 ], [ 60, 69 ] ] }, { "pmid": "12650833", "text": "Neither okadaic acid nor cantharidin (1-10000 nM) displaced", "type": "CHEMICAL", "entities": [ "okadaic acid", "cantharidin" ], "offsets": [ [ 8, 20 ], [ 25, 36 ] ] }, { "pmid": "12650833", "text": "[3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level.", "type": "CHEMICAL", "entities": [ "[3H]naloxone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "12650833", "text": "The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.).", "type": "CHEMICAL", "entities": [ "okadaic acid", "cantharidin", "morphine" ], "offsets": [ [ 47, 59 ], [ 83, 94 ], [ 206, 214 ] ] }, { "pmid": "12650833", "text": "However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine.", "type": "CHEMICAL", "entities": [ "L-nor-okadaone", "okadaic acid", "morphine" ], "offsets": [ [ 9, 23 ], [ 76, 88 ], [ 181, 189 ] ] }, { "pmid": "12650833", "text": "On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception.", "type": "CHEMICAL", "entities": [ "morphine", "okadaic acid", "cantharidin", "calyculin-A" ], "offsets": [ [ 244, 252 ], [ 33, 45 ], [ 72, 83 ], [ 136, 147 ] ] }, { "pmid": "12650833", "text": "These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.", "type": "CHEMICAL", "entities": [ "serine", "threonine", "morphine" ], "offsets": [ [ 53, 59 ], [ 60, 69 ], [ 140, 148 ] ] }, { "pmid": "20185318", "text": "Carbonic anhydrase inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20185318", "text": "Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids.\n", "type": "CHEMICAL", "entities": [ "polyphenols", "phenolic acids" ], "offsets": [ [ 72, 83 ], [ 88, 102 ] ] }, { "pmid": "20185318", "text": "A series of phenolic acids and phenol natural products, such as p-hydroxybenzoic acid, p-coumaric acid, caffeic acid, ferulic acid, gallic acid, syringic acid, quercetin, and ellagic acid, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1).", "type": "CHEMICAL", "entities": [ "caffeic acid", "ferulic acid", "phenolic acids", "gallic acid", "syringic acid", "quercetin", "ellagic acid", "phenol", "p-hydroxybenzoic acid", "p-coumaric acid" ], "offsets": [ [ 104, 116 ], [ 118, 130 ], [ 12, 26 ], [ 132, 143 ], [ 145, 158 ], [ 160, 169 ], [ 175, 187 ], [ 31, 37 ], [ 64, 85 ], [ 87, 102 ] ] }, { "pmid": "20185318", "text": "All mammalian isozymes of human (h) or murine (m) origin hCA I-hCA XII, mCA XIII and hCA XIV were inhibited in the low micromolar or submicromolar range by these (poly)phenols (K(I)s in the range of 0.87-7.79 microM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20185318", "text": "p-Hydroxybenzoic acid was the best inhibitor of all isozymes (K(I)s of 0.87-35.4 microM) and the different isozymes showed very variable inhibition profiles with these derivatives.", "type": "CHEMICAL", "entities": [ "p-Hydroxybenzoic acid" ], "offsets": [ [ 0, 21 ] ] }, { "pmid": "20185318", "text": "Phenols like the ones investigated here possess a CA inhibition mechanism distinct of that of the sulfonamides/sulfamates used clinically or the coumarins.", "type": "CHEMICAL", "entities": [ "Phenols", "sulfonamides", "sulfamates", "coumarins" ], "offsets": [ [ 0, 7 ], [ 98, 110 ], [ 111, 121 ], [ 145, 154 ] ] }, { "pmid": "20185318", "text": "Unlike the sulfonamides, which bind to the catalytic zinc ion, phenols are anchored at the Zn(II)-coordinated water molecule and bind more externally within the active site cavity, making contacts with various amino acid residues.", "type": "CHEMICAL", "entities": [ "amino acid", "sulfonamides", "zinc", "phenols", "Zn(II)" ], "offsets": [ [ 210, 220 ], [ 11, 23 ], [ 53, 57 ], [ 63, 70 ], [ 91, 97 ] ] }, { "pmid": "20185318", "text": "As this is the region with the highest variability between the many CA isozymes found in mammals, this class of compounds may lead to isoform-selective inhibitors targeting just one or few of the medicinally relevant CAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15689518", "text": "Crystal structure of the pyridoxal-5'-phosphate-dependent serine dehydratase from human liver.\n", "type": "CHEMICAL", "entities": [ "pyridoxal-5'-phosphate", "serine" ], "offsets": [ [ 25, 47 ], [ 58, 64 ] ] }, { "pmid": "15689518", "text": "L-serine dehydratase (SDH), a member of the beta-family of pyridoxal phosphate-dependent (PLP) enzymes, catalyzes the deamination of L-serine and L-threonine to yield pyruvate or 2-oxobutyrate.", "type": "CHEMICAL", "entities": [ "L-serine", "L-serine", "L-threonine", "pyruvate", "2-oxobutyrate", "pyridoxal phosphate" ], "offsets": [ [ 0, 8 ], [ 133, 141 ], [ 146, 157 ], [ 167, 175 ], [ 179, 192 ], [ 59, 78 ] ] }, { "pmid": "15689518", "text": "The crystal structure of L-serine dehydratase from human liver (hSDH) has been solved at 2.5 A-resolution by molecular replacement.", "type": "CHEMICAL", "entities": [ "L-serine" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "15689518", "text": "The structure is a homodimer and reveals a fold typical for beta-family PLP-dependent enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15689518", "text": "Each monomer serves as an active unit and is subdivided into two distinct domains: a small domain and a PLP-binding domain that covalently anchors the cofactor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15689518", "text": "Both domains show the typical open alpha/beta architecture of PLP enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15689518", "text": "Comparison with the rSDH-(PLP-OMS) holo-enzyme reveals a large structural difference in active sites caused by the artifical O-methylserine.", "type": "CHEMICAL", "entities": [ "O-methylserine" ], "offsets": [ [ 125, 139 ] ] }, { "pmid": "15689518", "text": "Furthermore, the activity of hSDH-PLP was assayed and it proved to show catalytic activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15689518", "text": "That suggests that the structure of hSDH-PLP is the first structure of the active natural holo-SDH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578688", "text": "Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor.\n", "type": "CHEMICAL", "entities": [ "carbamoylmethylene", "BMS-582949" ], "offsets": [ [ 28, 46 ], [ 66, 76 ] ] }, { "pmid": "23578688", "text": "A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated.", "type": "CHEMICAL", "entities": [ "carbamoylmethylene", "BMS-582949" ], "offsets": [ [ 11, 29 ], [ 52, 62 ] ] }, { "pmid": "23578688", "text": "Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions.", "type": "CHEMICAL", "entities": [ "phosphoryloxymethylene carbamates", "α-aminoacyloxymethylene carbamates", "fumaric acid", "acyloxymethylene carbamates" ], "offsets": [ [ 9, 42 ], [ 61, 95 ], [ 155, 167 ], [ 176, 203 ] ] }, { "pmid": "23578688", "text": "Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578688", "text": "At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578688", "text": "At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578688", "text": "To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.", "type": "CHEMICAL", "entities": [ "secondary amides" ], "offsets": [ [ 140, 156 ] ] }, { "pmid": "23473030", "text": "Iron and diabetes risk.\n", "type": "CHEMICAL", "entities": [ "Iron" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23473030", "text": "Iron overload is a risk factor for diabetes.", "type": "CHEMICAL", "entities": [ "Iron" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23473030", "text": "The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk.", "type": "CHEMICAL", "entities": [ "iron", "iron" ], "offsets": [ [ 151, 155 ], [ 17, 21 ] ] }, { "pmid": "23473030", "text": "Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance.", "type": "CHEMICAL", "entities": [ "Iron" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23473030", "text": "Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 120, 124 ] ] }, { "pmid": "23473030", "text": "The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12956944", "text": "Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: naloxone reversal.\n", "type": "CHEMICAL", "entities": [ "ethanol", "naloxone", "cAMP" ], "offsets": [ [ 107, 114 ], [ 123, 131 ], [ 30, 34 ] ] }, { "pmid": "12956944", "text": "AIM: To study the changes in the expression and phosphorylation of cAMP response element binding protein (CREB) in the rat nucleus accumbens after chronic ethanol intake and its withdrawal.", "type": "CHEMICAL", "entities": [ "ethanol", "cAMP" ], "offsets": [ [ 155, 162 ], [ 67, 71 ] ] }, { "pmid": "12956944", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12956944", "text": "Ethanol was given in drinking water at the concentration of 6 % (v/v), for one month.", "type": "CHEMICAL", "entities": [ "Ethanol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "12956944", "text": "Changes in the levels of CREB and phospho-CREB (p-CREB) protein in the nucleus accumbens were measured by immunohistochemistry methods.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12956944", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12956944", "text": "Ethanol given to rats in drinking water decreased the level of p-CREB protein in the nucleus accumbens (-75 %) at the time of exposure to ethanol.", "type": "CHEMICAL", "entities": [ "Ethanol", "ethanol" ], "offsets": [ [ 0, 7 ], [ 138, 145 ] ] }, { "pmid": "12956944", "text": "The decrement of p-CREB protein in the nucleus accumbens remained at 24 h (-35 %) and 72 h (-28 %) of ethanol withdrawal, which recovered toward control level after 7 d of ethanol withdrawal.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 102, 109 ], [ 172, 179 ] ] }, { "pmid": "12956944", "text": "However, chronic ethanol, as well as ethanol withdrawal failed to produce any significant alteration in the level of CREB protein in the nucleus accumbens.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 17, 24 ], [ 37, 44 ] ] }, { "pmid": "12956944", "text": "Naloxone (alone) treatment of rats had no effect on the levels of CREB and p-CREB protein in the nucleus accumbens.", "type": "CHEMICAL", "entities": [ "Naloxone" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12956944", "text": "However, when naloxone was administered concurrently with ethanol treatment, it antagonized the down-regulation of p-CREB protein in the nucleus accumbens (142 %) of rats exposed to ethanol.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 58, 65 ], [ 182, 189 ] ] }, { "pmid": "12956944", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12956944", "text": "A long-term intake of ethanol solution down-regulates the phosphorylation of CREB in the nucleus accumbens, and those changes can be reversed by naloxone, which may be one kind of the molecular mechanisms associated with ethanol dependence.", "type": "CHEMICAL", "entities": [ "ethanol", "naloxone", "ethanol" ], "offsets": [ [ 22, 29 ], [ 145, 153 ], [ 221, 228 ] ] }, { "pmid": "23397055", "text": "Impaired function of prejunctional adenosine A1 receptors expressed by perivascular sympathetic nerves in DOCA-salt hypertensive rats.\n", "type": "CHEMICAL", "entities": [ "DOCA", "adenosine" ], "offsets": [ [ 106, 110 ], [ 35, 44 ] ] }, { "pmid": "23397055", "text": "Increased sympathetic nervous system activity contributes to deoxycorticosterone acetate (DOCA)-salt hypertension in rats.", "type": "CHEMICAL", "entities": [ "deoxycorticosterone acetate", "DOCA" ], "offsets": [ [ 61, 88 ], [ 90, 94 ] ] }, { "pmid": "23397055", "text": "ATP and norepinephrine (NE) are coreleased from perivascular sympathetic nerves.", "type": "CHEMICAL", "entities": [ "ATP", "norepinephrine" ], "offsets": [ [ 0, 3 ], [ 8, 22 ] ] }, { "pmid": "23397055", "text": "NE acts at prejunctional α2-adrenergic receptors (α2ARs) to inhibit NE release, and α2AR function is impaired in DOCA-salt rats.", "type": "CHEMICAL", "entities": [ "DOCA" ], "offsets": [ [ 113, 117 ] ] }, { "pmid": "23397055", "text": "Adenosine, an enzymatic ATP degradation product, acts at prejunctional A1 adenosine receptors (A1Rs) to inhibit NE release.", "type": "CHEMICAL", "entities": [ "ATP", "adenosine" ], "offsets": [ [ 21, 24 ], [ 71, 80 ] ] }, { "pmid": "23397055", "text": "We tested the hypothesis that prejunctional A1R function is impaired in sympathetic nerves supplying mesenteric arteries (MAs) and veins (MVs) of DOCA-salt rats.", "type": "CHEMICAL", "entities": [ "DOCA" ], "offsets": [ [ 143, 147 ] ] }, { "pmid": "23397055", "text": "Electrically evoked NE release and constrictions of blood vessels were studied in vitro with use of amperometry to measure NE oxidation currents and video microscopy, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397055", "text": "Immunohistochemical methods were used to localize tyrosine hydroxylase (TH) and A1Rs in perivascular sympathetic nerves.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 47, 55 ] ] }, { "pmid": "23397055", "text": "TH and A1Rs colocalized to perivascular sympathetic nerves.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397055", "text": "Adenosine and N(6)-cyclopentyl-adenosine (CPA, A1R agonist) constricted MVs but not MAs.", "type": "CHEMICAL", "entities": [ "CPA", "N(6)-cyclopentyl-adenosine" ], "offsets": [ [ 39, 42 ], [ 11, 37 ] ] }, { "pmid": "23397055", "text": "Adenosine and CPA (0.001-10 µM) inhibited neurogenic constrictions and NE release in MAs and MVs.", "type": "CHEMICAL", "entities": [ "CPA" ], "offsets": [ [ 11, 14 ] ] }, { "pmid": "23397055", "text": "DOCA-salt arteries were resistant to adenosine and CPA-mediated inhibition of NE release and constriction.", "type": "CHEMICAL", "entities": [ "adenosine", "CPA" ], "offsets": [ [ 33, 42 ], [ 47, 50 ] ] }, { "pmid": "23397055", "text": "The A2A adenosine receptor agonist CGS21680 (C23H29N7O6.HCl.xH2O) (0.001-0.1 μM) did not alter NE oxidation currents.", "type": "CHEMICAL", "entities": [ "adenosine", "CGS21680", "C23H29N7O6.HCl.xH2O" ], "offsets": [ [ 4, 13 ], [ 31, 39 ], [ 41, 60 ] ] }, { "pmid": "23397055", "text": "We conclude that there are prejunctional A1Rs in arteries and both pre- and postjunctional A1Rs in veins; thus, adenosine selectively constricts the veins.", "type": "CHEMICAL", "entities": [ "adenosine" ], "offsets": [ [ 107, 116 ] ] }, { "pmid": "23397055", "text": "Prejunctional A1R function is impaired in arteries, but not veins, from DOCA-salt rats.", "type": "CHEMICAL", "entities": [ "DOCA" ], "offsets": [ [ 67, 71 ] ] }, { "pmid": "23397055", "text": "Sympathetic autoreceptor dysfunction is not specific to α2ARs, but there is a more general disruption of prejunctional mechanisms controlling sympathetic neurotransmitter release in DOCA-salt hypertension.", "type": "CHEMICAL", "entities": [ "DOCA" ], "offsets": [ [ 177, 181 ] ] }, { "pmid": "11351021", "text": "Functional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes.\nIKs, the slow component of the delayed rectifier potassium current, figures prominently in the repolarization of heart cells.", "type": "CHEMICAL", "entities": [ "potassium", "K+" ], "offsets": [ [ 175, 184 ], [ 59, 61 ] ] }, { "pmid": "11351021", "text": "The K+ channel gene KvLQT1 is mutated in the heritable long QT (LQT) syndrome.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 4, 6 ] ] }, { "pmid": "11351021", "text": "Heterologous coexpression of KvLQT1 and the accessory protein minK yields an IKs-like current.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "Nevertheless, the links between KvLQT1 and cardiac IKs are largely inferential.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "Since the LQT syndrome mutant KvLQT1-G306R suppresses channel activity when coexpressed with wild-type KvLQT1 in a heterologous system, overexpression of this mutant in cardiomyocytes should reduce or eliminate native IKs if KvLQT1 is indeed the major molecular component of this current.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "To test this idea, we created the adenovirus AdRMGI-KvLQT1-G306R, which overexpresses KvLQT1-G306R channels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "In > 60 % of neonatal mouse myocytes, a sizable IKs could be measured using perforated-patch recordings (8.0 +/- 1.6 pA pF-1, n = 13).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "IKs was increased by forskolin and blocked by clofilium or indapamide but not by E-4031.", "type": "CHEMICAL", "entities": [ "forskolin", "clofilium", "indapamide", "E-4031" ], "offsets": [ [ 21, 30 ], [ 46, 55 ], [ 59, 69 ], [ 81, 87 ] ] }, { "pmid": "11351021", "text": "While cells infected with a reporter virus expressing only green fluorescent protein (GFP) displayed IKs similar to that in uninfected cells, AdRMGI-KvLQT1-G306R-infected cells showed a significantly reduced IKs (2.4 +/- 1.1 pA pF-1, n = 10, P < 0.01) when measured 60-72 h after infection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "Similar results were observed in adult guinea-pig myocytes (5.9 +/- 1.2 pA pF-1, n = 9, for control vs. 0.1 +/- 0.1 pA pF-1, n = 5, for AdRMGI-KvLQT1-G306R-infected cells).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "We conclude that KvLQT1 is the major molecular component of IKs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11351021", "text": "Our results further establish a dominant-negative mechanism for the G306R LQT syndrome mutation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23605695", "text": "Pasireotide: A Review of Its Use in Cushing's Disease.\n", "type": "CHEMICAL", "entities": [ "Pasireotide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23605695", "text": "Pasireotide (Signifor(®)) is a new subcutaneous somatostatin analogue that acts via somatostatin receptors to inhibit the secretion of corticotropin from the pituitary adenoma in patients with Cushing's disease.", "type": "CHEMICAL", "entities": [ "Pasireotide", "Signifor", "somatostatin", "somatostatin" ], "offsets": [ [ 0, 11 ], [ 13, 21 ], [ 48, 60 ], [ 84, 96 ] ] }, { "pmid": "23605695", "text": "Pasireotide has a receptor binding profile that is distinct from that of other somatostatin analogues, binding with high affinity to somatostatin receptor subtype 5, which is strongly over expressed in corticotroph adenoma cells.", "type": "CHEMICAL", "entities": [ "somatostatin", "somatostatin" ], "offsets": [ [ 78, 90 ], [ 132, 144 ] ] }, { "pmid": "23605695", "text": "Pasireotide is the first pituitary-directed agent to be approved for use in Cushing's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23605695", "text": "In a phase III clinical trial in patients with Cushing's disease, twice-daily pasireotide 600 or 900 μg for 6 months led to normalization of urinary free cortisol (UFC) levels in up to a quarter of all patients (primary endpoint) and significantly reduced mean UFC levels.", "type": "CHEMICAL", "entities": [ "pasireotide", "cortisol" ], "offsets": [ [ 77, 88 ], [ 153, 161 ] ] }, { "pmid": "23605695", "text": "The reduction in UFC levels is rapid (within one to two months) and sustained (up to 24 months).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23605695", "text": "Most patients who do not have an early response to pasireotide do not respond at a later time point.", "type": "CHEMICAL", "entities": [ "pasireotide" ], "offsets": [ [ 46, 57 ] ] }, { "pmid": "23605695", "text": "Decreases in UFC levels achieved during pasireotide treatment are accompanied by decreases in serum and salivary cortisol levels, as well as improvements in clinical signs and symptoms, including body weight, blood pressure and health-related quality-of-life.", "type": "CHEMICAL", "entities": [ "pasireotide", "cortisol" ], "offsets": [ [ 35, 46 ], [ 108, 116 ] ] }, { "pmid": "23605695", "text": "Pasireotide has a generally similar tolerability profile to that of other somatostatin analogues, but is associated with a relatively high incidence of hyperglycaemia, requiring the addition or intensification of glucose-lowering medication in a substantial proportion of patients.", "type": "CHEMICAL", "entities": [ "somatostatin", "glucose" ], "offsets": [ [ 69, 81 ], [ 208, 215 ] ] }, { "pmid": "23605695", "text": "Thus, pasireotide, together with on-going patient monitoring, provides a promising new option for the medical management of Cushing's disease.", "type": "CHEMICAL", "entities": [ "pasireotide" ], "offsets": [ [ 1, 12 ] ] }, { "pmid": "23017388", "text": "SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway.\n", "type": "CHEMICAL", "entities": [ "SB365", "Pulsatilla saponin D" ], "offsets": [ [ 0, 5 ], [ 7, 27 ] ] }, { "pmid": "23017388", "text": "Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017388", "text": "The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer.", "type": "CHEMICAL", "entities": [ "SB365", "Pulsatilla saponin D" ], "offsets": [ [ 46, 51 ], [ 53, 73 ] ] }, { "pmid": "23017388", "text": "We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis.", "type": "CHEMICAL", "entities": [ "SB365" ], "offsets": [ [ 14, 19 ] ] }, { "pmid": "23017388", "text": "Also, SB365 showed anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF.", "type": "CHEMICAL", "entities": [ "SB365" ], "offsets": [ [ 6, 11 ] ] }, { "pmid": "23017388", "text": "These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU.", "type": "CHEMICAL", "entities": [ "SB365", "5-FU" ], "offsets": [ [ 61, 66 ], [ 204, 208 ] ] }, { "pmid": "23017388", "text": "When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "SB365" ], "offsets": [ [ 51, 56 ] ] }, { "pmid": "23017388", "text": "Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis.", "type": "CHEMICAL", "entities": [ "SB365" ], "offsets": [ [ 43, 48 ] ] }, { "pmid": "23017388", "text": "Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer.", "type": "CHEMICAL", "entities": [ "SB365" ], "offsets": [ [ 10, 15 ] ] }, { "pmid": "15777622", "text": "Apolipoprotein E3 (apoE3) safeguards pig proximal tubular LLC-PK1 cells against reduction in SGLT1 activity induced by gentamicin C.\nMegalin, a family of endocytic receptors related to the low-density lipoprotein (LDL) receptor, is a major pathway for proximal tubular aminoglycoside accumulation.", "type": "CHEMICAL", "entities": [ "aminoglycoside", "gentamicin C" ], "offsets": [ [ 269, 283 ], [ 119, 131 ] ] }, { "pmid": "15777622", "text": "We previously reported that aminoglycoside antibiotics reduce SGLT1-dependent glucose transport in pig proximal tubular epithelial LLC-PK1 cells in parallel with the order of their nephrotoxicity.", "type": "CHEMICAL", "entities": [ "aminoglycoside", "glucose" ], "offsets": [ [ 28, 42 ], [ 78, 85 ] ] }, { "pmid": "15777622", "text": "In this study, using a model of gentamicin C (GMC)-induced reduction in SGLT1 activity, we examined whether ligands for megalin protect LLC-PK1 cells from the GMC-induced reduction in SGLT1 activity.", "type": "CHEMICAL", "entities": [ "gentamicin C", "GMC", "GMC" ], "offsets": [ [ 32, 44 ], [ 46, 49 ], [ 159, 162 ] ] }, { "pmid": "15777622", "text": "We employed apolipoprotein E3 (apoE3) and lactoferrin as ligands for megalin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15777622", "text": "Then the cells were treated with various concentrations of apoE3, lactoferrin and bovine serum albumin with or without 100 microg/ml of GMC, and the SGLT1-dependent methyl alpha-D-glucopyranoside (AMG) uptake and levels of SGLT1 expression were determined.", "type": "CHEMICAL", "entities": [ "GMC", "methyl alpha-D-glucopyranoside", "AMG" ], "offsets": [ [ 136, 139 ], [ 165, 195 ], [ 197, 200 ] ] }, { "pmid": "15777622", "text": "As a result, we demonstrated that the apoE3 significantly protects these cells from GMC-induced reduction in AMG uptake, but neither lactoferrin nor albumin does.", "type": "CHEMICAL", "entities": [ "AMG", "GMC" ], "offsets": [ [ 109, 112 ], [ 84, 87 ] ] }, { "pmid": "15777622", "text": "In accord with a rise in AMG uptake activity, the mRNA and protein levels of SGLT1 were apparently up-regulated in the presence of apoE3.", "type": "CHEMICAL", "entities": [ "AMG" ], "offsets": [ [ 25, 28 ] ] }, { "pmid": "15777622", "text": "Furthermore, we found that the uptake of [3H] gentamicin is decreased by apoE3, and that apoE3 showed obvious protection against the GMC-dependent N-acetyl-beta-D-glucosamidase (NAG) release from LLC-PK1 cells.", "type": "CHEMICAL", "entities": [ "[3H] gentamicin", "GMC", "N-acetyl-beta-D-glucosamidase", "NAG" ], "offsets": [ [ 41, 56 ], [ 133, 136 ], [ 147, 176 ], [ 178, 181 ] ] }, { "pmid": "15777622", "text": "Thus, these results indicate that apoE3 could be a valuable tool for the prevention of aminoglycoside nephrotoxicity.", "type": "CHEMICAL", "entities": [ "aminoglycoside" ], "offsets": [ [ 87, 101 ] ] }, { "pmid": "2877081", "text": "Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs.\n", "type": "CHEMICAL", "entities": [ "nizatidine", "histamine" ], "offsets": [ [ 11, 21 ], [ 35, 44 ] ] }, { "pmid": "2877081", "text": "Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion.", "type": "CHEMICAL", "entities": [ "Nizatidine", "LY139037", "histamine" ], "offsets": [ [ 0, 10 ], [ 12, 20 ], [ 35, 44 ] ] }, { "pmid": "2877081", "text": "It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog.", "type": "CHEMICAL", "entities": [ "cimetidine", "histamine" ], "offsets": [ [ 31, 41 ], [ 45, 54 ] ] }, { "pmid": "2877081", "text": "Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration.", "type": "CHEMICAL", "entities": [ "Nizatidine", "cimetidine" ], "offsets": [ [ 0, 10 ], [ 38, 48 ] ] }, { "pmid": "2877081", "text": "Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration.", "type": "CHEMICAL", "entities": [ "histamine", "methacholine", "nizatidine", "cimetidine" ], "offsets": [ [ 132, 141 ], [ 143, 155 ], [ 169, 179 ], [ 233, 243 ] ] }, { "pmid": "2877081", "text": "Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m.", "type": "CHEMICAL", "entities": [ "Nizatidine", "cimetidine", "histamine", "nizatidine" ], "offsets": [ [ 0, 10 ], [ 82, 92 ], [ 170, 179 ], [ 217, 227 ] ] }, { "pmid": "2877081", "text": "Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.", "type": "CHEMICAL", "entities": [ "nizatidine" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "23172777", "text": "3D-QSAR-assisted drug design: identification of a potent quinazoline-based Aurora kinase inhibitor.\n", "type": "CHEMICAL", "entities": [ "quinazoline" ], "offsets": [ [ 57, 68 ] ] }, { "pmid": "23172777", "text": "We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC(50) values toward Aurora kinase A ranging from 33 nM to 10.5 μM.", "type": "CHEMICAL", "entities": [ "pyrazole", "furanopyrimidine" ], "offsets": [ [ 71, 79 ], [ 94, 110 ] ] }, { "pmid": "23172777", "text": "The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r(2) (CV) =0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R(2) (pred) =0.52 and 0.67, CoMFA and CoMSIA).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC(50)", "type": "CHEMICAL", "entities": [ "furanopyrimidine" ], "offsets": [ [ 30, 46 ] ] }, { "pmid": "23172777", "text": "=43 nM;", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "HCT-116 IC(50)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "=400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC(50)", "type": "CHEMICAL", "entities": [ "quinazoline" ], "offsets": [ [ 9, 20 ] ] }, { "pmid": "23172777", "text": "=25 nM;", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "=23 nM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23172777", "text": "Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23585058", "text": "NMDA Receptor Activation Down-Regulates Expression of δ Subunit-Containing GABA-A Receptors in Cultured Hippocampal Neurons.\n", "type": "CHEMICAL", "entities": [ "NMDA", "GABA" ], "offsets": [ [ 0, 4 ], [ 75, 79 ] ] }, { "pmid": "23585058", "text": "Neurosteroids are endogenous allosteric modulators of γ amino-butyric acid type A receptors (GABARs), and enhance GABAR-mediated inhibition.", "type": "CHEMICAL", "entities": [ "γ amino-butyric acid" ], "offsets": [ [ 53, 73 ] ] }, { "pmid": "23585058", "text": "However, GABARs expressed on hippocampal dentate granule neurons of epileptic animals are modified such that their neurosteroid sensitivity is reduced and δ subunit expression is diminished.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23585058", "text": "The molecular mechanisms triggering this GABAR plasticity were explored.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23585058", "text": "In the cultured hippocampal neurons treatment with NMDA (10 μM) for 48 hrs reduced surface expression of δ and α4 subunits, but did not increase expression of γ2 subunits.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 48, 52 ] ] }, { "pmid": "23585058", "text": "The tonic current recorded from neurons in NMDA-treated cultures was reduced, and its neurosteroid modulation was also diminished.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 36, 40 ] ] }, { "pmid": "23585058", "text": "In contrast, synaptic inhibition and its modulation by neurosteroids were preserved in these neurons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23585058", "text": "The time course of NMDA effects on surface and total δ subunit expression were distinct; shorter (6 hrs) treatment decreased surface expression, whereas longer treatment reduced both surface and total expression.", "type": "CHEMICAL", "entities": [ "APV", "NMDA" ], "offsets": [ [ 206, 209 ], [ 12, 16 ] ] }, { "pmid": "23585058", "text": "APV blocked NMDA effects on δ subunit expression.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 4, 8 ] ] }, { "pmid": "23585058", "text": "Chelation of calcium ions by BAPTA-AM or blockade of ERK1/2 activation by UO126 also prevented the NMDA effects.", "type": "CHEMICAL", "entities": [ "calcium", "BAPTA-AM", "UO126", "NMDA" ], "offsets": [ [ 4, 11 ], [ 20, 28 ], [ 65, 70 ], [ 90, 94 ] ] }, { "pmid": "23585058", "text": "Thus prolonged activation of NMDA receptors in hippocampal neurons reduced GABAR δ subunit expression through Ca2+ entry and at least in part by ERK1/2 activation.", "type": "CHEMICAL", "entities": [ "NMDA", "Ca2+" ], "offsets": [ [ 20, 24 ], [ 101, 105 ] ] }, { "pmid": "23578644", "text": "Conjugated linoleic acid and calcium co-supplementation improves bone health in ovariectomised mice.\n", "type": "CHEMICAL", "entities": [ "linoleic acid", "calcium" ], "offsets": [ [ 11, 24 ], [ 29, 36 ] ] }, { "pmid": "23578644", "text": "Osteoporosis is a significant health concern for the elderly; conjugated linoleic acid (CLA) has been shown to improve overall bone mass when calcium is included as a co-supplement.", "type": "CHEMICAL", "entities": [ "calcium", "linoleic acid" ], "offsets": [ [ 142, 149 ], [ 73, 86 ] ] }, { "pmid": "23578644", "text": "However, potential effects of CLA and calcium on bone mass during a period of bone loss have not been reported.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 38, 45 ] ] }, { "pmid": "23578644", "text": "The purpose of this study was to determine how dietary calcium modulates the effects of conjugated linoleic acid (CLA) in preventing bone loss, using an ovariectomised mouse model.", "type": "CHEMICAL", "entities": [ "calcium", "linoleic acid" ], "offsets": [ [ 55, 62 ], [ 99, 112 ] ] }, { "pmid": "23578644", "text": "CLA supplementation significantly prevented ovariectomy-associated weight and fat mass gain, compared to non-supplemented controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578644", "text": "CLA significantly increased bone markers without major changes in bone mineral composition in the femur compared to respective controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578644", "text": "CLA treatment increased serum parathyroid hormone (PTH) significantly (p=0.0172), while serum 1,25-dihydroxyvitamin D3 concentration was not changed by CLA.", "type": "CHEMICAL", "entities": [ "1,25-dihydroxyvitamin D3" ], "offsets": [ [ 94, 118 ] ] }, { "pmid": "23578644", "text": "Meanwhile, CLA significantly reduced femur tartrate resistant acid phosphatase (TRAP) activity, suggesting potential reduction of osteoclastogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578644", "text": "The data suggest that CLA, along with dietary calcium, has great potential to be used to prevent bone loss and weight gain associated with menopause.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23332447", "text": "Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet.\n", "type": "CHEMICAL", "entities": [ "Testosterone", "triglycerides" ], "offsets": [ [ 0, 12 ], [ 57, 70 ] ] }, { "pmid": "23332447", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "Although low serum testosterone (T) is associated with metabolic disorders, the mechanism of this association is unclear.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 19, 31 ] ] }, { "pmid": "23332447", "text": "The objective of the present study was to investigate the combined effects of T deficiency and a high-fat diet (HFD) on hepatic lipid homeostasis in mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "MATERIALS/METHODS: Orchiectomized (ORX) mice and sham-operated (SHAM) mice were randomly divided into five groups: SHAM mice fed a standard diet (SD), SHAM mice fed HFD, ORX mice fed SD, ORX mice fed HFD, and ORX mice fed HFD with T supplementation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "After 4weeks of treatment, we investigated the synthesis and secretion of lipids in the liver and detailed serum lipoprotein profiles in each group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "ORX mice fed HFD showed increased hepatic steatosis, markedly decreased serum triglyceride (TG) and TG-VLDL content, and increased serum very small-LDL content.", "type": "CHEMICAL", "entities": [ "triglyceride" ], "offsets": [ [ 78, 90 ] ] }, { "pmid": "23332447", "text": "Gene expression analysis revealed that ORX mice fed HFD showed significantly decreased expression of microsomal triglyceride transfer protein, lipin-1, peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ coactivator 1-α, and significantly increased sterol regulatory element-binding protein-1, diacylglycerol acyltransferase-2 and fatty acid synthase.", "type": "CHEMICAL", "entities": [ "sterol", "diacylglycerol", "fatty acid", "triglyceride" ], "offsets": [ [ 260, 266 ], [ 305, 319 ], [ 342, 352 ], [ 112, 124 ] ] }, { "pmid": "23332447", "text": "Reduction of hepatic AMPK phosphorylation was observed in ORX mice fed HFD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "These perturbations in ORX mice fed HFD were normalized to the levels of SHAM mice fed HFD by T supplementation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23332447", "text": "T deficiency is associated with failure of lipid homeostasis mediated by altered expression of genes involved in hepatic assembly and secretion of lipids.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305949", "text": "Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305949", "text": "Topoisomerase 1 (Top1) resolves transcription-associated supercoils by generating transient single-strand breaks in DNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305949", "text": "Top1 activity in yeast is a major source of transcription-associated mutagenesis, generating a distinctive mutation signature characterized by deletions in short, tandem repeats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305949", "text": "A similar signature is associated with the persistence of ribonucleoside monophosphates (rNMPs) in DNA, and it also depends on Top1 activity.", "type": "CHEMICAL", "entities": [ "ribonucleoside monophosphates", "rNMPs" ], "offsets": [ [ 58, 87 ], [ 89, 94 ] ] }, { "pmid": "23305949", "text": "There is only partial overlap, however, between Top1-dependent deletion hotspots identified in highly transcribed DNA and those associated with rNMPs, suggesting the existence of both rNMP-dependent and rNMP-independent events.", "type": "CHEMICAL", "entities": [ "rNMPs", "rNMP", "rNMP" ], "offsets": [ [ 144, 149 ], [ 184, 188 ], [ 203, 207 ] ] }, { "pmid": "23305949", "text": "Here, we present genetic studies confirming that there are two distinct types of hotspots.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23305949", "text": "Data suggest a novel model in which rNMP-dependent hotspots are generated by sequential Top1 reactions and are consistent with rNMP-independent hotspots reflecting processing of a trapped Top1 cleavage complex.", "type": "CHEMICAL", "entities": [ "rNMP", "rNMP" ], "offsets": [ [ 36, 40 ], [ 127, 131 ] ] }, { "pmid": "18162179", "text": "Covalent modification of stathmin by CCNU determined by FTMS analysis of modified proteins and tryptic peptides.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18162179", "text": "Chemical modification of proteins is often carried out to generate protein-small molecule conjugates for various applications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18162179", "text": "The high resolution and mass accuracy of a Fourier transform mass spectrometer is particularly useful for assessing the extent or sites of covalent modifications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18162179", "text": "As protein-small molecule reactions often produce products with variable numbers of the compound incorporated at different sites, a direct mass analysis of the reaction products at times yields mass spectra hard to interpret.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18162179", "text": "Chromatographic separation at protein level could reduce the complexity of a sample, thus allowing more accurate mass spectrometric analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18162179", "text": "In this report, we demonstrate the utility of reversed-phase protein chromatography and FT-ICR mass spectrometry in analyzing CCNU (lomustine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitroso-urea, MW: 233.7Da) modification of stathmin.", "type": "CHEMICAL", "entities": [ "lomustine", "1-(2-chloroethyl)-3-cyclohexyl-1-nitroso-urea" ], "offsets": [ [ 132, 141 ], [ 143, 188 ] ] }, { "pmid": "18162179", "text": "With this combined approach, we determined the stoichiometry as well as sites of CCNU incorporation into the protein, demonstrating differential reactivity of several lysyl residues to CCNU alkylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19549602", "text": "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity.\n", "type": "CHEMICAL", "entities": [ "Amitriptyline" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "19549602", "text": "Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19549602", "text": "We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation.", "type": "CHEMICAL", "entities": [ "amitriptyline" ], "offsets": [ [ 20, 33 ] ] }, { "pmid": "19549602", "text": "Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells.", "type": "CHEMICAL", "entities": [ "Amitriptyline", "tricyclic", "serotonin" ], "offsets": [ [ 0, 13 ], [ 33, 42 ], [ 56, 65 ] ] }, { "pmid": "19549602", "text": "Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization.", "type": "CHEMICAL", "entities": [ "Amitriptyline" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "19549602", "text": "Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline.", "type": "CHEMICAL", "entities": [ "amitriptyline", "amitriptyline" ], "offsets": [ [ 14, 27 ], [ 89, 102 ] ] }, { "pmid": "19549602", "text": "Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death.", "type": "CHEMICAL", "entities": [ "amitriptyline", "kainic acid" ], "offsets": [ [ 18, 31 ], [ 91, 102 ] ] }, { "pmid": "19549602", "text": "Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19549602", "text": "Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity.", "type": "CHEMICAL", "entities": [ "amitriptyline" ], "offsets": [ [ 6, 19 ] ] }, { "pmid": "14737100", "text": "Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016.\n", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 165, 173 ] ] }, { "pmid": "14737100", "text": "The expression of the NH2 terminally truncated ErbB2 receptor (p95ErbB2) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185ErbB2.", "type": "CHEMICAL", "entities": [ "NH2" ], "offsets": [ [ 22, 25 ] ] }, { "pmid": "14737100", "text": "We now show that heregulin (HRG), but not EGF, stimulates p95ErbB2 phosphorylation in BT474 breast cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14737100", "text": "Furthermore, phospho-p95ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185ErbB2 heterodimerizes with both EGFR and ErbB3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14737100", "text": "The predilection of p95ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14737100", "text": "GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95ErbB2 phosphorylation in BT474 cells and tumor xenografts.", "type": "CHEMICAL", "entities": [ "GW572016", "tyrosine" ], "offsets": [ [ 0, 8 ], [ 66, 74 ] ] }, { "pmid": "14737100", "text": "Inhibition of p95ErbB2, p185ErbB2, and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 63, 71 ] ] }, { "pmid": "14737100", "text": "Increased phosphorylation of p95ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 101, 109 ] ] }, { "pmid": "14737100", "text": "In contrast, trastuzumab did not inhibit p95ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14737100", "text": "It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95ErbB2-expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95ErbB2-ErbB3 heterodimers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14737100", "text": "Thus, p95ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 94, 102 ] ] }, { "pmid": "17409426", "text": "Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17409426", "text": "To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells.", "type": "CHEMICAL", "entities": [ "sulindac" ], "offsets": [ [ 149, 157 ] ] }, { "pmid": "17409426", "text": "Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "Sulindac sulfide" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17409426", "text": "Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29.", "type": "CHEMICAL", "entities": [ "Sulindac sulfone" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17409426", "text": "Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac.", "type": "CHEMICAL", "entities": [ "Indomethacin", "SC-236", "sulindac" ], "offsets": [ [ 0, 12 ], [ 17, 23 ], [ 101, 109 ] ] }, { "pmid": "17409426", "text": "Sulindac suppressed 14-3-3epsilon promoter activity.", "type": "CHEMICAL", "entities": [ "Sulindac" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "17409426", "text": "As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17409426", "text": "Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity.", "type": "CHEMICAL", "entities": [ "Sulindac sulfide" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17409426", "text": "Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin.", "type": "CHEMICAL", "entities": [ "sulindac", "indomethacin" ], "offsets": [ [ 102, 110 ], [ 114, 126 ] ] }, { "pmid": "17409426", "text": "NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17409426", "text": "Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17409426", "text": "Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17409426", "text": "These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15795320", "text": "Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells.\n", "type": "CHEMICAL", "entities": [ "pemetrexed", "gemcitabine" ], "offsets": [ [ 71, 81 ], [ 86, 97 ] ] }, { "pmid": "15795320", "text": "Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells.", "type": "CHEMICAL", "entities": [ "Gemcitabine", "pemetrexed" ], "offsets": [ [ 0, 11 ], [ 16, 26 ] ] }, { "pmid": "15795320", "text": "Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index.", "type": "CHEMICAL", "entities": [ "pemetrexed", "gemcitabine" ], "offsets": [ [ 24, 34 ], [ 39, 50 ] ] }, { "pmid": "15795320", "text": "The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies.", "type": "CHEMICAL", "entities": [ "gemcitabine", "deoxycytidine", "cytidine", "thymidylate", "dihydrofolate", "glycinamide ribonucleotide" ], "offsets": [ [ 31, 42 ], [ 88, 101 ], [ 137, 145 ], [ 197, 208 ], [ 224, 237 ], [ 260, 286 ] ] }, { "pmid": "15795320", "text": "The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with enzyme-linked immunosorbent assay, whereas quantitative polymerase chain reaction (PCR) was used to study target gene-expression profiles and its modulation by each drug.", "type": "CHEMICAL", "entities": [ "gemcitabine" ], "offsets": [ [ 14, 25 ] ] }, { "pmid": "15795320", "text": "Synergistic cytotoxicity was demonstrated, and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis, and increased the expression of dCK in A549 and Calu-6 cells, as well as the expression of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines.", "type": "CHEMICAL", "entities": [ "pemetrexed", "nucleoside" ], "offsets": [ [ 47, 57 ], [ 237, 247 ] ] }, { "pmid": "15795320", "text": "PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, whereas expression of TS, DHFR, and GARFT was predictive of pemetrexed chemosensitivity.", "type": "CHEMICAL", "entities": [ "gemcitabine", "pemetrexed" ], "offsets": [ [ 58, 69 ], [ 143, 153 ] ] }, { "pmid": "15795320", "text": "These data demonstrated that 1) gemcitabine and pemetrexed synergistically interact against NSCLC cells through the suppression of Akt phosphorylation and induction of apoptosis; 2) the gene expression profile of critical genes may predict for drug chemosensitivity; and 3) pemetrexed enhances dCK and hENT1 expression, thus suggesting the role of gene-expression modulation for rational development of chemotherapy combinations.", "type": "CHEMICAL", "entities": [ "gemcitabine", "pemetrexed", "pemetrexed" ], "offsets": [ [ 32, 43 ], [ 48, 58 ], [ 274, 284 ] ] }, { "pmid": "12850267", "text": "Tissue expression and translational control of rat kynurenine aminotransferase/glutamine transaminase K mRNAs.\n", "type": "CHEMICAL", "entities": [ "kynurenine", "glutamine" ], "offsets": [ [ 51, 61 ], [ 79, 88 ] ] }, { "pmid": "12850267", "text": "Kynurenic acid (KA) is an endogenous glutamate receptor antagonist at the level of the different ionotropic glutamate receptors.", "type": "CHEMICAL", "entities": [ "Kynurenic acid", "glutamate", "KA", "glutamate" ], "offsets": [ [ 0, 14 ], [ 108, 117 ], [ 16, 18 ], [ 37, 46 ] ] }, { "pmid": "12850267", "text": "One of the enzymes responsible for the production of KA, kynurenine aminotransferase I (KATI), also catalyses the reversible transamination of glutamine to oxoglutaramic acid (GTK, EC 2.6.1.15).", "type": "CHEMICAL", "entities": [ "KA", "kynurenine", "glutamine", "oxoglutaramic acid" ], "offsets": [ [ 53, 55 ], [ 57, 67 ], [ 143, 152 ], [ 156, 174 ] ] }, { "pmid": "12850267", "text": "The enzyme exists in a cytosolic and in a mitochondrial form because of the presence of two different KATI mRNAs", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "coding for a protein respectively with and without leader sequence targeting the protein into mitochondria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "We have cloned from a phage library of rat kidney cDNA", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "four new KATI cDNAs containing different 5' untranslated regions (UTRs).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "One of the transcripts (+14KATI cDNA) contains an alternative site of initiation of translation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "The tissue distribution of the different transcripts was studied by RT-PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "The study demonstrated that several KATI mRNAs are constitutively expressed in ubiquitous manner, while +14KATI mRNA is present only in kidney.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "The translational efficiency of the different transcripts was studied in vitro and enzymatic activities were measured in transiently transfected Cos-1 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "Each KATI mRNA exhibits a different in vitro translational efficiency, which corresponds to different levels of KAT enzymatic activity in transfected cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "Both findings correlate with the predicted accessibility of the ribosomal binding sites of the different mRNAs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "The structure of the rat KATI/GTK gene was also studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12850267", "text": "The expression of several KATI mRNAs with different 5'UTRs represents an interesting example of transcriptional/translational control on the expression of pyridoxal phosphate (PLP)-dependent aminotransferases.", "type": "CHEMICAL", "entities": [ "pyridoxal phosphate", "PLP" ], "offsets": [ [ 155, 174 ], [ 176, 179 ] ] }, { "pmid": "23628791", "text": "Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.\n", "type": "CHEMICAL", "entities": [ "manganese" ], "offsets": [ [ 76, 85 ] ] }, { "pmid": "23628791", "text": "The extra-pyramidal symptoms associated with manganism often overlap with that seen in Parkinsonism suggesting a common link between the two disorders.", "type": "CHEMICAL", "entities": [ "manganism" ], "offsets": [ [ 45, 54 ] ] }, { "pmid": "23628791", "text": "Since wide deviations are observed in susceptibility and characteristics of the symptoms observed in manganism, these differences may be due to underlying genetic variability.", "type": "CHEMICAL", "entities": [ "manganism" ], "offsets": [ [ 101, 110 ] ] }, { "pmid": "23628791", "text": "Genes linked to early onset of Parkinsonism which includes ATP13A2 and parkin have already been suggested to promote development of Mn toxicity.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 132, 134 ] ] }, { "pmid": "23628791", "text": "Of the other Parkinson-linked genes, mutations in LRRK2, an autosomal dominant gene, represent another likely candidate involved in the development of manganism.", "type": "CHEMICAL", "entities": [ "manganism" ], "offsets": [ [ 151, 160 ] ] }, { "pmid": "23628791", "text": "In this paper the effect of shRNA LRRK2 knock-down on Mn toxicity was examined in control and DAT transfected HEK293 cells.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 54, 56 ] ] }, { "pmid": "23628791", "text": "Results demonstrate that LRRK2 down-regulation potentiates Mn toxicity in both control and DAT-transfected cell as well as potentiates DA toxicity.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 59, 61 ] ] }, { "pmid": "23628791", "text": "Combined treatment of Mn and DA further augments cell toxicity, ROS production and JNK phosphorylation in LRRK2 deficient cells compared to controls.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 22, 24 ] ] }, { "pmid": "23628791", "text": "Consistent with studies demonstrating that LRRK2 plays a role in the phosphorylation of p38, our results similarly demonstrate a decrease in p38 activation in LRRK2 knock-down cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23628791", "text": "Our findings suggest that null mutations in LRRK2 which cause Parkinsonism potentiate Mn toxicity and increase susceptibility to develop manganism.", "type": "CHEMICAL", "entities": [ "Mn", "manganism" ], "offsets": [ [ 86, 88 ], [ 137, 146 ] ] }, { "pmid": "22983867", "text": "Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets.\n", "type": "CHEMICAL", "entities": [ "monosodium L-glutamate", "tyrosine" ], "offsets": [ [ 17, 39 ], [ 90, 98 ] ] }, { "pmid": "22983867", "text": "The goal of the present study was to investigate changes on glucose homoeostasis and of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) signalling in pancreatic islets from MSG-obese mice submitted to or not submitted to swim training.", "type": "CHEMICAL", "entities": [ "MSG", "glucose" ], "offsets": [ [ 192, 195 ], [ 60, 67 ] ] }, { "pmid": "22983867", "text": "Swim training of 90-day-old MSG mice was used to evaluate whether signalling pathways of the IR and IRS-1 in islets are involved with the insulin resistance and glucose intolerance observed in this obese animal model.", "type": "CHEMICAL", "entities": [ "MSG", "glucose" ], "offsets": [ [ 28, 31 ], [ 161, 168 ] ] }, { "pmid": "22983867", "text": "The results showed that IR tyrosine phosphorylation (pIR) was reduced by 42 % in MSG-obese mice (MSG, 6.7 ± 0.2 arbitrary units (a.u.); control, 11.5 ± 0.4 a.u.); on the other hand, exercise training increased pIR by 76 % in MSG mice without affecting control mice (MSG, 11.8 ± 0.3; control, 12.8 ± 0.2 a.u.).", "type": "CHEMICAL", "entities": [ "tyrosine", "MSG", "MSG", "MSG", "MSG" ], "offsets": [ [ 27, 35 ], [ 81, 84 ], [ 97, 100 ], [ 225, 228 ], [ 266, 269 ] ] }, { "pmid": "22983867", "text": "Although the treatment with MSG increased IRS-1 tyrosine phosphorylation (pIRS-1) by 96 % (MSG, 17.02 ± 0.6; control, 8.7 ± 0.2 a.u.), exercise training also increased it in both groups (control, 13.6 ± 0.1; MSG, 22.2 ± 1.1 a.u.).", "type": "CHEMICAL", "entities": [ "MSG", "tyrosine", "MSG", "MSG" ], "offsets": [ [ 11, 14 ], [ 31, 39 ], [ 74, 77 ], [ 191, 194 ] ] }, { "pmid": "22983867", "text": "Current research shows that the practice of swim training increases the tyrosine phosphorylation of IRS-1 which can modulate the effect caused by obesity in insulin receptors.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "12614192", "text": "Long-term use of sildenafil.\n", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 17, 27 ] ] }, { "pmid": "12614192", "text": "The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12614192", "text": "The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans.", "type": "CHEMICAL", "entities": [ "cGMP" ], "offsets": [ [ 150, 154 ] ] }, { "pmid": "12614192", "text": "Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED.", "type": "CHEMICAL", "entities": [ "sildenafil", "Viagra" ], "offsets": [ [ 107, 117 ], [ 119, 125 ] ] }, { "pmid": "12614192", "text": "Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods.", "type": "CHEMICAL", "entities": [ "Sildenafil" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12614192", "text": "Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12614192", "text": "The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 69, 79 ] ] }, { "pmid": "12614192", "text": "Adverse events are usually associated with the vascular changes from PDE5 inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12614192", "text": "These include headache and flushing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12614192", "text": "Each of these adverse events, however, declines with medication use.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12614192", "text": "With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 16, 26 ] ] }, { "pmid": "17545671", "text": "Cytosolic aspartate aminotransferase, a new partner in adipocyte glyceroneogenesis and an atypical target of thiazolidinedione.\n", "type": "CHEMICAL", "entities": [ "aspartate", "thiazolidinedione" ], "offsets": [ [ 10, 19 ], [ 109, 126 ] ] }, { "pmid": "17545671", "text": "We show that cytosolic aspartate aminotransferase (cAspAT) is involved in adipocyte glyceroneogenesis, a regulated pathway that controls fatty acid homeostasis by promoting glycerol 3-phosphate formation for fatty acid re-esterification during fasting.", "type": "CHEMICAL", "entities": [ "fatty acid", "glycerol 3-phosphate", "fatty acid", "aspartate" ], "offsets": [ [ 137, 147 ], [ 173, 193 ], [ 208, 218 ], [ 23, 32 ] ] }, { "pmid": "17545671", "text": "cAspAT activity, as well as the incorporation of [(14)C]aspartate into the neutral lipid fraction of 3T3-F442A adipocytes was stimulated by the thiazolidinedione (TZD) rosiglitazone.", "type": "CHEMICAL", "entities": [ "[(14)C]aspartate", "thiazolidinedione", "TZD", "rosiglitazone" ], "offsets": [ [ 49, 65 ], [ 144, 161 ], [ 163, 166 ], [ 168, 181 ] ] }, { "pmid": "17545671", "text": "Conversely, the ratio of fatty acid to glycerol released into the medium decreased.", "type": "CHEMICAL", "entities": [ "fatty acid", "glycerol" ], "offsets": [ [ 25, 35 ], [ 39, 47 ] ] }, { "pmid": "17545671", "text": "Regulation of cAspAT gene expression was specific to differentiated adipocytes and did not require any peroxisome proliferator-activated receptor gamma (PPARgamma)/retinoid X receptor-alpha direct binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17545671", "text": "Nevertheless, PPARgamma is indirectly necessary for both cAspAT basal expression and TZD responsiveness because they are, respectively, diminished and abolished by ectopic overexpression of a dominant negative PPARgamma.", "type": "CHEMICAL", "entities": [ "TZD" ], "offsets": [ [ 85, 88 ] ] }, { "pmid": "17545671", "text": "The cAspAT TZD-responsive site was restricted to a single AGGACA hexanucleotide located at -381 to -376 bp whose mutation impaired the specific RORalpha binding.", "type": "CHEMICAL", "entities": [ "AGGACA", "hexanucleotide", "TZD" ], "offsets": [ [ 58, 64 ], [ 65, 79 ], [ 11, 14 ] ] }, { "pmid": "17545671", "text": "RORalpha ectopic expression activated the cAspAT gene transcription in absence of rosiglitazone, and its protein amount in nuclear extracts is 1.8-fold increased by rosiglitazone treatment of adipocytes.", "type": "CHEMICAL", "entities": [ "rosiglitazone", "rosiglitazone" ], "offsets": [ [ 82, 95 ], [ 165, 178 ] ] }, { "pmid": "17545671", "text": "Finally, the amounts of RORalpha and cAspAT mRNAs were similarly increased by TZD treatment of human adipose tissue explants, confirming coordinated regulation.", "type": "CHEMICAL", "entities": [ "TZD" ], "offsets": [ [ 78, 81 ] ] }, { "pmid": "17545671", "text": "Our data identify cAspAT as a new member of glyceroneogenesis, transcriptionally regulated by TZD via the control of RORalpha expression by PPARgamma in adipocytes.", "type": "CHEMICAL", "entities": [ "TZD" ], "offsets": [ [ 94, 97 ] ] }, { "pmid": "23291630", "text": "ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.\n", "type": "CHEMICAL", "entities": [ "ABT-199" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23291630", "text": "Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291630", "text": "This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291630", "text": "The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers.", "type": "CHEMICAL", "entities": [ "navitoclax" ], "offsets": [ [ 107, 117 ] ] }, { "pmid": "23291630", "text": "However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291630", "text": "Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199.", "type": "CHEMICAL", "entities": [ "navitoclax", "ABT-199" ], "offsets": [ [ 37, 47 ], [ 126, 133 ] ] }, { "pmid": "23291630", "text": "This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291630", "text": "A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.", "type": "CHEMICAL", "entities": [ "ABT-199" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "23618901", "text": "Smad3 mediates cigarette smoke extract (CSE) induction of VEGF release by human fetal lung fibroblasts.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), yet pathogenic mechanisms are not fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Vascular endothelial growth factor (VEGF) is one of the major regulators of endothelial cell survival and is believed to play a role in the pathogenesis of COPD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Fibroblasts are a significant source of VEGF in the lungs; however the effect of cigarette smoke exposure on VEGF release by fibroblasts is not fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "We hypothesized that cigarette smoke-induced disturbed VEGF release by human lung fibroblasts is a potential pathogenic mechanism that could contribute to COPD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Cigarette smoke extract (CSE) was prepared by modification of the methods of Carp and Janoff (American Review of Respiratory Disease, 1978).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Human fetal lung fibroblasts (HFL-1) were exposed to different concentrations of CSE and for different durations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "VEGF release into the media was measured using ELISA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "TGF-β1 receptor (TβR1)/Smad3 as a potential pathway for CSE modulated VEGF release was also investigated using biochemical analyses and siRNA inhibition of Smad3 and siRNA and pharmacologic inhibition of TβR1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "CSE induced VEGF release by HFL-1 in concentration and time dependent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "This was confirmed in two additional types of primary human fetal lung fibroblasts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "CSE induced Smad3 phosphorylation and nuclear translocation in HFL-1 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Silencing of Smad3 by siRNA not only eliminated the stimulatory effect of CSE on VEGF release but also inhibited baseline VEGF production.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Suppression of TβR1 by the pharmacological inhibitor (SB431542) markedly reduced VEGF release by HFL-1 in response to CSE and this effect was confirmed by TβR1 siRNA.", "type": "CHEMICAL", "entities": [ "SB431542" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23618901", "text": "In contrast, nicotine inhibited VEGF release by HFL-1 in a dose and time dependent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Our findings indicate that CSE stimulates Smad3-mediated VEGF release by lung fibroblasts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "Nicotine does not account for the CSE stimulation of VEGF in HFL-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23618901", "text": "The ability of lung fibroblasts to produce VEGF may play a role in pathogenesis of cigarette smoke induced lung disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23348500", "text": "A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling.\n", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "23348500", "text": "Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "23348500", "text": "Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23348500", "text": "Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23348500", "text": "Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site.", "type": "CHEMICAL", "entities": [ "MPEP", "2-Methyl-6-(phenylethynyl)pyridine" ], "offsets": [ [ 90, 94 ], [ 96, 130 ] ] }, { "pmid": "23348500", "text": "However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5.", "type": "CHEMICAL", "entities": [ "CPPHA", "N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide" ], "offsets": [ [ 24, 29 ], [ 31, 119 ] ] }, { "pmid": "23348500", "text": "Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide).", "type": "CHEMICAL", "entities": [ "CPPHA", "NCFP", "N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide" ], "offsets": [ [ 134, 139 ], [ 154, 158 ], [ 160, 236 ] ] }, { "pmid": "23348500", "text": "NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems.", "type": "CHEMICAL", "entities": [ "NCFP", "CPPHA" ], "offsets": [ [ 0, 4 ], [ 18, 23 ] ] }, { "pmid": "23348500", "text": "However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations.", "type": "CHEMICAL", "entities": [ "NCFP", "CPPHA" ], "offsets": [ [ 9, 13 ], [ 67, 72 ] ] }, { "pmid": "23348500", "text": "Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs.", "type": "CHEMICAL", "entities": [ "NCFP", "MPEP" ], "offsets": [ [ 13, 17 ], [ 156, 160 ] ] }, { "pmid": "23348500", "text": "This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23348500", "text": "Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11961111", "text": "G protein-coupled receptors as direct targets of inhaled anesthetics.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11961111", "text": "The molecular pharmacology of inhalational anesthetics remains poorly understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11961111", "text": "Despite accumulating evidence suggesting that neuronal membrane proteins are potential targets of inhaled anesthetics, most currently favored membrane protein targets lack any direct evidence for anesthetic binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11961111", "text": "We report herein the location of the binding site for the inhaled anesthetic halothane at the amino acid residue level of resolution in the ligand binding cavity in a prototypical G protein-coupled receptor, bovine rhodopsin.", "type": "CHEMICAL", "entities": [ "halothane", "amino acid" ], "offsets": [ [ 77, 86 ], [ 94, 104 ] ] }, { "pmid": "11961111", "text": "Tryptophan fluorescence quenching and direct photoaffinity labeling with [(14)C]halothane suggested an interhelical location of halothane with a stoichiometry of 1 (halothane/rhodopsin molar ratio).", "type": "CHEMICAL", "entities": [ "Tryptophan", "[(14)C]halothane", "halothane", "halothane" ], "offsets": [ [ 0, 10 ], [ 73, 89 ], [ 128, 137 ], [ 165, 174 ] ] }, { "pmid": "11961111", "text": "Radiosequence analysis of [(14)C]halothane-labeled rhodopsin revealed that halothane contacts an amino acid residue (Trp265) lining the ligand binding cavity in the transmembrane core of the receptor.", "type": "CHEMICAL", "entities": [ "[(14)C]halothane", "halothane", "amino acid" ], "offsets": [ [ 26, 42 ], [ 75, 84 ], [ 97, 107 ] ] }, { "pmid": "11961111", "text": "The predicted functional consequence, competition between halothane and the ligand retinal, was shown here by spectroscopy and is known to exist in vivo.", "type": "CHEMICAL", "entities": [ "halothane" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "11961111", "text": "These data suggest that competition with endogenous ligands may be a general mechanism of the action of halothane at this large family of signaling proteins.", "type": "CHEMICAL", "entities": [ "halothane" ], "offsets": [ [ 104, 113 ] ] }, { "pmid": "10462128", "text": "Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism.\n", "type": "CHEMICAL", "entities": [ "venlafaxine", "5-HT", "noradrenaline" ], "offsets": [ [ 11, 22 ], [ 58, 62 ], [ 67, 80 ] ] }, { "pmid": "10462128", "text": "Venlafaxine is a novel serotonin/noradrenaline reuptake inhibitor (SNRI) which has been shown clinically to be an effective antidepressant (AD) with a faster onset of action than serotonin specific reuptake inhibitors (SSRI).", "type": "CHEMICAL", "entities": [ "Venlafaxine", "serotonin", "serotonin", "noradrenaline" ], "offsets": [ [ 0, 11 ], [ 179, 188 ], [ 23, 32 ], [ 33, 46 ] ] }, { "pmid": "10462128", "text": "Preclinically, venlafaxine has been shown to potently inhibit dorsal raphe neuronal (DRN) firing through a 5-HT1A mediated mechanism, in a similar manner to SSRIs.", "type": "CHEMICAL", "entities": [ "venlafaxine" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "10462128", "text": "Here we demonstrate the acute neurochemical effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline (NA) from the rat frontal cortex using in vivo microdialysis.", "type": "CHEMICAL", "entities": [ "venlafaxine", "5-HT", "noradrenaline", "NA" ], "offsets": [ [ 55, 66 ], [ 102, 106 ], [ 111, 124 ], [ 126, 128 ] ] }, { "pmid": "10462128", "text": "Administration of venlafaxine (3-50 mg/kg s.c.) resulted in a significant dose-dependent increase in extracellular NA, but produced no significant increase in 5-HT concentrations.", "type": "CHEMICAL", "entities": [ "venlafaxine", "NA", "5-HT" ], "offsets": [ [ 18, 29 ], [ 115, 117 ], [ 159, 163 ] ] }, { "pmid": "10462128", "text": "Combination treatment with the selective 5-HT1A antagonist WAY100635 produced a dose-dependent augmentation of venlafaxine-induced (3-30 mg/kg s.c) extracellular 5-HT concentrations, but had no further effect on NA above that produced by venlafaxine alone.", "type": "CHEMICAL", "entities": [ "WAY100635", "venlafaxine", "5-HT", "NA", "venlafaxine" ], "offsets": [ [ 59, 68 ], [ 111, 122 ], [ 162, 166 ], [ 212, 214 ], [ 238, 249 ] ] }, { "pmid": "10462128", "text": "WAY100635, at doses as low as 0.03 mg/kg s.c., maintained this potentiation effect.", "type": "CHEMICAL", "entities": [ "WAY100635" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10462128", "text": "The beta-adrenergic/5-HT1A receptor antagonist (+/-)pindolol and the selective 5-HT1B/D antagonist GR127935 produced no significant augmentation of venlafaxine-induced changes in either 5-HT or NA.", "type": "CHEMICAL", "entities": [ "(+/-)pindolol", "GR127935", "venlafaxine", "5-HT", "NA" ], "offsets": [ [ 47, 60 ], [ 99, 107 ], [ 148, 159 ], [ 186, 190 ], [ 194, 196 ] ] }, { "pmid": "10462128", "text": "Using the alpha1 and alpha2-adrenoceptor antagonists, prazosin and idazoxane, we also demonstrate the role of the alpha-adrenoceptors in the augmentation of venlafaxine-induced changes.", "type": "CHEMICAL", "entities": [ "prazosin", "idazoxane", "venlafaxine" ], "offsets": [ [ 54, 62 ], [ 67, 76 ], [ 157, 168 ] ] }, { "pmid": "10462128", "text": "The possible mechanisms underlying venlafaxines improved clinical AD action and the potential for further enhancement of this SNRIs clinical effects are discussed.", "type": "CHEMICAL", "entities": [ "venlafaxines" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "12724156", "text": "GluR5 kainate receptors, seizures, and the amygdala.\n", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 6, 13 ] ] }, { "pmid": "12724156", "text": "The amygdala is a critical brain region for limbic seizure activity, but the mechanisms underlying its epileptic susceptibility are obscure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12724156", "text": "Several lines of evidence implicate GluR5 (GLU(K5))", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12724156", "text": "kainate receptors, a type of ionotropic glutamate receptor, in the amygdala's vulnerability to seizures and epileptogenesis.", "type": "CHEMICAL", "entities": [ "kainate", "glutamate" ], "offsets": [ [ 0, 7 ], [ 40, 49 ] ] }, { "pmid": "12724156", "text": "GluR5 mRNA is abundant in temporal lobe structures including the amygdala.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12724156", "text": "Brain slice recordings indicate that GluR5 kainate receptors mediate a portion of the synaptic excitation of neurons in the rat basolateral amygdala.", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "12724156", "text": "Whole-cell voltage-clamp studies demonstrate that GluR5 kainate receptor-mediated synaptic currents are inwardly rectifying and are likely to be calcium permeable.", "type": "CHEMICAL", "entities": [ "kainate", "calcium" ], "offsets": [ [ 56, 63 ], [ 145, 152 ] ] }, { "pmid": "12724156", "text": "Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium-dependent process.", "type": "CHEMICAL", "entities": [ "kainate", "calcium" ], "offsets": [ [ 51, 58 ], [ 121, 128 ] ] }, { "pmid": "12724156", "text": "The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558.", "type": "CHEMICAL", "entities": [ "LY293558", "kainate", "kainate" ], "offsets": [ [ 151, 159 ], [ 20, 27 ], [ 123, 130 ] ] }, { "pmid": "12724156", "text": "Intra-amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12724156", "text": "Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long-term plasticity mechanisms that underlie some forms of epileptogenesis.", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "12724156", "text": "Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments.", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 19, 26 ] ] }, { "pmid": "12724156", "text": "Most antiepileptic drugs do not act through effects on glutamate receptors.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 55, 64 ] ] }, { "pmid": "12724156", "text": "However, topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor-mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses.", "type": "CHEMICAL", "entities": [ "topiramate", "kainate", "kainate" ], "offsets": [ [ 9, 19 ], [ 74, 81 ], [ 243, 250 ] ] }, { "pmid": "22899102", "text": "Multidrug resistance-associated proteins are involved in the transport of the glutathione conjugates of the ultimate carcinogen of benzo[a]pyrene in human Caco-2 cells.\n", "type": "CHEMICAL", "entities": [ "benzo[a]pyrene", "glutathione" ], "offsets": [ [ 131, 145 ], [ 78, 89 ] ] }, { "pmid": "22899102", "text": "A wide variety of contaminants are ingested through food, among them the pro-carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) that is resorbed and partially metabolized in the enterocytes of the small intestine.", "type": "CHEMICAL", "entities": [ "benzo[a]pyrene" ], "offsets": [ [ 122, 136 ] ] }, { "pmid": "22899102", "text": "Previous in vitro studies have revealed that BP phenols are excreted as Phase II metabolites including glucuronides and sulfates.", "type": "CHEMICAL", "entities": [ "BP phenols", "sulfates" ], "offsets": [ [ 45, 55 ], [ 120, 128 ] ] }, { "pmid": "22899102", "text": "This export is mediated by the breast cancer resistance protein (ABCG2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22899102", "text": "The ultimate carcinogenic Phase I BP metabolite anti-BP-7,8-dihydrodiol-9,10-epoxide (BPDE) can be detoxified by glutathione conjugate formation catalyzed by glutathione S-transferases.", "type": "CHEMICAL", "entities": [ "BP-7,8-dihydrodiol-9,10-epoxide", "BPDE", "glutathione", "glutathione", "S" ], "offsets": [ [ 53, 84 ], [ 86, 90 ], [ 113, 124 ], [ 158, 169 ], [ 170, 171 ] ] }, { "pmid": "22899102", "text": "In the present study, differentiated human intestinal Caco-2 cells were used as a model for the human small intestine to investigate the detoxification of BPDE and excretion of stereoisomeric glutathione conjugates in the presence of an inhibitor of the glutathione-cleaving enzyme γ-glutamyl transpeptidase at the cell surface.", "type": "CHEMICAL", "entities": [ "BPDE", "glutathione", "glutathione" ], "offsets": [ [ 155, 159 ], [ 192, 203 ], [ 254, 265 ] ] }, { "pmid": "22899102", "text": "The results indicate that the glutathione conjugates of BPDE are formed and excreted mainly to the apical and to a minor extent to the basolateral side of polarized Caco-2 monolayers.", "type": "CHEMICAL", "entities": [ "BPDE", "glutathione" ], "offsets": [ [ 55, 59 ], [ 29, 40 ] ] }, { "pmid": "22899102", "text": "Inhibition studies revealed that the multidrug resistance-associated proteins (ABCCs) are involved in the transport of BPDE glutathione conjugates.", "type": "CHEMICAL", "entities": [ "BPDE glutathione" ], "offsets": [ [ 118, 134 ] ] }, { "pmid": "22899102", "text": "Stable ABCC1, ABCC2 and ABCC3 knockdown cell lines were generated, thus making it possible to demonstrate that ABCC1 mediates the basolateral and ABCC2 the apical excretion of BPDE glutathione conjugates.", "type": "CHEMICAL", "entities": [ "BPDE glutathione" ], "offsets": [ [ 175, 191 ] ] }, { "pmid": "22899102", "text": "In conclusion, the ultimate carcinogen BPDE is detoxified via glutathione conjugation and subsequently excreted by Caco-2 cells in both apical and basolateral directions.", "type": "CHEMICAL", "entities": [ "BPDE", "glutathione" ], "offsets": [ [ 38, 42 ], [ 61, 72 ] ] }, { "pmid": "22899102", "text": "This finding is equivalent to a transport into feces as well as blood system in the in vivo situation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265491", "text": "Evaluation of biological activities of a groundnut (Apios americana Medik) extract containing a novel isoflavone.\n", "type": "CHEMICAL", "entities": [ "isoflavone" ], "offsets": [ [ 102, 112 ] ] }, { "pmid": "23265491", "text": "Groundnut (Apios americana Medik) contains a novel isoflavone, genistein-7-O-gentiobioside.", "type": "CHEMICAL", "entities": [ "isoflavone", "genistein-7-O-gentiobioside" ], "offsets": [ [ 51, 61 ], [ 63, 90 ] ] }, { "pmid": "23265491", "text": "In the present study, we examined the biological activities of an alcohol extract of groundnut containing genistein-7-O-gentiobioside as the main component.", "type": "CHEMICAL", "entities": [ "alcohol", "genistein-7-O-gentiobioside" ], "offsets": [ [ 66, 73 ], [ 106, 133 ] ] }, { "pmid": "23265491", "text": "Although the groundnut extract by itself did not show antioxidative activity, it drove the antioxidative system in cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265491", "text": "Pretreatment of human breast carcinoma MCF-7 cells for 24 h with the groundnut extract and soybean isoflavone increased gene expression of heme oxygenase-1 (HO-1), a major antioxidative stress enzyme.", "type": "CHEMICAL", "entities": [ "isoflavone" ], "offsets": [ [ 99, 109 ] ] }, { "pmid": "23265491", "text": "These groundnut extract-treated cells showed antioxidative activity against free radicals derived from a radical initiator.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265491", "text": "Pretreatment of cells with 100 μg/mL groundnut extract prevented the depletion of glutathione by the radical initiator; however, treatment with 100 μg/mL of soybean isoflavone injured the cell membrane, indicating that glutathione might be released to the extracellular environment.", "type": "CHEMICAL", "entities": [ "glutathione", "isoflavone", "glutathione" ], "offsets": [ [ 82, 93 ], [ 165, 175 ], [ 219, 230 ] ] }, { "pmid": "23265491", "text": "These results suggest that the groundnut extract had isoflavone-like activity.", "type": "CHEMICAL", "entities": [ "isoflavone" ], "offsets": [ [ 51, 61 ] ] }, { "pmid": "23265491", "text": "Like soybean, groundnuts are a good source of isoflavones.", "type": "CHEMICAL", "entities": [ "isoflavones" ], "offsets": [ [ 44, 55 ] ] }, { "pmid": "16846546", "text": "Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium.\n", "type": "CHEMICAL", "entities": [ "bromfenac sodium", "ketorolac tromethamine" ], "offsets": [ [ 116, 132 ], [ 89, 111 ] ] }, { "pmid": "16846546", "text": "OBJECTIVE: To compare the cyclooxygenase (COX) activity and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketorolac tromethamine (ketorolac) and bromfenac sodium (bromfenac).", "type": "CHEMICAL", "entities": [ "ketorolac tromethamine", "ketorolac", "bromfenac sodium", "bromfenac" ], "offsets": [ [ 139, 161 ], [ 163, 172 ], [ 178, 194 ], [ 196, 205 ] ] }, { "pmid": "16846546", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "Cyclooxygenase activity and selectivity was determined in vitro by measuring prostaglandin E(2) (PGE(2))", "type": "CHEMICAL", "entities": [ "prostaglandin E(2)", "PGE(2)" ], "offsets": [ [ 77, 95 ], [ 97, 103 ] ] }, { "pmid": "16846546", "text": "production following incubation of varying concentrations of NSAID with human recombinant COX-1 or COX-2 and arachidonic acid.", "type": "CHEMICAL", "entities": [ "arachidonic acid" ], "offsets": [ [ 109, 125 ] ] }, { "pmid": "16846546", "text": "Anti-inflammatory effects were evaluated in a rabbit model in which an ocular inflammatory response was induced by intravenous injection of 10 microg/kg lipopolysaccharide (LPS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "In study animals, one eye was treated with 50 microL (+/-)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50 microL buffered saline.", "type": "CHEMICAL", "entities": [ "Acular LS", "bromfenac", "Xibrom" ], "offsets": [ [ 16, 25 ], [ 30, 39 ], [ 47, 53 ] ] }, { "pmid": "16846546", "text": "In control animals, both eyes were treated with vehicle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "All animals were treated twice: 2 hours and 1 hour before LPS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "MAIN OUTCOME MEASURES: PGE(2) production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE(2) levels in vivo, measured by ELISA immunoassay.", "type": "CHEMICAL", "entities": [ "FITC", "PGE(2)", "PGE(2)", "fluorescein isothiocyanate" ], "offsets": [ [ 111, 115 ], [ 198, 204 ], [ 23, 29 ], [ 83, 109 ] ] }, { "pmid": "16846546", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "Ketorolac was six times more active against COX-1 (IC(50) = 0.02 microM) than COX-2 (IC(50) = 0.12 microM) while bromfenac was approximately 32 times more active against COX-2 (IC(50) = 0.0066 microM) than COX-1 (IC(50) = 0.210 microM).", "type": "CHEMICAL", "entities": [ "Ketorolac", "bromfenac" ], "offsets": [ [ 0, 9 ], [ 113, 122 ] ] }, { "pmid": "16846546", "text": "In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE(2) production in the anterior chamber of treated eyes.", "type": "CHEMICAL", "entities": [ "FITC", "PGE(2)" ], "offsets": [ [ 74, 78 ], [ 99, 105 ] ] }, { "pmid": "16846546", "text": "There was also a 79% inhibition (p < 0.001) of FITC-dextran leakage in the contralateral eyes of bromfenac-treated rabbits, and a 22.5% inhibition (not statistically significant) in the contralateral eyes of ketorolac-treated rabbits.", "type": "CHEMICAL", "entities": [ "FITC", "bromfenac", "ketorolac" ], "offsets": [ [ 47, 51 ], [ 97, 106 ], [ 208, 217 ] ] }, { "pmid": "16846546", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16846546", "text": "Ketorolac is relatively COX-1 selective while bromfenac is potently selective for COX-2 over COX-1.", "type": "CHEMICAL", "entities": [ "Ketorolac", "bromfenac" ], "offsets": [ [ 0, 9 ], [ 46, 55 ] ] }, { "pmid": "16846546", "text": "In the animal model, both ketorolac 0.4% and bromfenac 0.09% demonstrated maximal anti-inflammatory activity in treated eyes.", "type": "CHEMICAL", "entities": [ "ketorolac", "bromfenac" ], "offsets": [ [ 26, 35 ], [ 45, 54 ] ] }, { "pmid": "16846546", "text": "Only bromfenac 0.09% had a significant effect on the contralateral eye, suggesting possible systemic absorption of this drug.", "type": "CHEMICAL", "entities": [ "bromfenac" ], "offsets": [ [ 5, 14 ] ] }, { "pmid": "18715952", "text": "Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets.\n", "type": "CHEMICAL", "entities": [ "prostaglandin E2" ], "offsets": [ [ 40, 56 ] ] }, { "pmid": "18715952", "text": "Prostaglandin E(2) (PGE(2)) has been shown to play important roles in several aspects of tumor development and progression.", "type": "CHEMICAL", "entities": [ "Prostaglandin E(2)", "PGE(2)" ], "offsets": [ [ 0, 18 ], [ 20, 26 ] ] }, { "pmid": "18715952", "text": "PGE(2) is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin E synthases (PGES) and mediates its biological activity through binding to the four prostanoid receptors EP(1) through EP(4).", "type": "CHEMICAL", "entities": [ "PGE(2)", "arachidonic acid", "prostaglandin E" ], "offsets": [ [ 0, 6 ], [ 27, 43 ], [ 73, 88 ] ] }, { "pmid": "18715952", "text": "In this study, we show for the first time that medulloblastoma (MB), the most common malignant childhood brain tumor, expresses high levels of COX-2, microsomal prostaglandin E synthase-1, and EP(1) through EP(4) and secretes PGE(2).", "type": "CHEMICAL", "entities": [ "prostaglandin E", "PGE(2)" ], "offsets": [ [ 161, 176 ], [ 226, 232 ] ] }, { "pmid": "18715952", "text": "PGE(2) and the EP(2) receptor agonist butaprost stimulated MB cell proliferation.", "type": "CHEMICAL", "entities": [ "PGE(2)" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "18715952", "text": "Treatment of MB cells with COX inhibitors suppressed PGE(2) production and induced caspase-dependent apoptosis.", "type": "CHEMICAL", "entities": [ "PGE(2)" ], "offsets": [ [ 53, 59 ] ] }, { "pmid": "18715952", "text": "Similarly, specific COX-2 silencing by small interfering RNA inhibited MB cell growth.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18715952", "text": "EP(1) and EP(3) receptor antagonists ONO-8713 and ONO-AE3-240, but not the EP(4) antagonists ONO-AE3-208 and AH 23848, inhibited tumor cell proliferation, indicating the significance of EP(1) and EP(3) but not EP(4) for MB growth.", "type": "CHEMICAL", "entities": [ "ONO-8713", "ONO-AE3-240", "ONO-AE3-208", "AH 23848" ], "offsets": [ [ 37, 45 ], [ 50, 61 ], [ 93, 104 ], [ 109, 117 ] ] }, { "pmid": "18715952", "text": "Administration of COX inhibitors at clinically achievable nontoxic concentrations significantly inhibited growth of established human MB xenografts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18715952", "text": "Apoptosis was increased, proliferation was reduced, and angiogenesis was inhibited in MBs treated with COX inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18715952", "text": "This study suggests that PGE(2) is important for MB growth and that therapies targeting the prostanoid metabolic pathway are potentially beneficial and should be tested in clinical settings for treatment of children with MB.", "type": "CHEMICAL", "entities": [ "PGE(2)" ], "offsets": [ [ 25, 31 ] ] }, { "pmid": "8646863", "text": "Fluticasone propionate: safety profile.\n", "type": "CHEMICAL", "entities": [ "Fluticasone propionate" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "8646863", "text": "Fluticasone propionate is a potent fluorinated corticosteroid used for the topical therapy of dermatoses and as inhalation therapy for bronchial asthma and allergic rhinitis.", "type": "CHEMICAL", "entities": [ "Fluticasone propionate" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "8646863", "text": "This agent has a good safety profile with a low propensity for systemic side effects, such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis, and a low incidence of local side effects such as pruritus, burning, or skin atrophy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8646863", "text": "The pharmacologic properties of fluticasone propionate-including high lipophilicity, high selectivity and affinity for the glucocorticoid receptor, low systemic absorption, and rapid metabolism and clearance-combine to give fluticasone propionate a high therapeutic index.", "type": "CHEMICAL", "entities": [ "fluticasone propionate", "fluticasone propionate" ], "offsets": [ [ 32, 54 ], [ 224, 246 ] ] }, { "pmid": "23259985", "text": "Bioreducible polymers as a determining factor for polyplex decomplexation rate and transfection.\n", "type": "CHEMICAL", "entities": [ "polyplex" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23259985", "text": "Polyplex formation (complexation) and gene release from the polyplexes (decomplexation) are major events in polymeric gene delivery; however, the effect of the decomplexation rate on transfection has been rarely investigated.", "type": "CHEMICAL", "entities": [ "Polyplex", "polyplexes" ], "offsets": [ [ 0, 8 ], [ 60, 70 ] ] }, { "pmid": "23259985", "text": "This study employed mixed polymers of poly((L)-lysine)", "type": "CHEMICAL", "entities": [ "poly((L)-lysine)" ], "offsets": [ [ 38, 54 ] ] }, { "pmid": "23259985", "text": "(PLL: MW ~7.4 kDa) and reducible PLL (RPLL) (MW ~6.7 kDa) to design decomplexation rate-controllable PLL(100-x)RPLL(x)/pDNA complexes (PRL(x) polyplexes).", "type": "CHEMICAL", "entities": [ "PLL", "PLL", "PLL", "polyplexes" ], "offsets": [ [ 1, 4 ], [ 33, 36 ], [ 101, 104 ], [ 142, 152 ] ] }, { "pmid": "23259985", "text": "The transfection efficiency of a model gene (luciferase) in MCF7 and HEK293 cell lines increased with increasing x (RPLL content) in the PRL(x) polyplexes until peaking at x = 2.5 and 10, respectively, after which point transfection efficiency declined rapidly.", "type": "CHEMICAL", "entities": [ "polyplexes" ], "offsets": [ [ 144, 154 ] ] }, { "pmid": "23259985", "text": "In MCF7 cells, PRL(2.5) polyplex produced 3 or 223 times higher gene expression than PLL or RPLL polyplexes, respectively.", "type": "CHEMICAL", "entities": [ "polyplex", "PLL", "polyplexes" ], "offsets": [ [ 24, 32 ], [ 85, 88 ], [ 97, 107 ] ] }, { "pmid": "23259985", "text": "Similarly, the transfection efficiency of PRL(10) polyplex-transfected HEK293 cells was 3.8 or 67 times higher than that of PLL or RPLL polyplexes, respectively.", "type": "CHEMICAL", "entities": [ "polyplex", "PLL", "polyplexes" ], "offsets": [ [ 50, 58 ], [ 124, 127 ], [ 136, 146 ] ] }, { "pmid": "23259985", "text": "The transfection results were not apparently related to the particle size, surface charge, complexation/compactness, cellular uptake, or cytotoxicity of the tested polyplexes.", "type": "CHEMICAL", "entities": [ "polyplexes" ], "offsets": [ [ 164, 174 ] ] }, { "pmid": "23259985", "text": "However, the decomplexation rate varied by RPLL content in the polyplexes, which in turn influenced the gene transfection.", "type": "CHEMICAL", "entities": [ "polyplexes" ], "offsets": [ [ 63, 73 ] ] }, { "pmid": "23259985", "text": "The nuclear localization of pDNA delivered by PRL(x) polyplexes showed a similar trend to their transfection efficiencies.", "type": "CHEMICAL", "entities": [ "polyplexes" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "23259985", "text": "This study suggests that an optimum decomplexation rate may result in high nuclear localization of pDNA and transfection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23259985", "text": "Understanding in decomplexation and intracellular localization of pDNA may help develop more effective polyplexes.", "type": "CHEMICAL", "entities": [ "polyplexes" ], "offsets": [ [ 103, 113 ] ] }, { "pmid": "18282775", "text": "Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol.\n", "type": "CHEMICAL", "entities": [ "salbutamol" ], "offsets": [ [ 110, 120 ] ] }, { "pmid": "18282775", "text": "In asthma and chronic obstructive pulmonary disease (COPD), the number of eosinophils and neutrophils in the lung is increased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18282775", "text": "One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18282775", "text": "Selective inhibitors of phosphodiesterases (PDEs) are under development for the treatment of lung diseases because of their anti-inflammatory and bronchodilator activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18282775", "text": "The aim of the present study was to establish whether inhibitors of PDE3, PDE4 and PDE5 modulate human eosinophil or neutrophil apoptosis or beta 2-adrenoceptor agonist- or cytokine-afforded survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18282775", "text": "We also evaluated whether a PDE4 inhibitor could modulate the effect of a corticosteroid on eosinophil and neutrophil apoptosis.", "type": "CHEMICAL", "entities": [ "corticosteroid" ], "offsets": [ [ 74, 88 ] ] }, { "pmid": "18282775", "text": "Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18282775", "text": "Inhibitors of PDE4 (rolipram; 0.1-10 microM) and PDE3 (cilostazol; 0.1-10 microM) delayed spontaneous eosinophil apoptosis maximally by 25% and 15%, respectively.", "type": "CHEMICAL", "entities": [ "rolipram", "cilostazol" ], "offsets": [ [ 20, 28 ], [ 55, 65 ] ] }, { "pmid": "18282775", "text": "A combination of a PDE4 or PDE3 inhibitor (10 microM) with salbutamol (100 nM) further delayed eosinophil apoptosis maximally by 42-49%.", "type": "CHEMICAL", "entities": [ "salbutamol" ], "offsets": [ [ 59, 69 ] ] }, { "pmid": "18282775", "text": "In neutrophils, rolipram (10 microM) also decreased apoptosis with a maximal inhibition of 13%.", "type": "CHEMICAL", "entities": [ "rolipram" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "18282775", "text": "The combination of rolipram (10 microM) and salbutamol (100 nM) produced a 27% inhibition of neutrophil apoptosis.", "type": "CHEMICAL", "entities": [ "rolipram", "salbutamol" ], "offsets": [ [ 19, 27 ], [ 44, 54 ] ] }, { "pmid": "18282775", "text": "Inhibitor of cGMP-specific PDE5 (zaprinast; 0.1-10 microM) did not affect eosinophil apoptosis and only slightly increased spontaneous neutrophil apoptosis.", "type": "CHEMICAL", "entities": [ "cGMP", "zaprinast" ], "offsets": [ [ 13, 17 ], [ 33, 42 ] ] }, { "pmid": "18282775", "text": "The effect of budesonide on apoptosis was not significantly modulated by a PDE4 inhibitor in eosinophils or neutrophils.", "type": "CHEMICAL", "entities": [ "budesonide" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "18282775", "text": "The present results show that selective inhibitors of cAMP-hydrolyzing PDEs (PDE3 and PDE4) delay eosinophil apoptosis and, thus, increase their survival in vitro.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 54, 58 ] ] }, { "pmid": "18282775", "text": "Furthermore, beta 2-adrenoceptor agonists enhance the anti-apoptotic effects of PDE3 and PDE4 inhibitors, suggesting that such drug combinations may prolong eosinophil and neutrophil longevity in the lung.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "Significance of the transient receptor potential canonical 2 (TRPC2) channel in the regulation of rat thyroid FRTL-5 cell proliferation, migration, adhesion and invasion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "Mammalian transient receptor potential (TRP) channels are involved in many physiologically important processes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "Here, we have studied the significance of the TRPC2 channel in the regulation of rat thyroid FRTL-5 cell proliferation, migration, adhesion and invasion, using stable TRPC2 (shTRPC2) knock-down cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "In the shTRPC2 cells, proliferation was decreased due to a prolonged G1/S cell cycle phase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "The tumor suppressor p53 and the cyclin-dependant kinase inhibitors p27 and p21 were upregulated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "Cell invasion, adhesion and migration were also attenuated in shTRPC2 cells, probably due to decreased activity of both Rac and calpain, and a decreased secretion and activity of matrix metalloproteinase 2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578584", "text": "The attenuated proliferation, migration, invasion and ATP-evoked calcium entry was mimicked by overexpressing a non-conducting, truncated TRPC2 (TRPC2-DN) in wild type cells, and was reversed by overexpression of TRPC2-GFP in shTRPC2 cells.", "type": "CHEMICAL", "entities": [ "ATP", "calcium" ], "offsets": [ [ 54, 57 ], [ 65, 72 ] ] }, { "pmid": "23578584", "text": "In conclusion, TRPC2 is an important regulator of rat thyroid cell function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "Lutein and eicosapentaenoic acid interact to modify iNOS mRNA levels through the PPARgamma/RXR pathway in chickens and HD11 cell lines.\n", "type": "CHEMICAL", "entities": [ "eicosapentaenoic acid" ], "offsets": [ [ 11, 32 ] ] }, { "pmid": "16702329", "text": "Two experiments were conducted to investigate the effect of lutein and fat or eicosapentaenoic acid (EPA) interaction on inducible nitric oxide synthase (iNOS), PPARs alpha, beta, and gamma, and retinoic acid X receptor (RXR) alpha and gamma mRNA levels.", "type": "CHEMICAL", "entities": [ "EPA", "nitric oxide", "retinoic acid", "eicosapentaenoic acid" ], "offsets": [ [ 101, 104 ], [ 131, 143 ], [ 195, 208 ], [ 78, 99 ] ] }, { "pmid": "16702329", "text": "In Expt.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "1, macrophages were collected from broiler chicks fed 3 or 6% dietary fat (g/100 g) with 0, 25, and 50 mg lutein/kg feed for 23 d. In Expt.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "2, using a 3 x 3 factorial, eicosapentaenoic acid (EPA) at 0, 15 and 50 micromol/L and lutein at 0, 10 and 100 micromol/L were applied to HD11 cell culture for 24 h. In both experiments, cells were stimulated with lipopolysaccharide before RNA isolation.", "type": "CHEMICAL", "entities": [ "eicosapentaenoic acid", "EPA" ], "offsets": [ [ 28, 49 ], [ 51, 54 ] ] }, { "pmid": "16702329", "text": "Lutein interacted with fat in Expt.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "1 and with EPA in Expt.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "2 to affect mRNA levels of iNOS, PPARgamma, and RXRalpha in chicken macrophages and HD11 cells, respectively (P < 0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "At 3% dietary fat or up to 15 micromol/L EPA in the medium, increasing lutein increased the iNOS mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "However, at 6% dietary fat or 50 micromol/L EPA, lutein did not cause a rise in iNOS mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "Increasing lutein in the medium from 0 to 100 micromol/L decreased iNOS mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "Increasing lutein with high fat (6%) or EPA (15 micromol/L EPA) increased PPARgamma and RXRalpha mRNA levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "Lutein increased PPARalpha mRNA levels in both macrophages (P < 0.01) and HD11 (P = 0.01) cells and RXRgamma (P < 0.01) mRNA levels in macrophages.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "GW9662, a PPARgamma antagonist, prevented (P < 0.01)", "type": "CHEMICAL", "entities": [ "GW9662" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "16702329", "text": "the lutein-induced iNOS mRNA downregulation in HD11 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "LG101208, a RXR antagonist, prevented (P < 0.01) iNOS upregulation induced by 10 micromol/L lutein and iNOS mRNA downregulation induced by 100 micromol/L lutein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16702329", "text": "We conclude that lutein and EPA interact through the PPARgamma and RXR pathways to modulate iNOS mRNA.", "type": "CHEMICAL", "entities": [ "EPA" ], "offsets": [ [ 28, 31 ] ] }, { "pmid": "17111172", "text": "Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol.\n", "type": "CHEMICAL", "entities": [ "flupentixol", "dopamine", "risperidone", "haloperidol", "serotonin" ], "offsets": [ [ 102, 113 ], [ 13, 21 ], [ 133, 144 ], [ 149, 160 ], [ 38, 47 ] ] }, { "pmid": "17111172", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades.", "type": "CHEMICAL", "entities": [ "Flupentixol", "FLX" ], "offsets": [ [ 0, 11 ], [ 13, 16 ] ] }, { "pmid": "17111172", "text": "In vitro data show comparable affinity to dopamine D(2), D(1) and 5-HT(2A) receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT(2A) and/or D(1) receptors.", "type": "CHEMICAL", "entities": [ "dopamine", "FLX", "risperidone" ], "offsets": [ [ 42, 50 ], [ 99, 102 ], [ 132, 143 ] ] }, { "pmid": "17111172", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day).", "type": "CHEMICAL", "entities": [ "risperidone", "haloperidol" ], "offsets": [ [ 130, 141 ], [ 180, 191 ] ] }, { "pmid": "17111172", "text": "MATERIALS AND METHODS: Each patient underwent two PET scans with 3-N-[(11)C]methylspiperone (target: frontal 5-HT(2A)),", "type": "CHEMICAL", "entities": [ "3-N-[(11)C]methylspiperone" ], "offsets": [ [ 65, 91 ] ] }, { "pmid": "17111172", "text": "[(11)C]SCH23390 (striatal D(1)) or [(11)C]raclopride (striatal D(2)).", "type": "CHEMICAL", "entities": [ "[(11)C]SCH23390", "[(11)C]raclopride" ], "offsets": [ [ 0, 15 ], [ 35, 52 ] ] }, { "pmid": "17111172", "text": "RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "D(2)-RO under FLX was between 50% and 70%, indicating an ED(50) of about 0.7 ng/ml serum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "5-HT(2A) and D(1)-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "Under HAL, D(1)-RO was 14 +/- 6% and under RIS not significantly different from zero.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "We were able to demonstrate a moderate 5-HT(2A) and D(1) occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation.", "type": "CHEMICAL", "entities": [ "flupentixol" ], "offsets": [ [ 102, 113 ] ] }, { "pmid": "17111172", "text": "Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT(2A) and/or D(1) receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17111172", "text": "However, these data suggest that mechanisms other than D(1) or 5-HT(2A) antagonism may contribute to flupentixol's efficacy on negative symptoms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373557", "text": "Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers.\n", "type": "CHEMICAL", "entities": [ "monoamine", "meta-hydroxyephedrine" ], "offsets": [ [ 29, 38 ], [ 62, 83 ] ] }, { "pmid": "12373557", "text": "Meta-hydroxyephedrine (HED) comprises four stereoisomers consisting of two enantiomeric pairs related to ephedrine and pseudoephedrine.", "type": "CHEMICAL", "entities": [ "Meta-hydroxyephedrine", "ephedrine", "pseudoephedrine", "HED" ], "offsets": [ [ 0, 21 ], [ 105, 114 ], [ 119, 134 ], [ 23, 26 ] ] }, { "pmid": "12373557", "text": "HED is transported into adrenergic neurons and radiolabeled HED has been employed in positron emission tomography (PET) to image adrenergic neurons in vivo.", "type": "CHEMICAL", "entities": [ "HED", "HED" ], "offsets": [ [ 0, 3 ], [ 60, 63 ] ] }, { "pmid": "12373557", "text": "To extend structure-activity analyses of binding sites within monoamine transporters and to determine which stereoisomer displayed the best selectivity for PET imaging applications, we tested the HED compounds for their abilities to inhibit [(3)H]neurotransmitter uptake into platelets, transfected cells, and chromaffin vesicles.", "type": "CHEMICAL", "entities": [ "monoamine", "HED", "(3)H" ], "offsets": [ [ 62, 71 ], [ 196, 199 ], [ 242, 246 ] ] }, { "pmid": "12373557", "text": "We hypothesized that the HED compounds would be most potent at the norepinephrine transporter (NET) compared to the serotonin or dopamine transporters and that the 1R diastereomers would be more effective than 1S diastereomers.", "type": "CHEMICAL", "entities": [ "HED", "norepinephrine", "serotonin", "dopamine" ], "offsets": [ [ 25, 28 ], [ 67, 81 ], [ 116, 125 ], [ 129, 137 ] ] }, { "pmid": "12373557", "text": "Supporting the hypotheses, all stereoisomers were most potent at the NET and the 1R,2S stereoisomer was the most potent inhibitor overall.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12373557", "text": "However, the 1S,2R isomer may be preferred for PET applications because of better selectivity among the transporters and reduced neuronal recycling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23429912", "text": "TCDD inhibition of canonical wnt signaling disrupts prostatic bud formation in mouse urogenital sinus.\n", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23429912", "text": "In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis.", "type": "CHEMICAL", "entities": [ "2,3,7,8-tetrachlorodibenzo-p- dioxin", "TCDD" ], "offsets": [ [ 30, 66 ], [ 68, 72 ] ] }, { "pmid": "23429912", "text": "The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 45, 49 ] ] }, { "pmid": "23429912", "text": "Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23429912", "text": "In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD.", "type": "CHEMICAL", "entities": [ "TCDD", "TCDD", "TCDD", "TCDD" ], "offsets": [ [ 655, 659 ], [ 34, 38 ], [ 108, 112 ], [ 241, 245 ] ] }, { "pmid": "23429912", "text": "Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 10, 14 ] ] }, { "pmid": "23429912", "text": "This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation.", "type": "CHEMICAL", "entities": [ "TCDD", "TCDD" ], "offsets": [ [ 55, 59 ], [ 160, 164 ] ] }, { "pmid": "23429912", "text": "We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 71, 75 ] ] }, { "pmid": "23446230", "text": "CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice.\n", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 32, 36 ] ] }, { "pmid": "23446230", "text": "Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on the cardiovascular system.", "type": "CHEMICAL", "entities": [ "EETs", "arachidonic acids", "epoxyeicosatrienoic acids" ], "offsets": [ [ 106, 110 ], [ 53, 70 ], [ 79, 104 ] ] }, { "pmid": "23446230", "text": "However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown.", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 28, 32 ] ] }, { "pmid": "23446230", "text": "Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-deficient mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23446230", "text": "rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation.", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 79, 83 ] ] }, { "pmid": "23446230", "text": "It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic inflammation and macrophage infiltration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23446230", "text": "In cultured vascular smooth muscle cells (VSMCs), rAAV-mediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced inflammatory cytokine expression.", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 90, 94 ] ] }, { "pmid": "23446230", "text": "Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system.", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 35, 39 ] ] }, { "pmid": "23446230", "text": "We further indicated that these protective effects were mediated by peroxisome proliferator-activated receptor (PPAR)γ activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23446230", "text": "Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPARγ activation and anti-inflammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA.", "type": "CHEMICAL", "entities": [ "EETs" ], "offsets": [ [ 206, 210 ] ] }, { "pmid": "23536521", "text": "Differential effects of organic and inorganic selenium compounds on adenosine deaminase activity and scavenger capacity in cerebral cortex slices of young rats.\n", "type": "CHEMICAL", "entities": [ "selenium", "adenosine" ], "offsets": [ [ 46, 54 ], [ 68, 77 ] ] }, { "pmid": "23536521", "text": "Selenium (Se) has anti-inflammatory and antioxidant properties and is necessary for the development and normal function of the central nervous system.", "type": "CHEMICAL", "entities": [ "Selenium", "Se" ], "offsets": [ [ 0, 8 ], [ 10, 12 ] ] }, { "pmid": "23536521", "text": "This study was aimed to compare the in vitro effects of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one (C21H2HOSe; organoselenium) and sodium selenate (inorganic Se) on adenosine deaminase (ADA) activity, cell viability, lipid peroxidation, scavenger of nitric oxide (NO) and nonprotein thiols (NP-SH) content in the cerebral cortex slices of the young rats.", "type": "CHEMICAL", "entities": [ "3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one", "C21H2HOSe", "organoselenium", "sodium selenate", "Se", "adenosine", "nitric oxide", "NO", "thiols", "SH" ], "offsets": [ [ 56, 104 ], [ 106, 115 ], [ 117, 131 ], [ 137, 152 ], [ 164, 166 ], [ 171, 180 ], [ 256, 268 ], [ 270, 272 ], [ 289, 295 ], [ 300, 302 ] ] }, { "pmid": "23536521", "text": "A decrease in ADA activity was observed when the slices were exposed to organoselenium at the concentrations of 1, 10 and 30 µM. The same compound showed higher scavenger capacity of NO than the inorganic compound.", "type": "CHEMICAL", "entities": [ "organoselenium", "NO" ], "offsets": [ [ 72, 86 ], [ 183, 185 ] ] }, { "pmid": "23536521", "text": "Inorganic Se was able to protect against sodium nitroprusside-induced oxidative damage and increased the NP-SH content.", "type": "CHEMICAL", "entities": [ "Se", "sodium nitroprusside", "SH" ], "offsets": [ [ 9, 11 ], [ 40, 60 ], [ 107, 109 ] ] }, { "pmid": "23536521", "text": "Both the compounds displayed distinctive antioxidant capacities and were not cytotoxic for the cerebral cortex slices in the conditions tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23536521", "text": "These findings are likely to be related to immunomodulatory and antioxidant properties of this compound.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "Antigenotoxic potencies of a lichen species, Evernia prunastri.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "In this article, the genotoxic and antigenotoxic effects of methanol extract of Evernia prunastri (Huds.)", "type": "CHEMICAL", "entities": [ "methanol" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23293129", "text": "Willd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "(MEP) were studied using WP2, Ames (TA1535 and TA1537) and sister chromatid exchange (SCE) test systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "The results obtained from bacterial test systems demonstrated that MEP has strong antimutagenic potencies on TA1537 and WP2 strains.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "The highest inhibition rates for MEP on TA1537 and WP2 strains were 37.70% and 69.70%, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "According to the SCE test system, MEP reduced the genotoxic effects of aflatoxin.", "type": "CHEMICAL", "entities": [ "aflatoxin" ], "offsets": [ [ 71, 80 ] ] }, { "pmid": "23293129", "text": "In order to clarify the mechanism underlying the antigenotoxic effects of MEP, the antioxidants were determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "Cotreatments of 5, 10 and 20 µg/mL concentrations of MEP with aflatoxin B(1) decreased the frequencies of SCE and the malondialdehyde level and increased amount of superoxide dismutase, glutathione and glutathione peroxidase which were decreased by aflatoxin.", "type": "CHEMICAL", "entities": [ "aflatoxin B(1)", "malondialdehyde", "superoxide", "glutathione", "glutathione", "aflatoxin" ], "offsets": [ [ 62, 76 ], [ 118, 133 ], [ 164, 174 ], [ 186, 197 ], [ 202, 213 ], [ 249, 258 ] ] }, { "pmid": "23293129", "text": "The data obtained from this work have clearly shown that MEP has significant antigenotoxic effects which are thought to be partly due to the antioxidant activities and antioxidant inducing capability of MEP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23293129", "text": "This is the first report indicating the antigenotoxic activities of MEP against several mutagen agents such as N-methyl-N'-nitro-N-nitrosoguanidine, acridin and aflatoxin.", "type": "CHEMICAL", "entities": [ "N-methyl-N'-nitro-N-nitrosoguanidine", "acridin", "aflatoxin" ], "offsets": [ [ 110, 146 ], [ 148, 155 ], [ 160, 169 ] ] }, { "pmid": "23528251", "text": "Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression.\n", "type": "CHEMICAL", "entities": [ "androstane" ], "offsets": [ [ 32, 42 ] ] }, { "pmid": "23528251", "text": "Hypoxia inducible factor (HIF) and 5'-AMP-activated protein kinase are often activated under similar physiological conditions.", "type": "CHEMICAL", "entities": [ "5'-AMP" ], "offsets": [ [ 35, 41 ] ] }, { "pmid": "23528251", "text": "Constitutive androstane receptor (CAR) translocates into the nucleus in accordance with 5'-AMP-activated protein kinase and thus confers transactivation.", "type": "CHEMICAL", "entities": [ "androstane", "5'-AMP" ], "offsets": [ [ 13, 23 ], [ 88, 94 ] ] }, { "pmid": "23528251", "text": "The aim of the present study was to investigate a possible link between CAR and HIFα. Phenobarbital (PB), a typical CAR activator, increased the gene expression of HIF-target genes in the livers of mice, including erythropoietin, heme oxygenase-1 and vascular endothelial growth factor-a. PB induced an accumulation of nuclear HIF-1α and an increase in the HIF-responsive element-mediated transactivation in HepG2 cells.", "type": "CHEMICAL", "entities": [ "Phenobarbital" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "23528251", "text": "Cobalt chloride, a typical HIF activator, induced the gene expression of CAR-target genes, including cyp2b9 and cyp2b10, an accumulation of nuclear CAR and an increase in the PB-responsive enhancer module-mediated transactivation in the mouse liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23528251", "text": "Immunoprecipitation-immunoblot and chromatin immunoprecipitation analyses suggest that CAR binds to the PB-responsive enhancer module with HIF-1α in the liver of untreated mice and that the complex dissociates upon PB treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23528251", "text": "Taken together these results suggest that CAR and HIF-α interact and reciprocally modulate the functions of each other.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma.\nBACKGROUND & AIMS:", "type": "CHEMICAL", "entities": [ "Methionine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12671891", "text": "Of the 2 genes (MAT1A, MAT2A) encoding methionine adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, MAT1A, is expressed in liver, whereas MAT2A is expressed in extrahepatic tissues.", "type": "CHEMICAL", "entities": [ "S-adenosylmethionine", "methionine" ], "offsets": [ [ 99, 119 ], [ 39, 49 ] ] }, { "pmid": "12671891", "text": "In liver, MAT2A expression associates with growth, dedifferentiation, and cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "Here, we identified the beta subunit as a regulator of proliferation in human hepatoma cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "The beta subunit has been cloned and shown to lower the K(m) of methionine adenosyltransferase II alpha2 (the MAT2A product) for methionine and to render the enzyme more susceptible to S-adenosylmethionine inhibition.", "type": "CHEMICAL", "entities": [ "methionine", "methionine", "S-adenosylmethionine" ], "offsets": [ [ 64, 74 ], [ 129, 139 ], [ 185, 205 ] ] }, { "pmid": "12671891", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "Methionine adenosyltransferase II alpha2 and beta subunit expression was analyzed in human and rat liver and hepatoma cell lines and their interaction studied in HuH7 cells.", "type": "CHEMICAL", "entities": [ "Methionine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12671891", "text": "beta Subunit expression was up- and down-regulated in human hepatoma cell lines and the effect on DNA synthesis determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "We found that beta subunit is expressed in rat extrahepatic tissues but not in normal liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "In human liver, beta subunit expression associates with cirrhosis and hepatoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "beta Subunit is expressed in most (HepG2, PLC, and Hep3B) but not all (HuH7) hepatoma cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12671891", "text": "Transfection of beta subunit reduced S-adenosylmethionine content and stimulated DNA synthesis in HuH7 cells, whereas down-regulation of beta subunit expression diminished DNA synthesis in HepG2.", "type": "CHEMICAL", "entities": [ "S-adenosylmethionine" ], "offsets": [ [ 37, 57 ] ] }, { "pmid": "12671891", "text": "The interaction between methionine adenosyltransferase II alpha2 and beta subunit was demonstrated in HuH7 cells.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "12671891", "text": "CONCLUSIONS: Our findings indicate that beta subunit associates with cirrhosis and cancer providing a proliferative advantage in hepatoma cells through its interaction with methionine adenosyltransferase II alpha2 and down-regulation of S-adenosylmethionine levels.", "type": "CHEMICAL", "entities": [ "methionine", "S-adenosylmethionine" ], "offsets": [ [ 173, 183 ], [ 237, 257 ] ] }, { "pmid": "16962597", "text": "Temporal profile of brain and pituitary GnRHs, GnRH-R and gonadotropin mRNA expression and content during early development in European sea bass (Dicentrarchus labrax L.).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16962597", "text": "A likely endocrine control mechanism for sexual differentiation in size-graded populations of European sea bass (Dicentrarchus labrax) is proposed by evaluating the brain expression and pituitary content of two forms of gonadotropin-releasing hormone (GnRH), namely sea bream (sbGnRH) and salmon (sGnRH), the pituitary expression of one subtype of GnRH receptor (dlGnRH-R-2A) and the three gonadotropin (GtH) subunits, namely glycoprotein alpha (GPalpha), follicle-stimulating hormone beta (FSHbeta) and luteinizing hormone beta (LHbeta), as well as the pituitary and plasma LH levels between 50 and 300 days post-hatching (dph).", "type": "CHEMICAL", "entities": [ "gonadotropin-releasing hormone", "GnRH", "GnRH" ], "offsets": [ [ 220, 250 ], [ 252, 256 ], [ 348, 352 ] ] }, { "pmid": "16962597", "text": "Four gradings were conducted between 2 and 8 months after hatching, resulting in a population of large and small individuals, having 96.5% females (female-dominant population) and 69.2% males (male-dominant population), respectively, after the last grading.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16962597", "text": "The onset of gonadal differentiation was different in the two sexes, and coincided with a peak of expression of sbGnRH or sGnRH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16962597", "text": "Furthermore, the expression of these GnRHs was correlated with the expression of dlGnRH-R-2A. Sex-related differences in the brain and pituitary content of sbGnRH were also found at the time of sexual differentiation.", "type": "CHEMICAL", "entities": [ "GnRHs" ], "offsets": [ [ 37, 42 ] ] }, { "pmid": "16962597", "text": "Moreover, the observed sexual dimorphism at the transcriptional or synthesis level of these GnRH forms suggests that a different neuro-hormonal regulation is operating according to sex.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 92, 96 ] ] }, { "pmid": "16962597", "text": "At the onset of sex differentiation, FSHbeta transcriptional activity reached maximal values, which were maintained until the completion of the process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16962597", "text": "The present study suggests a role for sbGnRH, sGnRH and the dlGnRH-R-2A during gonadal differentiation, possibly through enhancement of FSHbeta gene expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16962597", "text": "In males, a different endocrine regulation seems to exist also during spermiogenesis and spermiation, when gene transcription, peptide synthesis and release of LH are of greater importance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23147414", "text": "Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.\n", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol", "GABA" ], "offsets": [ [ 104, 111 ], [ 37, 44 ], [ 8, 12 ] ] }, { "pmid": "23147414", "text": "GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors.", "type": "CHEMICAL", "entities": [ "GABA", "ethanol", "GABA", "ethanol" ], "offsets": [ [ 0, 4 ], [ 132, 139 ], [ 23, 27 ], [ 52, 59 ] ] }, { "pmid": "23147414", "text": "We studied null mutant mice for six different GABA(A)-R subunits (α1, α2, α3, α4, α5 and δ).", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "23147414", "text": "Only mice lacking the α2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 83, 90 ] ] }, { "pmid": "23147414", "text": "These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the α2-subunit (Blednov et al., 2011).", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 74, 81 ] ] }, { "pmid": "23147414", "text": "All together, they indicate that aversive property of ethanol is dependent on ethanol action on α2-containing GABA(A)-R. Deletion of the α2-subunit led to faster recovery whereas absence of the α3-subunit slowed recovery from ethanol-induced incoordination (rotarod).", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "GABA", "ethanol" ], "offsets": [ [ 45, 52 ], [ 69, 76 ], [ 101, 105 ], [ 217, 224 ] ] }, { "pmid": "23147414", "text": "Deletion of the other four subunits did not affect this behavior.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23147414", "text": "Similar changes in this behavior for the α2 and α3 null mutants were found for flurazepam motor incoordination.", "type": "CHEMICAL", "entities": [ "flurazepam" ], "offsets": [ [ 67, 77 ] ] }, { "pmid": "23147414", "text": "However, no differences in recovery were found in motor-incoordinating effects of an α1-selective modulator (zolpidem) or an α4-selective agonist (gaboxadol).", "type": "CHEMICAL", "entities": [ "zolpidem", "gaboxadol" ], "offsets": [ [ 95, 103 ], [ 133, 142 ] ] }, { "pmid": "23147414", "text": "Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: α2 and α3.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 54, 58 ] ] }, { "pmid": "23147414", "text": "For motor activity, α3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both α2 (-/-) and α3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg).", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 49, 56 ], [ 138, 145 ] ] }, { "pmid": "23147414", "text": "These studies demonstrate that the effects of ethanol at GABAergic synapses containing α2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the α2 subunit with human alcoholism.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 23, 30 ], [ 124, 131 ] ] }, { "pmid": "23378624", "text": "Pancreatic β-Cell Dysfunction and Risk of New-Onset Diabetes After Kidney Transplantation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "OBJECTIVEChronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "Pancreatic β-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for β-cell dysfunction may have additive value for predicting NODAT in this population.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic β-cell dysfunction, is associated with future development of NODAT and improves prediction of it.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "RESEARCH DESIGN AND METHODSAll RTR between 2001 and 2003 with a functioning graft for ≥1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "We recorded incidence of NODAT until April 2012.RESULTSA total of 487 RTR (age 50 ± 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6-11.5) years after transplantation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "Median fasting proinsulin levels were 16.6 (IQR, 11.0-24.2) pmol/L.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "During median follow-up for 10.1 (IQR, 9.1-10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% confidence interval, 1.85-2.83; P < 0.001) was strongly associated with NODAT development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment.", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 52, 64 ] ] }, { "pmid": "23378624", "text": "CONCLUSIONSIn conclusion, fasting proinsulin is strongly associated with NODAT development in RTR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23378624", "text": "Our results highlight the role of β-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23023136", "text": "Resveratrol attenuates hepatotoxicity of rats exposed to arsenic trioxide.\n", "type": "CHEMICAL", "entities": [ "Resveratrol", "arsenic trioxide" ], "offsets": [ [ 0, 11 ], [ 57, 73 ] ] }, { "pmid": "23023136", "text": "Arsenic trioxide (As(2)O(3)) is an environmental pollutant and potent toxicant to humans.", "type": "CHEMICAL", "entities": [ "Arsenic trioxide", "As(2)O(3)" ], "offsets": [ [ 0, 16 ], [ 18, 27 ] ] }, { "pmid": "23023136", "text": "However, it also shows substantial anti-cancer activity in individuals with acute promyelocytic leukemia (APL).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23023136", "text": "Unfortunately, As(2)O(3)-treated leukemia patients suffer hepatotoxicity.", "type": "CHEMICAL", "entities": [ "As(2)O(3)" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "23023136", "text": "Resveratrol has been demonstrated to have efficient antioxidant and antineoplastic activities.", "type": "CHEMICAL", "entities": [ "Resveratrol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23023136", "text": "The study that how As(2)O(3) in combination with resveratrol affects hepatotoxicity and arsenic accumulation in the liver is lacking, and the present study tackles this question.", "type": "CHEMICAL", "entities": [ "As(2)O(3)", "resveratrol", "arsenic" ], "offsets": [ [ 19, 28 ], [ 49, 60 ], [ 88, 95 ] ] }, { "pmid": "23023136", "text": "Wistar rats were injected with 3mg/kg As(2)O(3) on alternate days; resveratrol (8mg/kg) was administered 1h before As(2)O(3).", "type": "CHEMICAL", "entities": [ "As(2)O(3)", "resveratrol", "As(2)O(3)" ], "offsets": [ [ 38, 47 ], [ 67, 78 ], [ 115, 124 ] ] }, { "pmid": "23023136", "text": "Rats were killed on the 8th day to determine histological liver damage, the antioxidant enzymes in serum, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and arsenic accumulation in the liver.", "type": "CHEMICAL", "entities": [ "reduced glutathione", "GSH", "oxidized glutathione", "GSSG", "arsenic" ], "offsets": [ [ 119, 138 ], [ 140, 143 ], [ 148, 168 ], [ 170, 174 ], [ 181, 188 ] ] }, { "pmid": "23023136", "text": "In the resveratrol+As(2)O(3) group, activities of superoxide dismutase, catalase in serum and GSH/GSSG were significantly increased, histopathological effects were reduced, and arsenic accumulation markedly decreased in the liver, compared with the As(2)O(3)-treated group.", "type": "CHEMICAL", "entities": [ "arsenic", "As(2)O(3)", "resveratrol", "As(2)O(3)", "superoxide", "GSH", "GSSG" ], "offsets": [ [ 177, 184 ], [ 249, 258 ], [ 7, 18 ], [ 19, 28 ], [ 50, 60 ], [ 94, 97 ], [ 98, 102 ] ] }, { "pmid": "23023136", "text": "Thus, resveratrol attenuated As(2)O(3)-induced hepatotoxicity by decreasing oxidative stress and arsenic accumulation in the liver.", "type": "CHEMICAL", "entities": [ "resveratrol", "As(2)O(3)", "arsenic" ], "offsets": [ [ 6, 17 ], [ 29, 38 ], [ 97, 104 ] ] }, { "pmid": "23023136", "text": "These data suggest that use of resveratrol as post-remission therapy of APL and adjunctive therapy in patients with chronic exposure to arsenic may decrease arsenic hepatotoxicity.", "type": "CHEMICAL", "entities": [ "resveratrol", "arsenic", "arsenic" ], "offsets": [ [ 31, 42 ], [ 136, 143 ], [ 157, 164 ] ] }, { "pmid": "22968082", "text": "Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "In the present studies, dose-response curves for d-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism.", "type": "CHEMICAL", "entities": [ "d-amphetamine", "AMPH" ], "offsets": [ [ 49, 62 ], [ 64, 68 ] ] }, { "pmid": "22968082", "text": "AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming.", "type": "CHEMICAL", "entities": [ "AMPH", "AMPH" ], "offsets": [ [ 0, 4 ], [ 182, 186 ] ] }, { "pmid": "22968082", "text": "We then tested AMPH in B6 and BTBR on the 3-chambered social approach task.", "type": "CHEMICAL", "entities": [ "AMPH" ], "offsets": [ [ 15, 19 ] ] }, { "pmid": "22968082", "text": "One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "This finding replicated across multiple cohorts treated with AMPH and saline vehicle.", "type": "CHEMICAL", "entities": [ "AMPH" ], "offsets": [ [ 61, 65 ] ] }, { "pmid": "22968082", "text": "In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task.", "type": "CHEMICAL", "entities": [ "AMPH", "AMPH" ], "offsets": [ [ 32, 36 ], [ 141, 145 ] ] }, { "pmid": "22968082", "text": "Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22968082", "text": "This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23393216", "text": "Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes.\n", "type": "CHEMICAL", "entities": [ "glucose", "25-hydroxycholecalciferol" ], "offsets": [ [ 130, 137 ], [ 34, 59 ] ] }, { "pmid": "23393216", "text": "OBJECTIVE To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects.", "type": "CHEMICAL", "entities": [ "glucose", "vitamin D" ], "offsets": [ [ 102, 109 ], [ 43, 52 ] ] }, { "pmid": "23393216", "text": "RESEARCH DESIGN AND METHODS", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23393216", "text": "In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40-70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1-37.5, 37.6-50, 50.1-75, and >75 nmol/L. RESULTS", "type": "CHEMICAL", "entities": [ "25-hydroxycholecalciferol", "25-OHD", "25-OHD" ], "offsets": [ [ 201, 226 ], [ 228, 234 ], [ 339, 345 ] ] }, { "pmid": "23393216", "text": "The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23393216", "text": "During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23393216", "text": "A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes.", "type": "CHEMICAL", "entities": [ "cholesterol", "triglycerides", "25-OHD", "vitamin D" ], "offsets": [ [ 129, 140 ], [ 142, 155 ], [ 348, 354 ], [ 94, 103 ] ] }, { "pmid": "23393216", "text": "The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03-1.24), 1.77 (1.11-2.83), and 1.43 (1.16-1.76), respectively].", "type": "CHEMICAL", "entities": [ "25-OHD", "25-OHD" ], "offsets": [ [ 127, 133 ], [ 194, 200 ] ] }, { "pmid": "23393216", "text": "CONCLUSIONS Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes.", "type": "CHEMICAL", "entities": [ "Vitamin D" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "8636122", "text": "Structural features of the central cannabinoid CB1 receptor involved in the binding of the specific CB1 antagonist SR 141716A.\nThe antagonist SR 141716A has a high specificity for the central CB1 cannabinoid receptor and negligeable affinity for the peripheral CB2 receptor, making it an excellent tool for probing receptor structure-activity relationships.", "type": "CHEMICAL", "entities": [ "SR 141716A", "cannabinoid", "SR 141716A", "cannabinoid" ], "offsets": [ [ 142, 152 ], [ 196, 207 ], [ 115, 125 ], [ 35, 46 ] ] }, { "pmid": "8636122", "text": "From binding experiments with mutated CB1 and with chimeric CB1/CB2 receptors we have begun to identify the domains of CB1 implicated in the recognition of SR 141716A. Receptors were transiently expressed in COS-3 cells, and their binding characteristics were studied with SR 141716A and with CP 55,940, an agonist recognized equally well by the two receptors.", "type": "CHEMICAL", "entities": [ "SR 141716A", "SR 141716A", "CP 55,940" ], "offsets": [ [ 156, 166 ], [ 273, 283 ], [ 293, 302 ] ] }, { "pmid": "8636122", "text": "The region delineated by the fourth and fifth transmembrane helices of CB1 proved to be crucial for high affinity binding of SR 141716A. The CB1 and CB2 second extracellular loops, e2, were exchanged, modifications that had no effect on SR 141716A binding in the CB1 variant but that eliminated CP 55,940 binding in both mutants.", "type": "CHEMICAL", "entities": [ "SR 141716A", "SR 141716A", "CP 55,940" ], "offsets": [ [ 125, 135 ], [ 237, 247 ], [ 295, 304 ] ] }, { "pmid": "8636122", "text": "The replacement of the conserved cysteine residues in e2 of CB2 by serine also eliminated CP 55,940 binding, but replacement of those in CB1 resulted in the sequestration of the mutated receptors in the cell cytoplasm.", "type": "CHEMICAL", "entities": [ "CP 55,940", "cysteine", "serine" ], "offsets": [ [ 90, 99 ], [ 33, 41 ], [ 67, 73 ] ] }, { "pmid": "8636122", "text": "The e2 domain thus plays some role in CP 55,940 binding but none in SR 141716A recognition, binding of the latter clearly implicating residues in the adjoining transmembrane helices.", "type": "CHEMICAL", "entities": [ "CP 55,940", "SR 141716A" ], "offsets": [ [ 38, 47 ], [ 68, 78 ] ] }, { "pmid": "7885191", "text": "Drosophila GABA-gated chloride channel: modified [3H]EBOB binding site associated with Ala-->Ser or Gly mutants of Rdl subunit.\n", "type": "CHEMICAL", "entities": [ "Gly", "GABA", "chloride", "[3H]EBOB", "Ala", "Ser" ], "offsets": [ [ 100, 103 ], [ 11, 15 ], [ 22, 30 ], [ 49, 57 ], [ 87, 90 ], [ 93, 96 ] ] }, { "pmid": "7885191", "text": "The non-competitive blocker site of the GABA-gated chloride ion channel in normal susceptible strains of Drosophila melanogaster and simulans binds 4-n-[3H]propyl-4'-ethynylbicycloorthobenzoate ([3H]EBOB) at specific sites with KdS of 1.6-1.9 nM and BmaxS of 171-181 fmol/mg protein.", "type": "CHEMICAL", "entities": [ "4-n-[3H]propyl-4'-ethynylbicycloorthobenzoate", "[3H]EBOB", "GABA", "chloride" ], "offsets": [ [ 148, 193 ], [ 195, 203 ], [ 40, 44 ], [ 51, 59 ] ] }, { "pmid": "7885191", "text": "This specific binding of [3H]EBOB is strongly inhibited by: a large number and variety of insecticidal channel blockers at 20 nM (lindane, alpha-endosulfan, dieldrin, 12-ketoendrin, fipronil, and a representative bicycloorthobenzoate and dithiane) or 200 nM (picrotoxinin); the insecticidal channel activators avermectin and moxidectin at 20 nM; muscimol at 30 microM and GABA at 300 microM. Cyclodiene resistance in D. melanogaster has been attributed to a mutation resulting in an Ala302-->Ser replacement in the Rdl GABA receptor subunit and in D. simulans to an homologous Ala-->Ser or Gly replacement.", "type": "CHEMICAL", "entities": [ "[3H]EBOB", "lindane", "alpha-endosulfan", "dieldrin", "12-ketoendrin", "fipronil", "bicycloorthobenzoate", "dithiane", "picrotoxinin", "avermectin", "moxidectin", "muscimol", "GABA", "Cyclodiene", "Ser", "GABA", "Ala", "Ser", "Gly" ], "offsets": [ [ 25, 33 ], [ 130, 137 ], [ 139, 155 ], [ 157, 165 ], [ 167, 180 ], [ 182, 190 ], [ 213, 233 ], [ 238, 246 ], [ 259, 271 ], [ 310, 320 ], [ 325, 335 ], [ 346, 354 ], [ 372, 376 ], [ 392, 402 ], [ 492, 495 ], [ 519, 523 ], [ 577, 580 ], [ 583, 586 ], [ 590, 593 ] ] }, { "pmid": "7885191", "text": "These mutations are shown here to greatly reduce [3H]EBOB binding, i.e. lower affinity and apparent number of binding sites.", "type": "CHEMICAL", "entities": [ "[3H]EBOB" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "7885191", "text": "The Ala-->Ser replacement with both melanogaster and simulans almost always reduces the potency in inhibiting [3H]EBOB binding of each of eight channel blockers and of muscimol and GABA.", "type": "CHEMICAL", "entities": [ "Ala", "Ser", "[3H]EBOB", "muscimol", "GABA" ], "offsets": [ [ 4, 7 ], [ 10, 13 ], [ 110, 118 ], [ 168, 176 ], [ 181, 185 ] ] }, { "pmid": "7885191", "text": "The Ala-->Gly replacement in D. simulans is generally less effective than the Ala-->Ser modification in reducing sensitivity to the channel blockers and to muscimol and GABA.", "type": "CHEMICAL", "entities": [ "Ala", "Gly", "Ala", "Ser", "muscimol", "GABA" ], "offsets": [ [ 4, 7 ], [ 10, 13 ], [ 78, 81 ], [ 84, 87 ], [ 156, 164 ], [ 169, 173 ] ] }, { "pmid": "7885191", "text": "The channel activators avermectin and moxidectin usually retain their inhibitory potency in the Rdl subunit mutants.", "type": "CHEMICAL", "entities": [ "avermectin", "moxidectin" ], "offsets": [ [ 23, 33 ], [ 38, 48 ] ] }, { "pmid": "7885191", "text": "Thus, it appears that replacement of Ala by Ser generally modifies the non-competitive blocker site and its coupling to the GABA-recognition site with less effect on the channel activator site.", "type": "CHEMICAL", "entities": [ "Ala", "Ser", "GABA" ], "offsets": [ [ 37, 40 ], [ 44, 47 ], [ 124, 128 ] ] }, { "pmid": "7885191", "text": "In contrast, the Ala-->Gly replacement has less impact in protecting the chloride channel from the action of insecticidal blockers.", "type": "CHEMICAL", "entities": [ "Ala", "Gly", "chloride" ], "offsets": [ [ 17, 20 ], [ 23, 26 ], [ 73, 81 ] ] }, { "pmid": "7885191", "text": "Each of the resistant strains has the same level of resistance to the lethal action of the five channel blockers examined but none to avermectins and muscimol.", "type": "CHEMICAL", "entities": [ "avermectins", "muscimol" ], "offsets": [ [ 134, 145 ], [ 150, 158 ] ] }, { "pmid": "15120421", "text": "In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone.\n", "type": "CHEMICAL", "entities": [ "CDB-2914", "CDB-4124", "mifepristone", "progestin" ], "offsets": [ [ 163, 171 ], [ 173, 181 ], [ 187, 199 ], [ 60, 69 ] ] }, { "pmid": "15120421", "text": "In determining the biological profiles of various antiprogestins, it is important to assess the hormonal and antihormonal activity, selectivity, and potency of their proximal metabolites.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15120421", "text": "The early metabolism of mifepristone is characterized by rapid demethylation and hydroxylation.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 24, 36 ] ] }, { "pmid": "15120421", "text": "Similar initial metabolic pathways have been proposed for CDB-2914 (CDB: Contraceptive Development Branch of NICHD) and CDB-4124, and their putative metabolites have been synthesized.", "type": "CHEMICAL", "entities": [ "CDB-2914", "CDB-4124" ], "offsets": [ [ 58, 66 ], [ 120, 128 ] ] }, { "pmid": "15120421", "text": "We have examined the functional activities and potencies, in various cell-based assays, and relative binding affinities (RBAs) for progesterone receptors (PR) and glucocorticoid receptors (GR) of the putative mono- and didemethylated metabolites of CDB-2914, CDB-4124, and mifepristone and of the 17alpha-hydroxy and aromatic A-ring derivatives of CDB-2914 and CDB-4124.", "type": "CHEMICAL", "entities": [ "progesterone", "CDB-2914", "CDB-4124", "mifepristone", "17alpha-hydroxy", "CDB-2914", "CDB-4124" ], "offsets": [ [ 131, 143 ], [ 249, 257 ], [ 259, 267 ], [ 273, 285 ], [ 297, 312 ], [ 348, 356 ], [ 361, 369 ] ] }, { "pmid": "15120421", "text": "The binding affinities of the monodemethylated metabolites for rabbit uterine PR and human PR-A and PR-B were similar to those of the parent compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15120421", "text": "Monodemethylated mifepristone bound to rabbit thymic GR with higher affinity than monodemethylated CDB-2914 or CDB-4124.", "type": "CHEMICAL", "entities": [ "mifepristone", "CDB-2914", "CDB-4124" ], "offsets": [ [ 17, 29 ], [ 99, 107 ], [ 111, 119 ] ] }, { "pmid": "15120421", "text": "T47D-CO cells were used to assess inhibition of R5020-stimulated endogenous alkaline phosphatase activity and transactivation of the PRE(2)-thymidine kinase (tk)-luciferase (LUC) reporter plasmid in transient transfections.", "type": "CHEMICAL", "entities": [ "thymidine" ], "offsets": [ [ 140, 149 ] ] }, { "pmid": "15120421", "text": "The antiprogestational potency was as follows:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15120421", "text": "mifepristone/CDB-2914/CDB-4124/monodemethylated metabolites (IC(50)'s approximately 10(-9)M) > aromatic A-ring derivatives (IC(50)'s approximately 10(-8)M) >", "type": "CHEMICAL", "entities": [ "mifepristone", "CDB-2914", "CDB-4124" ], "offsets": [ [ 0, 12 ], [ 13, 21 ], [ 22, 30 ] ] }, { "pmid": "15120421", "text": "didemethylated/17alpha-hydroxy derivatives (IC(50)'s approximately 10(-7)M).", "type": "CHEMICAL", "entities": [ "17alpha-hydroxy" ], "offsets": [ [ 15, 30 ] ] }, { "pmid": "15120421", "text": "Antiglucocorticoid activity was determined by inhibition of dexamethasone-stimulated transcriptional activity in HepG2 cells.", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 60, 73 ] ] }, { "pmid": "15120421", "text": "The mono- and didemethylated metabolites of CDB-2914 and CDB-4124 had less antiglucocorticoid activity (IC(50)'s approximately 10(-6)M) than monodemethylated mifepristone (IC(50) approximately 10(-8)M) or the other test compounds.", "type": "CHEMICAL", "entities": [ "CDB-2914", "CDB-4124", "mifepristone" ], "offsets": [ [ 44, 52 ], [ 57, 65 ], [ 158, 170 ] ] }, { "pmid": "15120421", "text": "At 10(-6)M in transcription assays, none of these compounds showed progestin agonist activity, whereas mifepristone and its monodemethylated metabolite manifested slight glucocorticoid agonist activity.", "type": "CHEMICAL", "entities": [ "progestin", "mifepristone" ], "offsets": [ [ 67, 76 ], [ 103, 115 ] ] }, { "pmid": "15120421", "text": "The reduced antiglucocorticoid activity of monodemethylated CDB-2914 and CDB-4124 was confirmed in vivo by the thymus involution assay in adrenalectomized male rats.", "type": "CHEMICAL", "entities": [ "CDB-2914", "CDB-4124" ], "offsets": [ [ 60, 68 ], [ 73, 81 ] ] }, { "pmid": "15120421", "text": "The aromatic A-ring derivatives-stimulated transcription of an estrogen-responsive reporter plasmid in MCF-7 and T47D-CO human breast cancer cells but were much less potent than estradiol.", "type": "CHEMICAL", "entities": [ "estrogen", "estradiol" ], "offsets": [ [ 63, 71 ], [ 178, 187 ] ] }, { "pmid": "15120421", "text": "Taken together, these data suggest that the proximal metabolites of mifepristone, CDB-2914, and CDB-4124 contribute significantly to the antiprogestational activity of the parent compounds in vivo.", "type": "CHEMICAL", "entities": [ "mifepristone", "CDB-2914", "CDB-4124" ], "offsets": [ [ 68, 80 ], [ 82, 90 ], [ 96, 104 ] ] }, { "pmid": "15120421", "text": "Furthermore, the reduced antiglucocorticoid activity of CDB-2914 and CDB-4124 compared to mifepristone in vivo may be due in part to decreased activity of their putative proximal metabolites.", "type": "CHEMICAL", "entities": [ "CDB-2914", "CDB-4124", "mifepristone" ], "offsets": [ [ 56, 64 ], [ 69, 77 ], [ 90, 102 ] ] }, { "pmid": "10891536", "text": "Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells.\n", "type": "CHEMICAL", "entities": [ "fluorinated pyrimidines" ], "offsets": [ [ 47, 70 ] ] }, { "pmid": "10891536", "text": "5-Fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FdUrd) and 5-trifluorothymidine (F3(d)Thd) are antimetabolites which are metabolized to their corresponding active forms which inhibit DNA synthesis via inhibition of thymidylate synthase (TS).", "type": "CHEMICAL", "entities": [ "5-Fluorouracil", "5-FU", "thymidylate", "5-fluoro-2'-deoxyuridine", "FdUrd", "5-trifluorothymidine", "F3(d)Thd" ], "offsets": [ [ 0, 14 ], [ 16, 20 ], [ 216, 227 ], [ 23, 47 ], [ 49, 54 ], [ 60, 80 ], [ 82, 90 ] ] }, { "pmid": "10891536", "text": "To investigate ways of overcoming 5-FU-resistance, we established acquired-resistant colorectal cancer cell lines against these three drugs by continuous and step-wise escalation of drugs, and analyzed the cytotoxicity and the mechanism of resistance to the drugs.", "type": "CHEMICAL", "entities": [ "5-FU" ], "offsets": [ [ 34, 38 ] ] }, { "pmid": "10891536", "text": "When cells were incubated with the 3 drugs for 72 h, the resistance ratio to parental DLD-1 human colorectal tumor cells was 65.2 for DLD-1/5-FU, 9.7 for DLD-1/FdUrd and 448.6 for DLD-1/F3(d)Thd cells.", "type": "CHEMICAL", "entities": [ "FdUrd", "F3(d)Thd" ], "offsets": [ [ 160, 165 ], [ 186, 194 ] ] }, { "pmid": "10891536", "text": "DLD-1/5-FU cells did not show any cross-resistance against FdUrd and F(3)dThd.", "type": "CHEMICAL", "entities": [ "5-FU", "FdUrd", "F(3)dThd" ], "offsets": [ [ 6, 10 ], [ 59, 64 ], [ 69, 77 ] ] }, { "pmid": "10891536", "text": "However, DLD-1/FdUrd cells showed 3- and 9-fold increased resistance to 5-FU and F3(d)Thd, respectively, and DLD-1/F3(d)Thd cells also showed about 90-fold resistance to FdUrd.", "type": "CHEMICAL", "entities": [ "FdUrd", "5-FU", "F3(d)Thd", "F3(d)Thd", "FdUrd" ], "offsets": [ [ 15, 20 ], [ 72, 76 ], [ 81, 89 ], [ 115, 123 ], [ 170, 175 ] ] }, { "pmid": "10891536", "text": "Analysis of enzyme activities and gene expression associated with pyrimidine metabolism indicated that a significant decrease in orotate phosphoribosyltransferase activity in DLD-1/5-FU cells, a 7-fold increase of TS mRNA in DLD-1/FdUrd cells, and a 37-fold decrease in thymidine kinase activity of DLD-1/F3(d)Thd cells were the major mechanisms of drug resistance.", "type": "CHEMICAL", "entities": [ "pyrimidine", "orotate", "5-FU", "FdUrd", "F3(d)Thd" ], "offsets": [ [ 66, 76 ], [ 129, 136 ], [ 181, 185 ], [ 231, 236 ], [ 305, 313 ] ] }, { "pmid": "10891536", "text": "These findings were closely associated with the cytotoxicity of 5-FU, FdUrd and F3(d)Thd against the established 5-FU-, FdUrd- or F3(d)Thd-resistant cells.", "type": "CHEMICAL", "entities": [ "5-FU", "FdUrd", "F3(d)Thd", "5-FU", "FdUrd", "F3(d)Thd" ], "offsets": [ [ 64, 68 ], [ 70, 75 ], [ 80, 88 ], [ 113, 117 ], [ 120, 125 ], [ 130, 138 ] ] }, { "pmid": "10891536", "text": "When DLD-1/FdUrd cells expressing increased TS mRNA were treated with FdUrd and F3(d)Thd for only 4 h, the resistance ratios of DLD-1/FdUrd cells to parental DLD-1 cells were markedly different for FdUrd and F3(d)Thd, suggesting that the cytotoxicity with short-time exposure to F3(d)Thd is due to a mechanism other than TS inhibition, although the cytotoxicity of F3(d)Thd in the short-time is low compared to that of long-time exposure.", "type": "CHEMICAL", "entities": [ "FdUrd", "FdUrd", "F3(d)Thd", "FdUrd", "FdUrd", "F3(d)Thd", "F3(d)Thd", "F3(d)Thd" ], "offsets": [ [ 11, 16 ], [ 70, 75 ], [ 80, 88 ], [ 134, 139 ], [ 198, 203 ], [ 208, 216 ], [ 279, 287 ], [ 365, 373 ] ] }, { "pmid": "10891536", "text": "In conclusion, F3(d)Thd, an antimetabolite that inhibits TS activity, may be effective against 5-FU and/or FdUrd-resistance in colorectal cancer cells caused by amplification of TS and/or deletion of orotate phosphoribosyltransferase.", "type": "CHEMICAL", "entities": [ "F3(d)Thd", "5-FU", "FdUrd", "orotate" ], "offsets": [ [ 15, 23 ], [ 95, 99 ], [ 107, 112 ], [ 200, 207 ] ] }, { "pmid": "1332478", "text": "Failure of ritodrine to prevent preterm labor in the sheep.\n", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 11, 20 ] ] }, { "pmid": "1332478", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1332478", "text": "The purpose of this study was to determine whether continuous infusion of ritodrine could prevent preterm delivery in sheep.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "1332478", "text": "STUDY DESIGN:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1332478", "text": "Sheep in preterm labor induced by RU 486 (mifepristone) received infusions of either ritodrine (n = 5) or saline solution (n = 5), and the progress of labor was monitored.", "type": "CHEMICAL", "entities": [ "RU 486", "mifepristone", "ritodrine" ], "offsets": [ [ 34, 40 ], [ 42, 54 ], [ 85, 94 ] ] }, { "pmid": "1332478", "text": "beta 2-Adrenergic receptor density and function (agonist-induced cyclic adenosine monophosphate production) was measured in myometrial samples from both groups.", "type": "CHEMICAL", "entities": [ "cyclic adenosine monophosphate" ], "offsets": [ [ 65, 95 ] ] }, { "pmid": "1332478", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1332478", "text": "Ritodrine initially inhibited labor contractions.", "type": "CHEMICAL", "entities": [ "Ritodrine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "1332478", "text": "This inhibition was only maintained for 16 hours, after which both the amplitude and frequency of electromyographic bursts and contractions returned.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1332478", "text": "The failure of the myometrium to respond to ritodrine (desensitization) was associated with significant reductions in agonist-induced cyclic adenosine monophosphate production and beta 2-adrenergic receptor concentration in myometrial tissue collected from these animals compared with the saline solution-treated controls.", "type": "CHEMICAL", "entities": [ "ritodrine", "cyclic adenosine monophosphate" ], "offsets": [ [ 44, 53 ], [ 134, 164 ] ] }, { "pmid": "1332478", "text": "CONCLUSIONS: Continuous infusion of ritodrine to sheep in preterm labor produces only a transient inhibition of contractions.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "1332478", "text": "This desensitization is caused by a down-regulation of myometrial beta 2-adrenergic receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "Smoothened is a fully competent activator of the heterotrimeric G protein G(i).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "Smoothened (Smo) is a 7-transmembrane protein essential to the activation of Gli transcription factors (Gli) by hedgehog morphogens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "The structure of Smo implies interactions with heterotrimeric G proteins, but the degree to which G proteins participate in the actions of hedgehogs remains controversial.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "We posit that the G(i) family of G proteins provides to hedgehogs the ability to expand well beyond the bounds of Gli.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "In this regard, we evaluate here the efficacy of Smo as it relates to the activation of G(i), by comparing Smo with the 5-hydroxytryptamine(1A) (5-HT(1A))", "type": "CHEMICAL", "entities": [ "5-hydroxytryptamine", "5-HT" ], "offsets": [ [ 120, 139 ], [ 145, 149 ] ] }, { "pmid": "23292797", "text": "receptor, a quintessential G(i)-coupled receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "We find that with use of [(35)S]guanosine 5'-(3-O-thio)triphosphate, first, with forms of G(i) endogenous to human embryonic kidney (HEK)-293 cells made to express epitope-tagged receptors and, second, with individual forms of Gα(i) fused to the C terminus of each receptor, Smo is equivalent to the 5-HT(1A) receptor in the assay as it relates to capacity to activate G(i).", "type": "CHEMICAL", "entities": [ "[(35)S]guanosine 5'-(3-O-thio)triphosphate", "5-HT" ], "offsets": [ [ 25, 67 ], [ 300, 304 ] ] }, { "pmid": "23292797", "text": "This finding is true regardless of subtype of G(i) (e.g., G(i2), G(o), and G(z)) tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23292797", "text": "We also find that Smo endogenous to HEK-293 cells, ostensibly through inhibition of adenylyl cyclase, decreases intracellular levels of cAMP.", "type": "CHEMICAL", "entities": [ "adenylyl", "cAMP" ], "offsets": [ [ 83, 91 ], [ 135, 139 ] ] }, { "pmid": "23292797", "text": "The results indicate that Smo is a receptor that can engage not only Gli but also other more immediate effectors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116965", "text": "Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes.\n", "type": "CHEMICAL", "entities": [ "(-)-epicatechin-3-gallate", "sodium" ], "offsets": [ [ 26, 51 ], [ 61, 67 ] ] }, { "pmid": "23116965", "text": "(-)-Epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility.", "type": "CHEMICAL", "entities": [ "(-)-Epicatechin-3-gallate", "ECG", "polyphenol" ], "offsets": [ [ 0, 25 ], [ 27, 30 ], [ 35, 45 ] ] }, { "pmid": "23116965", "text": "However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown.", "type": "CHEMICAL", "entities": [ "ECG" ], "offsets": [ [ 38, 41 ] ] }, { "pmid": "23116965", "text": "We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias.", "type": "CHEMICAL", "entities": [ "ECG" ], "offsets": [ [ 38, 41 ] ] }, { "pmid": "23116965", "text": "By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100 μM) with an EC(50) value of 3.8 μM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics.", "type": "CHEMICAL", "entities": [ "ECG", "Na(+)", "Na", "ECG", "Na", "Na" ], "offsets": [ [ 61, 64 ], [ 125, 130 ], [ 143, 145 ], [ 229, 232 ], [ 293, 295 ], [ 353, 355 ] ] }, { "pmid": "23116965", "text": "Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents.", "type": "CHEMICAL", "entities": [ "Na", "ECG", "K(+)", "Ca(2+)" ], "offsets": [ [ 36, 38 ], [ 53, 56 ], [ 96, 100 ], [ 121, 127 ] ] }, { "pmid": "23116965", "text": "With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116965", "text": "ECG increased the firing rate of normal sAP about two-fold without waveform alteration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23116965", "text": "Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform.", "type": "CHEMICAL", "entities": [ "ECG" ], "offsets": [ [ 78, 81 ] ] }, { "pmid": "23116965", "text": "The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 33, 39 ] ] }, { "pmid": "23116965", "text": "Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias.", "type": "CHEMICAL", "entities": [ "ECG", "Na" ], "offsets": [ [ 21, 24 ], [ 38, 40 ] ] }, { "pmid": "16920841", "text": "Liver choline dehydrogenase and kidney betaine-homocysteine methyltransferase expression are not affected by methionine or choline intake in growing rats.\n", "type": "CHEMICAL", "entities": [ "methionine", "choline", "betaine", "homocysteine", "choline" ], "offsets": [ [ 109, 119 ], [ 123, 130 ], [ 39, 46 ], [ 47, 59 ], [ 6, 13 ] ] }, { "pmid": "16920841", "text": "Choline dehydrogenase (CHDH) and betaine-homocysteine methyltransferase (BHMT) are 2 enzymes involved in choline oxidation.", "type": "CHEMICAL", "entities": [ "Choline", "choline", "betaine", "homocysteine" ], "offsets": [ [ 0, 7 ], [ 105, 112 ], [ 33, 40 ], [ 41, 53 ] ] }, { "pmid": "16920841", "text": "BHMT is expressed at high levels in rat liver and its expression is regulated by dietary Met and choline.", "type": "CHEMICAL", "entities": [ "Met", "choline" ], "offsets": [ [ 89, 92 ], [ 97, 104 ] ] }, { "pmid": "16920841", "text": "BHMT is also found in rat kidney, albeit in substantially lower amounts, but it is not known whether kidney BHMT expression is regulated by dietary Met or choline.", "type": "CHEMICAL", "entities": [ "Met", "choline" ], "offsets": [ [ 148, 151 ], [ 155, 162 ] ] }, { "pmid": "16920841", "text": "Similarly, CHDH activity is highest in the liver and kidney, but the regulation of its expression by diet has not been thoroughly investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16920841", "text": "Sprague Dawley rats ( approximately 50 g) were fed, for 9 d in 2 x 3 factorial design (n = 8), an l-amino acid-defined diet varying in l-Met (0.125, 0.3, or 0.8%) and choline (0 or 25 mmol/kg diet).", "type": "CHEMICAL", "entities": [ "l-amino acid", "l-Met", "choline" ], "offsets": [ [ 98, 110 ], [ 135, 140 ], [ 167, 174 ] ] }, { "pmid": "16920841", "text": "Liver and kidney BHMT and CHDH were assessed using enzymatic, Western blot, and real-time PCR analyses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16920841", "text": "Liver samples were also fixed for histological analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16920841", "text": "Liver BHMT activity was 1.3-fold higher in rats fed the Met deficient diet containing choline, which was reflected in corresponding increases in mRNA content and immunodetectable protein.", "type": "CHEMICAL", "entities": [ "Met", "choline" ], "offsets": [ [ 56, 59 ], [ 86, 93 ] ] }, { "pmid": "16920841", "text": "Independent of dietary choline, supplemental Met increased hepatic BHMT activity approximately 30%.", "type": "CHEMICAL", "entities": [ "choline", "Met" ], "offsets": [ [ 23, 30 ], [ 45, 48 ] ] }, { "pmid": "16920841", "text": "Kidney BHMT and liver CHDH expression were refractory to these diets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16920841", "text": "Some degree of fatty liver developed in all rats fed a choline-devoid diet, indicating that supplemental Met cannot completely compensate for the lack of dietary choline in growing rats.", "type": "CHEMICAL", "entities": [ "choline", "Met", "choline" ], "offsets": [ [ 55, 62 ], [ 105, 108 ], [ 162, 169 ] ] }, { "pmid": "23548896", "text": "Identification of a new interaction mode between the Src homology 2 (SH2) domain of C-terminal Src kinase (Csk) and Csk-binding protein (Cbp)/phosphoprotein associated with glycosphingolipid microdomains (PAG).\n", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 84, 85 ] ] }, { "pmid": "23548896", "text": "Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 63, 71 ] ] }, { "pmid": "23548896", "text": "Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23548896", "text": "However, these analyses have been performed using short peptides comprising phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites.", "type": "CHEMICAL", "entities": [ "phosphotyrosine", "amino acids" ], "offsets": [ [ 76, 91 ], [ 110, 121 ] ] }, { "pmid": "23548896", "text": "Here we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from Csk-binding protein (Cbp).", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 59, 60 ] ] }, { "pmid": "23548896", "text": "This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine-314 binding site of Cbp.", "type": "CHEMICAL", "entities": [ "phosphotyrosine" ], "offsets": [ [ 133, 148 ] ] }, { "pmid": "23548896", "text": "Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23548896", "text": "Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the βB/βC loop of the SH2 domain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Protective effects of protein transduction domain-metallothionein fusion proteins against hypoxia- and oxidative stress-induced apoptosis in an ischemia/reperfusion rat model.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Ischemic heart diseases caused by insufficient oxygen supply to the cardiac muscle require pharmaceutical agents for the prevention of the progress and recurrence.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 47, 53 ] ] }, { "pmid": "23391442", "text": "Metallothionein (MT) has a potential as a protein therapeutic for the treatment of this disease due to its anti-oxidative effects under stressful conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "In spite of its therapeutic potential, efficient delivery systems need to be developed to overcome limitations such as low transduction efficiency, instability and short half-life in the body.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "To enhance intra-cellular transduction efficiency, Tat sequence as a protein transduction domain (PTD) was fused with MT in a recombinant method.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Anti-apoptotic and anti-oxidative effects of Tat-MT fusion protein were evaluated under hyperglycemia and hypoxia stress conditions in cultured H9c2 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Recovery of cardiac functions by anti-apoptotic and anti-fibrotic effects of Tat-MT was confirmed in an ischemia/reperfusion (I/R) rat myocardial infarction model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Tat-MT fusion protein effectively protected H9c2 cells under stressful conditions by reducing intracellular ROS production and inhibiting caspase-3 activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391442", "text": "Tat-MT fusion protein inhibited apoptosis, reduced fibrosis area and enhanced cardiac functions in I/R. Tat-MT fusion protein could be a promising therapeutic for the treatment of ischemic heart diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418087", "text": "Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice.\n", "type": "CHEMICAL", "entities": [ "bisphenol a" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "23418087", "text": "Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern.", "type": "CHEMICAL", "entities": [ "Bisphenol A", "BPA" ], "offsets": [ [ 0, 11 ], [ 13, 16 ] ] }, { "pmid": "23418087", "text": "Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes.", "type": "CHEMICAL", "entities": [ "BPA", "calcium" ], "offsets": [ [ 43, 46 ], [ 88, 95 ] ] }, { "pmid": "23418087", "text": "We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 35, 38 ] ] }, { "pmid": "23418087", "text": "BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23418087", "text": "Echocardiography identified concentric remodeling in all BPA-treated males.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 55, 58 ] ] }, { "pmid": "23418087", "text": "Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 78, 81 ] ] }, { "pmid": "23418087", "text": "Diastolic blood pressure was increased in all BPA females.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "23418087", "text": "The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation.", "type": "CHEMICAL", "entities": [ "phospho", "calcium", "sodium", "calcium" ], "offsets": [ [ 128, 135 ], [ 2, 9 ], [ 79, 85 ], [ 86, 93 ] ] }, { "pmid": "23418087", "text": "Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes.", "type": "CHEMICAL", "entities": [ "calcium", "calcium" ], "offsets": [ [ 44, 51 ], [ 82, 89 ] ] }, { "pmid": "23418087", "text": "DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females.", "type": "CHEMICAL", "entities": [ "BPA", "BPA", "BPA" ], "offsets": [ [ 55, 58 ], [ 69, 72 ], [ 100, 103 ] ] }, { "pmid": "23418087", "text": "Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females.", "type": "CHEMICAL", "entities": [ "BPA", "BPA" ], "offsets": [ [ 38, 41 ], [ 67, 70 ] ] }, { "pmid": "23418087", "text": "BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island.", "type": "CHEMICAL", "entities": [ "CpG" ], "offsets": [ [ 59, 62 ] ] }, { "pmid": "23418087", "text": "These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23000445", "text": "Wogonoside induces autophagy in MDA-MB-231 cells by regulating MAPK-mTOR pathway.\n", "type": "CHEMICAL", "entities": [ "Wogonoside" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23000445", "text": "Previous studies have demonstrated that wogonoside, a bioactive flavonoid extracted from the root of Scutellaria baicalensis Gerogi, has anti-inflammatory and anti-angiogenic activities.", "type": "CHEMICAL", "entities": [ "wogonoside", "flavonoid" ], "offsets": [ [ 40, 50 ], [ 64, 73 ] ] }, { "pmid": "23000445", "text": "In this study, we evaluated wogonoside-induced autophagy on human breast MDA-MB-231 cells.", "type": "CHEMICAL", "entities": [ "wogonoside" ], "offsets": [ [ 28, 38 ] ] }, { "pmid": "23000445", "text": "We report that wogonoside triggered the formation of microtubule-associated protein-light chain 3 (MAP-LC3) positive autophagosomes and the accumulation of acidic vesicular and autolysosomes in MDA-MB-231 cells.", "type": "CHEMICAL", "entities": [ "wogonoside" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "23000445", "text": "In addition, cells treated by wogonoside developed autophagosome-like characteristics, including single and double membrane vacuoles containing intact and degraded cellular debris.", "type": "CHEMICAL", "entities": [ "wogonoside" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "23000445", "text": "The results showed that wogonoside promotes the expression of LC3-II and Beclin-1.", "type": "CHEMICAL", "entities": [ "wogonoside" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "23000445", "text": "Furthermore, wogonoside inhibited cell growth of MDA-MB-231 cells in a concentration- and time-dependent manner, which was associated with wogonoside-induced autophagy.", "type": "CHEMICAL", "entities": [ "wogonoside", "wogonoside" ], "offsets": [ [ 13, 23 ], [ 139, 149 ] ] }, { "pmid": "23000445", "text": "Wogonoside also suppressed the activation of mammalian target of rapamycin (mTOR) and p70-S6 kinase (p70S6K) by regulating the expression of the extracellular signal-regulated kinase (ERK1/2) and p38 involved mitogen-activated protein kinase (MAPK) signaling pathway.", "type": "CHEMICAL", "entities": [ "Wogonoside", "rapamycin" ], "offsets": [ [ 0, 10 ], [ 65, 74 ] ] }, { "pmid": "23000445", "text": "Taken together, these results suggest that wogonoside partially inhibits MDA-MB-231 cell growth by inducing autophagy through the MAPK-mTOR pathway and may be a promising anti-tumor agent.", "type": "CHEMICAL", "entities": [ "wogonoside" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "23125284", "text": "A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "The mitochondrial respiratory chain complex IV (cytochrome c oxidase) is a multi-subunit enzyme that transfers electrons from cytochrome c to molecular oxygen, yielding water.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 152, 158 ] ] }, { "pmid": "23125284", "text": "Its biogenesis requires concerted expression of mitochondria- and nuclear-encoded subunits and assembly factors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "In this report, we describe a homozygous missense mutation in FAM36A from a patient who displays ataxia and muscle hypotonia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "The FAM36A gene is a remote, putative ortholog of the fungal complex IV assembly factor COX20.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "Messenger RNA (mRNA) and protein co-expression analyses support the involvement of FAM36A in complex IV function in mammals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "The c.154A>C mutation in the FAM36A gene, a mutation that is absent in sequenced exomes, leads to a reduced activity and lower levels of complex IV and its protein subunits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "The FAM36A protein is nearly absent in patient's fibroblasts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "Lentiviral complementation of patient's fibroblasts with wild-type FAM36A increases the complex IV activity as well as the amount of holocomplex IV and of individual subunits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23125284", "text": "These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6687626", "text": "Deduced amino acid sequence from the bovine oxytocin-neurophysin I precursor cDNA.\n", "type": "CHEMICAL", "entities": [ "oxytocin", "amino acid" ], "offsets": [ [ 44, 52 ], [ 8, 18 ] ] }, { "pmid": "6687626", "text": "The nonapeptide hormone oxytocin-like arginine-vasopressin (AVP) is synthesized as part of a larger precursor polypeptide.", "type": "CHEMICAL", "entities": [ "oxytocin", "arginine", "vasopressin", "AVP" ], "offsets": [ [ 24, 32 ], [ 38, 46 ], [ 47, 58 ], [ 60, 63 ] ] }, { "pmid": "6687626", "text": "The precursor also includes the neurophysin molecule with which the hormone is associated in the neurosecretory granules of the hypothalamo-pituitary tract.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6687626", "text": "A protein of molecular weight (Mr) approximately 20,000 has been isolated from supraoptic nuclei of rat hypothalami which, after tryptic cleavage, released a neurophysin-like molecule of Mr approximately 10,000 and an oligopeptide related to oxytocin.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 242, 250 ] ] }, { "pmid": "6687626", "text": "This result was complemented by in vitro translation of bovine hypothalamic mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "6687626", "text": "Among the primary translation products a single polypeptide of Mr approximately 16,500 was shown to contain antigenic determinants recognized by specific antisera against bovine neurophysin I and oxytocin.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 196, 204 ] ] }, { "pmid": "6687626", "text": "Here we report the amino acid sequence of the bovine oxytocin-neurophysin I (OT-NpI) precursor which was derived from sequence analysis of the cloned cDNA.", "type": "CHEMICAL", "entities": [ "amino acid", "oxytocin" ], "offsets": [ [ 19, 29 ], [ 53, 61 ] ] }, { "pmid": "6687626", "text": "As is the case for the bovine arginine-vasopressin-neurophysin II (AVP-NpII) precursor, the signal sequence of the OT-NpI precursor is immediately followed by the nonapeptide hormone which is connected to neurophysin I by a Gly-Lys-Arg sequence.", "type": "CHEMICAL", "entities": [ "arginine", "vasopressin", "AVP", "Gly-Lys-Arg" ], "offsets": [ [ 30, 38 ], [ 39, 50 ], [ 67, 70 ], [ 224, 235 ] ] }, { "pmid": "6687626", "text": "A striking feature of the nucleic acid sequence is the 197-nucleotide long perfect homology with the AVP-NpII precursor mRNA sequence encoding the conserved middle part of neurophysins I and II.", "type": "CHEMICAL", "entities": [ "AVP" ], "offsets": [ [ 101, 104 ] ] }, { "pmid": "23419638", "text": "Pelargonidin activates the AhR and induces CYP1A1 in primary human hepatocytes and human cancer cell lines HepG2 and LS174T.\n", "type": "CHEMICAL", "entities": [ "Pelargonidin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23419638", "text": "We examined the effects of anthocyanidins (cyanidin, delphinidin, malvidin, peonidin, petunidin, pelargonidin) on the aryl hydrocarbon receptor (AhR)-CYP1A1 signaling pathway in human hepatocytes, hepatic HepG2 and intestinal LS174T cancer cells.", "type": "CHEMICAL", "entities": [ "aryl hydrocarbon", "anthocyanidins", "cyanidin", "delphinidin", "malvidin", "peonidin", "petunidin", "pelargonidin" ], "offsets": [ [ 118, 134 ], [ 27, 41 ], [ 43, 51 ], [ 53, 64 ], [ 66, 74 ], [ 76, 84 ], [ 86, 95 ], [ 97, 109 ] ] }, { "pmid": "23419638", "text": "AhR-dependent reporter gene expression in transfected HepG2 cells was increased by pelargonidin in a concentration-dependent manner at 24h.", "type": "CHEMICAL", "entities": [ "pelargonidin" ], "offsets": [ [ 83, 95 ] ] }, { "pmid": "23419638", "text": "Similarly, pelargonidin induced the expression of CYP1A1 mRNA up to 5-fold in HepG2 and LS174T cells relative to the induction by 5 nM 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the most potent activator of AhR. CYP1A1 and CYP1A2 mRNAs were also increased by pelargonidin in three primary human hepatocytes cultures (approximately 5% of TCDD potency) and the increase in CYP1A1 protein in HepG2 and LS174T cells was comparable to the increase in catalytic activity of CYP1A1 enzyme.", "type": "CHEMICAL", "entities": [ "pelargonidin", "2,3,7,8-tetrachlorodibenzodioxin", "TCDD", "pelargonidin", "TCDD" ], "offsets": [ [ 11, 23 ], [ 135, 167 ], [ 169, 173 ], [ 257, 269 ], [ 335, 339 ] ] }, { "pmid": "23419638", "text": "Ligand binding analysis demonstrated that pelargonidin was a weak ligand of AhR. Enzyme kinetic analyses using human liver microsomes revealed inhibition of CYP1A1 activity by delphinidin (IC50 78 μM) and pelargonidin (IC50 33 μM).", "type": "CHEMICAL", "entities": [ "delphinidin", "pelargonidin", "pelargonidin" ], "offsets": [ [ 176, 187 ], [ 205, 217 ], [ 42, 54 ] ] }, { "pmid": "23419638", "text": "Overall, although most anthocyanidins had no effects on AhR-CYP1A1 signaling, pelargonidin can bind to and activate the AhR and AhR-dependent gene expression, and pelargonidin and delphinidin inhibit the CYP1A1 catalytic activity.", "type": "CHEMICAL", "entities": [ "anthocyanidins", "pelargonidin", "pelargonidin", "delphinidin" ], "offsets": [ [ 21, 35 ], [ 76, 88 ], [ 161, 173 ], [ 178, 189 ] ] }, { "pmid": "7680751", "text": "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs.\n", "type": "CHEMICAL", "entities": [ "serotonin", "tricyclic" ], "offsets": [ [ 34, 43 ], [ 76, 85 ] ] }, { "pmid": "7680751", "text": "We have used the polymerase chain reaction technique to selectively amplify a guanine nucleotide-binding protein-coupled receptor cDNA sequence from rat striatal mRNA that exhibits high homology to previously cloned serotonin receptors.", "type": "CHEMICAL", "entities": [ "serotonin", "guanine nucleotide" ], "offsets": [ [ 216, 225 ], [ 78, 96 ] ] }, { "pmid": "7680751", "text": "Sequencing of a full length clone isolated from a rat striatal cDNA library revealed an open reading frame of 1311 base pairs, encoding a 437-residue protein with seven hydrophobic regions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7680751", "text": "Within these hydrophobic regions, this receptor was found to be 41-36% identical to the following serotonin", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 98, 107 ] ] }, { "pmid": "7680751", "text": "[5-hydroxytryptamine (5-HT)] receptors: 5-HT2 > 5-HT1D > 5-HT1C > 5-HT1B > 5-HT1A >", "type": "CHEMICAL", "entities": [ "5-hydroxytryptamine", "5-HT" ], "offsets": [ [ 1, 20 ], [ 22, 26 ] ] }, { "pmid": "7680751", "text": "5-HT1E. Northern blots revealed a approximately 4.2-kilobase transcript localized in various brain regions, with the following rank order of abundance: striatum >> olfactory tubercle >", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7680751", "text": "cerebral cortex > hippocampus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7680751", "text": "Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of (+)-[2-125I] iodolysergic acid diethylamide ([125I]LSD) with a Kd of 1.26 nM. Among endogenous biogenic amines, only 5-HT completely inhibited [125I]LSD binding (Ki = 150 nM).", "type": "CHEMICAL", "entities": [ "5-HT", "[125I]LSD", "(+)-[2-125I] iodolysergic acid diethylamide", "[125I]LSD" ], "offsets": [ [ 223, 227 ], [ 249, 258 ], [ 106, 149 ], [ 151, 160 ] ] }, { "pmid": "7680751", "text": "The inhibition of [125I]LSD binding by other serotonergic agonists and antagonists revealed a pharmacological profile that does not correlate with that of any previously described serotonin receptor subtype.", "type": "CHEMICAL", "entities": [ "[125I]LSD", "serotonin" ], "offsets": [ [ 18, 27 ], [ 180, 189 ] ] }, { "pmid": "7680751", "text": "In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs, including clozapine, amoxipine, and amitriptyline.", "type": "CHEMICAL", "entities": [ "tricyclic", "clozapine", "amoxipine", "amitriptyline" ], "offsets": [ [ 66, 75 ], [ 126, 135 ], [ 137, 146 ], [ 152, 165 ] ] }, { "pmid": "7680751", "text": "In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylyl cyclase activity, which is blocked by antipsychotic and antidepressant drugs.", "type": "CHEMICAL", "entities": [ "serotonin", "adenylyl" ], "offsets": [ [ 56, 65 ], [ 98, 106 ] ] }, { "pmid": "7680751", "text": "The distinct structural and pharmacological properties of this receptor site indicate that it represents a completely novel subtype of serotonin receptor.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 135, 144 ] ] }, { "pmid": "7680751", "text": "Based on its affinity for tricyclic psychotropic drugs and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.", "type": "CHEMICAL", "entities": [ "tricyclic" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "23489521", "text": "The use of insulin analogues in pregnancy.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "Excellent glycaemic control is essential in pregnancy to optimise maternal and foetal outcomes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "The aim of this review is to assess the efficacy and safety of insulin analogues in pregnancy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "Insulin lispro and insulin aspart are safe in pregnancy and may improve post-prandial glycaemic control in women with type 1 diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "However, a lack of data indicating improved foetal outcomes would suggest that there is no imperative to switch to a short-acting analogue where the woman's diabetes is well controlled with human insulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "There are no reports of the use of insulin glulisine in pregnancy and so its use cannot be recommended.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "Most studies of insulin glargine in pregnancy are small, retrospective and include women with pre-existing diabetes and gestational diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "There appear to be no major safety concerns and so it seems reasonable to continue insulin glargine if required to achieve excellent glycaemic control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "A head-to-head comparison between insulin detemir and NPH insulin in women with type 1 diabetes showed that while foetal outcomes did not differ, fasting plasma glucose improved with insulin detemir without an increased incidence of hypoglycaemia.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 161, 168 ] ] }, { "pmid": "23489521", "text": "The greater evidence base supports the use of insulin detemir as the first line long-acting analogue in pregnancy but the lack of definitive foetal benefits means that there is no strong need to switch a woman who is well controlled on NPH insulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23489521", "text": "There seems little justification in using long acting insulin analogues in women with gestational diabetes or type 2 diabetes where the risk of hypoglycaemia is low.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.\n", "type": "CHEMICAL", "entities": [ "alpha-Linolenic acid" ], "offsets": [ [ 0, 20 ] ] }, { "pmid": "17284757", "text": "BACKGROUND: Delta(6)-Desaturase (FADS2) is the rate-limiting step in the polyunsaturated fatty acid (PUFA) biosynthetic pathway.", "type": "CHEMICAL", "entities": [ "PUFA", "polyunsaturated fatty acid" ], "offsets": [ [ 101, 105 ], [ 73, 99 ] ] }, { "pmid": "17284757", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "The aim was to test whether the common deletion", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "[T/-] in the promoter of FADS2 affects the PUFA biosynthetic pathway and consequently modifies the effect of alpha-linolenic acid (ALA) on myocardial infarction (MI).", "type": "CHEMICAL", "entities": [ "PUFA", "alpha-linolenic acid", "ALA" ], "offsets": [ [ 43, 47 ], [ 109, 129 ], [ 131, 134 ] ] }, { "pmid": "17284757", "text": "DESIGN:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "Case subjects (n =1694) with a first nonfatal acute MI were matched by age, sex, and area of residence to 1694 population-based control subjects in Costa Rica.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "PUFAs were quantified by gas-liquid chromatography from plasma and adipose tissue samples.", "type": "CHEMICAL", "entities": [ "PUFAs" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "17284757", "text": "Least-squares means from generalized linear models and odds ratios (ORs) and 95% CIs from multiple conditional logistic regression models were estimated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "The prevalence of the variant T/- allele was 48%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "Eicosapentaenoic acid, gamma-linolenic acid, and arachidonic acid decreased in adipose tissue and plasma with increasing number of copies of the variant allele with a monotonic trend (P < 0.05 for all).", "type": "CHEMICAL", "entities": [ "Eicosapentaenoic acid", "gamma-linolenic acid", "arachidonic acid" ], "offsets": [ [ 0, 21 ], [ 23, 43 ], [ 49, 65 ] ] }, { "pmid": "17284757", "text": "Fasting plasma triacylglycerols by genotype were 2.08 mmol/L for TT, 2.16 mmol/L for T-, and 2.26 mmol/L for - - [ie, homozygous for the variant (deletion) allele]", "type": "CHEMICAL", "entities": [ "triacylglycerols" ], "offsets": [ [ 15, 31 ] ] }, { "pmid": "17284757", "text": "(P = 0.03).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "The FADS2 deletion was not associated with MI and did not significantly modify the association between adipose tissue ALA and the risk of MI.", "type": "CHEMICAL", "entities": [ "ALA" ], "offsets": [ [ 118, 121 ] ] }, { "pmid": "17284757", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17284757", "text": "The FADS2 deletion may prevent the conversion of ALA into very-long-chain PUFAs.", "type": "CHEMICAL", "entities": [ "ALA", "very-long-chain PUFAs" ], "offsets": [ [ 49, 52 ], [ 58, 79 ] ] }, { "pmid": "17284757", "text": "However, this metabolic effect is not translated into an attenuated risk between ALA and MI among carriers of the variant.", "type": "CHEMICAL", "entities": [ "ALA" ], "offsets": [ [ 81, 84 ] ] }, { "pmid": "17284757", "text": "It is possible that, at current intakes of ALA, any potential defect in the transcription of the gene is masked by the availability of substrate.", "type": "CHEMICAL", "entities": [ "ALA" ], "offsets": [ [ 43, 46 ] ] }, { "pmid": "17284757", "text": "Further research in populations deficient in ALA intake is warranted.", "type": "CHEMICAL", "entities": [ "ALA" ], "offsets": [ [ 45, 48 ] ] }, { "pmid": "10398211", "text": "Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy: role of nitric oxide.\n", "type": "CHEMICAL", "entities": [ "angiotensin II", "nitric oxide" ], "offsets": [ [ 26, 40 ], [ 86, 98 ] ] }, { "pmid": "10398211", "text": "We evaluated the effects of angiotensin II and an angiotensin-converting enzyme inhibitor (cilazapril) on nerve blood flow (NBF) and electrophysiology in control and diabetic rats.", "type": "CHEMICAL", "entities": [ "angiotensin II", "angiotensin", "cilazapril" ], "offsets": [ [ 28, 42 ], [ 50, 61 ], [ 91, 101 ] ] }, { "pmid": "10398211", "text": "When applied locally to the sciatic nerve, the dose-response curve of angiotensin II was more potent in experimental diabetic neuropathy (EDN) than control rats.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 70, 84 ] ] }, { "pmid": "10398211", "text": "No difference existed in plasma angiotensin II levels between EDN and controls.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 32, 46 ] ] }, { "pmid": "10398211", "text": "The rats were given typical rat pellets or pellets treated with 10 mg/kg per day cilazapril for 4 weeks.", "type": "CHEMICAL", "entities": [ "cilazapril" ], "offsets": [ [ 81, 91 ] ] }, { "pmid": "10398211", "text": "Diabetes caused a significant reduction in NBF, nerve conduction velocity, and compound muscle action potential (CMAP) amplitudes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10398211", "text": "NBF was significantly increased in diabetic rats supplemented with cilazapril diet, and nerve conduction velocity and amplitudes of the CMAP were also improved after 4 weeks on this diet.", "type": "CHEMICAL", "entities": [ "cilazapril" ], "offsets": [ [ 67, 77 ] ] }, { "pmid": "10398211", "text": "Direct application 10(-3)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10398211", "text": "mol/L cilazapril on sciatic nerve did not increase NBF in normal and EDN rats.", "type": "CHEMICAL", "entities": [ "cilazapril" ], "offsets": [ [ 6, 16 ] ] }, { "pmid": "10398211", "text": "We topically applied the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine, on sciatic nerve and observed reduced inhibition of NBF in EDN, which was correctable with a cilazapril diet.", "type": "CHEMICAL", "entities": [ "NG-nitro-L-arginine", "cilazapril", "nitric oxide" ], "offsets": [ [ 64, 83 ], [ 178, 188 ], [ 25, 37 ] ] }, { "pmid": "10398211", "text": "These results suggest that diabetic neuropathy may have an increasing vasopressor action with angiotensin II and this is likely to be the mechanism of NOS inhibition.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 94, 108 ] ] }, { "pmid": "10398211", "text": "Angiotensin II-converting enzyme inhibitors may have potential in the treatment of diabetic neuropathy.", "type": "CHEMICAL", "entities": [ "Angiotensin II" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "7824160", "text": "Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors.\n", "type": "CHEMICAL", "entities": [ "R(-) and S(+) isomers of MDA", "MDMA", "phosphatidyl inositol" ], "offsets": [ [ 14, 42 ], [ 47, 51 ], [ 55, 76 ] ] }, { "pmid": "7824160", "text": "The effect of the R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine (MDA) and its N-methyl analog 3,4-methylenedioxymethamphetamine (MDMA) on [3H]inositol monophosphate accumulation was studied in cells expressing either 5-HT2A or 5-HT2C receptors.", "type": "CHEMICAL", "entities": [ "MDMA", "[3H]inositol monophosphate", "R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine", "MDA", "N-methyl analog 3,4-methylenedioxymethamphetamine" ], "offsets": [ [ 138, 142 ], [ 147, 173 ], [ 18, 72 ], [ 74, 77 ], [ 87, 136 ] ] }, { "pmid": "7824160", "text": "The isomers of MDA produced a concentration dependent increase in phosphatidyl inositol (PI) hydrolysis at the 5-HT2A receptors, with the R(-) isomer of MDA being more potent than the S(+) at the 5-HT2A receptor.", "type": "CHEMICAL", "entities": [ "MDA", "phosphatidyl inositol", "PI", "R(-) isomer of MDA" ], "offsets": [ [ 15, 18 ], [ 66, 87 ], [ 89, 91 ], [ 138, 156 ] ] }, { "pmid": "7824160", "text": "The R(-) and S(+) isomers of MDMA were significantly less efficacious at the 5-HT2A receptor as compared to MDA; S(+)MDMA had no effect.", "type": "CHEMICAL", "entities": [ "R(-) and S(+) isomers of MDMA", "MDA", "S(+)MDMA" ], "offsets": [ [ 4, 33 ], [ 108, 111 ], [ 113, 121 ] ] }, { "pmid": "7824160", "text": "At the 5-HT2C receptor, both R(-) and S(+)MDA were equipotent at stimulating PI hydrolysis, with the S(+) isomer of MDMA being more efficacious at the 5-HT2C receptor compared with the R(-) isomer.", "type": "CHEMICAL", "entities": [ "R(-) and S(+)MDA", "PI", "S(+) isomer of MDMA" ], "offsets": [ [ 29, 45 ], [ 77, 79 ], [ 101, 120 ] ] }, { "pmid": "7824160", "text": "In all cases at both the 5-HT2A and 5-HT2C receptors, the affinities of the isomers of MDMA and MDA were at least 2-3 orders of magnitude less than 5-HT.", "type": "CHEMICAL", "entities": [ "MDMA", "MDA", "5-HT" ], "offsets": [ [ 87, 91 ], [ 96, 99 ], [ 148, 152 ] ] }, { "pmid": "7824160", "text": "Despite the weak effect of these compounds at the 5-HT2A and 5-HT2C receptors, these substituted amphetamines do possess intrinsic activity which may contribute to their neurotoxic effects when administered at high doses.", "type": "CHEMICAL", "entities": [ "amphetamines" ], "offsets": [ [ 97, 109 ] ] }, { "pmid": "23376140", "text": "Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src.\n", "type": "CHEMICAL", "entities": [ "cadmium" ], "offsets": [ [ 61, 68 ] ] }, { "pmid": "23376140", "text": "Although the liver is a cadmium-target organ, hepatocyte response involved in its toxicity is not yet elucidated.", "type": "CHEMICAL", "entities": [ "cadmium" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23376140", "text": "A link between this heavy metal treatment and Stat3 signaling pathways was examined in primary mouse hepatocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23376140", "text": "We provided evidence of a novel link among NADPH oxidase and Stat3 signaling, mediated by Src, EGFR, and Erk1/2.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 43, 48 ] ] }, { "pmid": "23376140", "text": "Cadmium activates NADPH oxidase.", "type": "CHEMICAL", "entities": [ "Cadmium", "NADPH" ], "offsets": [ [ 0, 7 ], [ 18, 23 ] ] }, { "pmid": "23376140", "text": "ROS produced by this oxidase activates Src, enable that in turn, transactivates EGFR that activates Stat3 in tyrosine, allowing its dimerization.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "23376140", "text": "Also, ROS from NADPH oxidase favors ERK1/2 activation that phosphorylates Stat3 in serine, resulting in a compensatory or adaptive survival response such as production of metallothionein-II in short Cd exposure times.", "type": "CHEMICAL", "entities": [ "NADPH", "serine", "Cd" ], "offsets": [ [ 15, 20 ], [ 83, 89 ], [ 199, 201 ] ] }, { "pmid": "23376140", "text": "However, after 12h CdCl2 treatment, cell viability diminished in 50%, accompanied by a drastic decrease of metallothionein-II production, and an increase in p53 activation and the pro-apoptotic protein Bax.", "type": "CHEMICAL", "entities": [ "CdCl2" ], "offsets": [ [ 19, 24 ] ] }, { "pmid": "16864089", "text": "[Screening of short peptides binding to cell surface interleukin-2 receptor alpha chain].\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "OBJECTIVE: To screen and characterize the short peptides which bind specifically to interleukin-2 (IL-2) receptor alpha chain (IL-2Ralpha) for acquisition of small antagonists for blocking the binding of IL-2 with IL-2Ralpha.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "METHODS: 12-mer phage displayed peptide library was screened with the target cells of MT-2 cells which expressed IL-2Ralpha at high levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "The binding phage clones were eluted by anti-IL-2Ralpha monoclonal antibody.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "After 3 rounds of screening, the positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, and the amino acid sequences of the positive clones were deduced from the DNA sequences.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 150, 160 ] ] }, { "pmid": "16864089", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "Seven positive clones were screened out of the 17 phage clones bound to MT-2 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "The positive clone M15 could bind specifically to MT-2 cell and PHA-activated peripheral blood monouclear cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "Amino acid sequence analysis identified 6 sequences, all of which contained hydrophilic residues, and 5 of these 6 sequences included Tyr, Phe and Leu conservative residues.", "type": "CHEMICAL", "entities": [ "Tyr", "Phe", "Leu", "Amino acid" ], "offsets": [ [ 134, 137 ], [ 139, 142 ], [ 147, 150 ], [ 0, 10 ] ] }, { "pmid": "16864089", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16864089", "text": "The peptide sequences containing Tyr, Phe conservative residues identified in this study can bind to cell surface IL-2Ralpha.", "type": "CHEMICAL", "entities": [ "Tyr", "Phe" ], "offsets": [ [ 33, 36 ], [ 38, 41 ] ] }, { "pmid": "23411217", "text": "Peyer's patch-mediated intestinal immune system modulating activity of pectic-type polysaccharide from peel of Citrus unshiu.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "An intestinal immune system modulating polysaccharide (CUI-3IIb-3-2, 18kDa) was purified from Citrus unshiu peel.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "CUI-3IIb-3-2 mainly comprised GalA, GlcA, Ara, Gal and Rha, and it consisted of 4-linked GalA, terminal Araf, 4- or 5-linked/3,4- or 3,5-branched Ara, terminal Gal, and 2-linked/2,4-branched Rha.", "type": "CHEMICAL", "entities": [ "GalA", "GlcA", "Ara", "Gal", "Rha", "GalA", "Araf", "Ara", "Gal", "Rha" ], "offsets": [ [ 30, 34 ], [ 36, 40 ], [ 42, 45 ], [ 47, 50 ], [ 55, 58 ], [ 89, 93 ], [ 104, 108 ], [ 146, 149 ], [ 160, 163 ], [ 191, 194 ] ] }, { "pmid": "23411217", "text": "After CUI-3IIb-3-2 digestion by endo-α-d-(1→4)-polygalacturonase, its hydrolysate was fractionated into PG-1 and PG-2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "Methylation analyses of PG-1 and PG-2 using base-catalysed β-elimination suggested that CUI-3IIb-3-2 be assumed as pectic-type polysaccharide.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "Since the activities of PG-1 and PG-2 were potently decreased, the whole polysaccharide structure of CUI-3IIb-3-2 would be essential to maintain the activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "Meanwhile, when CUI-3IIb was orally administered in mice, bone marrow cell proliferation and GM-CSF/IL-6 production from Peyer's patch cell were significantly higher (1.76- and 2.03/2.51-fold, respectively) than a saline.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23411217", "text": "Therefore, a pectic-type polysaccharide from citrus peel could stimulate Peyer's patches and produce hematopoietic growth factors resulted in bone marrow cell proliferation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "An Indian butyrylcholinesterase variant L307P is not structurally stable: A molecular dynamics simulation study.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "The human butyrylcholinesterase (BChE) activity is less than 1% in the serum of silent variant individuals of Vysya community in India.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "They are homozygous for a point mutation at codon 307 (CTT→CCT) resulting in the substitution of leucine 307 by proline.", "type": "CHEMICAL", "entities": [ "leucine", "proline" ], "offsets": [ [ 97, 104 ], [ 112, 119 ] ] }, { "pmid": "23123771", "text": "The reason for the disappearance of the protein in the serum has not been explicated till date.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "Based on this background, we performed molecular dynamics simulation to probe the structural stability of Indian variant (L307P) in comparison with wild and other BChE variants (D70G, E497V, V142M) having differential esterase activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "The simulation of all the mutants except D70G showed a much larger Cα root mean square deviation from the wild BChE crystal structure, showing the overall conformational disturbance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "Further analysis revealed that secondary structure of the mutant proteins was not stable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "The orientation of the catalytic triad is also distorted in all the mutants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "The distance between δ nitrogen of His438 to ε oxygen of Glu325 and ε nitrogen of His438 to γ oxygen of Ser198 were highly altered in L307P mutant than the wild and other three variants throughout the simulation.", "type": "CHEMICAL", "entities": [ "nitrogen", "His", "oxygen", "Ser", "nitrogen", "His", "oxygen", "Glu" ], "offsets": [ [ 67, 75 ], [ 79, 82 ], [ 91, 97 ], [ 101, 104 ], [ 20, 28 ], [ 32, 35 ], [ 44, 50 ], [ 54, 57 ] ] }, { "pmid": "23123771", "text": "Such disparity of distances between the catalytic residues may be due to the change in the protein conformation attributing to their differential catalytic activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "Our studies thus prove that the Indian BChE", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23123771", "text": "L307P mutant with negligible activity is possibly due to its structural instability when compared to other BChE variants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14642426", "text": "The inhibitory effect of ginseng saponins on the stress-induced plasma interleukin-6 level in mice.\n", "type": "CHEMICAL", "entities": [ "ginseng saponins" ], "offsets": [ [ 25, 41 ] ] }, { "pmid": "14642426", "text": "The effect of ginseng saponins on plasma interleukin-6 (IL-6) in non-stressed and immobilization-stressed mice were investigated.", "type": "CHEMICAL", "entities": [ "ginseng saponins" ], "offsets": [ [ 14, 30 ] ] }, { "pmid": "14642426", "text": "Ginseng total saponins, ginsenosides Rb2, Rg1 and Rd administered intraperitoneally attenuated the immobilization stress-induced increase in plasma IL-6 level.", "type": "CHEMICAL", "entities": [ "saponins", "ginsenosides Rb2, Rg1 and Rd" ], "offsets": [ [ 14, 22 ], [ 24, 52 ] ] }, { "pmid": "14642426", "text": "But, intracerebroventricular injection of each ginsenoside did not affect plasma IL-6 level induced by immobilization stress.", "type": "CHEMICAL", "entities": [ "ginsenoside" ], "offsets": [ [ 47, 58 ] ] }, { "pmid": "14642426", "text": "Ginsenosides Rb2, Rd and Rg1 significantly decreased norepinephrine and/or epinephrine-induced increase of IL-6 level in macrophage cell line (RAW 264.7).", "type": "CHEMICAL", "entities": [ "Ginsenosides Rb2, Rd and Rg1", "norepinephrine", "epinephrine" ], "offsets": [ [ 0, 28 ], [ 53, 67 ], [ 75, 86 ] ] }, { "pmid": "14642426", "text": "Thus, it can be suggested that the inhibitory action of ginseng saponins against the immobilization stress-induced increase of plasma IL-6 level would be in periphery; at least in part, mediated by blocking norepinephrine- and/or epinephrine-induced increase of IL-6 level in macrophage rather than in the brain.", "type": "CHEMICAL", "entities": [ "ginseng saponins", "norepinephrine", "epinephrine" ], "offsets": [ [ 56, 72 ], [ 207, 221 ], [ 230, 241 ] ] }, { "pmid": "14642426", "text": "Ginseng saponins might be proposed as a possible candidate in the research or therapeutic modulation of stress-related disorders.", "type": "CHEMICAL", "entities": [ "Ginseng saponins" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17352516", "text": "Sitagliptin.\n", "type": "CHEMICAL", "entities": [ "Sitagliptin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17352516", "text": "Sitagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, improves glycaemic control by inhibiting DPP-4 inactivation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.", "type": "CHEMICAL", "entities": [ "Sitagliptin", "glucose" ], "offsets": [ [ 0, 11 ], [ 176, 183 ] ] }, { "pmid": "17352516", "text": "This increases active incretin and insulin levels, and decreases glucagon levels and post-glucose-load glucose excursion.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 90, 97 ], [ 103, 110 ] ] }, { "pmid": "17352516", "text": "In large, well designed phase III trials in patients with type 2 diabetes mellitus, sitagliptin 100 or 200mg once daily alone or in combination with other antihyperglycaemics was associated with significant improvements relative to placebo in overall glycaemic control and indices for insulin response and beta-cell function.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 84, 95 ] ] }, { "pmid": "17352516", "text": "Improvements from baseline in mean glycosylated haemoglobin (HbA(1c)) were significantly greater with sitagliptin monotherapy than with placebo in patients with type 2 diabetes.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 102, 113 ] ] }, { "pmid": "17352516", "text": "As add-on therapy in patients with suboptimal glycaemic control despite oral antihyperglycaemic treatment, sitagliptin improved HbA(1c) to a significantly greater extent than placebo when added to metformin or pioglitazone and was noninferior to glipizide when added to metformin.", "type": "CHEMICAL", "entities": [ "metformin", "pioglitazone", "glipizide", "metformin", "sitagliptin" ], "offsets": [ [ 197, 206 ], [ 210, 222 ], [ 246, 255 ], [ 270, 279 ], [ 107, 118 ] ] }, { "pmid": "17352516", "text": "Sitagliptin was well tolerated when administered alone or in combination with other antihyperglycaemics, with an adverse event profile similar to that shown with placebo.", "type": "CHEMICAL", "entities": [ "Sitagliptin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17352516", "text": "The incidence of hypoglycaemia with sitagliptin was similar to that with placebo and, in combination with metformin, lower than that with glipizide.", "type": "CHEMICAL", "entities": [ "sitagliptin", "metformin", "glipizide" ], "offsets": [ [ 36, 47 ], [ 106, 115 ], [ 138, 147 ] ] }, { "pmid": "17352516", "text": "Sitagliptin had a generally neutral effect on bodyweight.", "type": "CHEMICAL", "entities": [ "Sitagliptin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23643883", "text": "Streptococcus pneumoniae ClpP protease induces apoptosis via caspase-independent pathway in human neuroblastoma cells: cytoplasmic relocalization of p53.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "Streptococcus pneumoniae causes the most severe form of the bacterial meningitis which is the major cause of bacterial meningitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "Virulence factors produced by S. pneumoniae have been known to contribute significantly to the disease process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "ClpP protease (ClpP) which is essential for virulence and survival under stress conditions in S. pneumonia was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human neuron-like cells, SK-N-SH neuroblastoma cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "ClpP inhibited cell growth and induced apoptosis in SK-N-SH cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "Treatment with ClpP resulted in hypodiploid DNA contents, increased Bax/ Bcl-2 ratio and induction of reactive oxygen species (ROS) production.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 111, 117 ] ] }, { "pmid": "23643883", "text": "The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was not observed in ClpP-treated cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "In addition, pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum of caspase inhibitor, could not rescue apoptotic cells from ClpP toxicity.", "type": "CHEMICAL", "entities": [ "Z-Val-Ala-Asp-fluoromethylketone", "Z-VAD-fmk" ], "offsets": [ [ 31, 63 ], [ 65, 74 ] ] }, { "pmid": "23643883", "text": "Coincidently, caspase-3 and -8 activation and cleavage of PARP were not detected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "Moreover, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria and translocated to the nucleus in response to ClpP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "We also found that ClpP treatment resulted in the increase of p53 activity and cytoplasmic p53 levels were increased by ClpP, suggesting that functional activation of p53 is intact despite increased cytoplasmic accumulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643883", "text": "Taken together, these data suggest that ClpP contributes to neuronal damage in meningitis and provide further insight into the mechanisms underlying action of pneumococcal virulence factors during bacterial pathogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "New aspects in the management of obesity: operation and the impact of lipase inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "Obesity is an increasing health problem in most developed countries and its prevalence is also increasing in developing countries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "There has been no great success with dietary means and life style modification for permanent weight loss.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "Various surgical treatment methods for obesity are now available.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "They are aimed at limiting oral energy intake with or without causing dumping or inducing selective maldigestion and malabsorption.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "Based on current literature, up to 75% of excess weight is lost by surgical treatment with concomitant disappearance of hyperlipidaemias, type 2 diabetes, hypertension or sleep apnoea.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "The main indication for operative treatment is morbid obesity (body mass index greater than 40 kg/m2) or severe obesity (body mass index > 35 kg/m2) with comorbidities of obesity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "Orlistat is a new inhibitor of pancreatic lipase enzyme.", "type": "CHEMICAL", "entities": [ "Orlistat" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "10095983", "text": "At doses of 120 mg three times per day with meals it results in a 30% reduction in dietary fat absorption, which equals approximately 200 kcal daily energy deficit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10095983", "text": "In the long term, orlistat has been shown to be more effective than placebo in reducing body weight and serum total and low-density lipoprotein cholesterol levels.", "type": "CHEMICAL", "entities": [ "orlistat", "cholesterol" ], "offsets": [ [ 18, 26 ], [ 144, 155 ] ] }, { "pmid": "10095983", "text": "Orlistat has a lowering effect on serum cholesterol independent of weight loss.", "type": "CHEMICAL", "entities": [ "Orlistat", "cholesterol" ], "offsets": [ [ 0, 8 ], [ 40, 51 ] ] }, { "pmid": "10095983", "text": "Along with weight loss, orlistat also favourably affects blood pressure and glucose and insulin levels in obese individuals and in obese type 2 diabetic patients.", "type": "CHEMICAL", "entities": [ "orlistat", "glucose" ], "offsets": [ [ 24, 32 ], [ 76, 83 ] ] }, { "pmid": "23435915", "text": "The characteristics of genistin-induced inhibitory effects on intestinal motility.\n", "type": "CHEMICAL", "entities": [ "genistin" ], "offsets": [ [ 23, 31 ] ] }, { "pmid": "23435915", "text": "Genistin belongs to isoflavones.", "type": "CHEMICAL", "entities": [ "Genistin", "isoflavones" ], "offsets": [ [ 0, 8 ], [ 20, 31 ] ] }, { "pmid": "23435915", "text": "Based on the facts that genistin exerts inhibitory effects on the contractility of vascular smooth muscle,the present study was designed to characterize the effects of genistin on intestinal contractility and evaluate its potential clinical implication.", "type": "CHEMICAL", "entities": [ "genistin", "genistin" ], "offsets": [ [ 168, 176 ], [ 24, 32 ] ] }, { "pmid": "23435915", "text": "Ex vivo [isolated jejunal segment (IJS) of rat], in vitro, and in vivo assays were used in the study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435915", "text": "The results indicated that genistin (5-80 μmol/L) inhibited the contraction of IJS in a dose-dependent manner and inhibited the increased-contractility of IJS induced by acetylcholine (ACh), histamine, high Ca(2+), and erythromycin, respectively.", "type": "CHEMICAL", "entities": [ "genistin", "acetylcholine", "ACh", "histamine", "Ca(2+)", "erythromycin" ], "offsets": [ [ 27, 35 ], [ 170, 183 ], [ 185, 188 ], [ 191, 200 ], [ 207, 213 ], [ 219, 231 ] ] }, { "pmid": "23435915", "text": "The inhibitory effects of genistin were correlated with the stimulation of alpha adrenergic and beta adrenergic receptors since these inhibitory effects were significantly blocked in the presence of phentolamine and propranolol respectively.", "type": "CHEMICAL", "entities": [ "genistin", "phentolamine", "propranolol" ], "offsets": [ [ 25, 33 ], [ 198, 210 ], [ 215, 226 ] ] }, { "pmid": "23435915", "text": "No further inhibitory effects of genistin were observed in the presence of verapamil or in Ca(2+)-free condition, indicating genistin-induced inhibitory effects are Ca(2+)-dependent.", "type": "CHEMICAL", "entities": [ "genistin", "Ca(2+)", "genistin", "verapamil", "Ca(2+)" ], "offsets": [ [ 124, 132 ], [ 164, 170 ], [ 32, 40 ], [ 74, 83 ], [ 90, 96 ] ] }, { "pmid": "23435915", "text": "Genistin decreased myosin light chain kinase (MLCK) protein contents and MLCK mRNA expression in IJS, and inhibited both phosphorylation and Mg(2+)-ATPase activity of purified myosin, implicating that the decrease of MLCK contents and inhibition of MLCK activity are involved in the genistin-induced inhibitory effects.", "type": "CHEMICAL", "entities": [ "Mg(2+)", "genistin" ], "offsets": [ [ 140, 146 ], [ 282, 290 ] ] }, { "pmid": "23435915", "text": "The study suggests the potential clinical implications of genistin in relieving intestinal hypercontractility.", "type": "CHEMICAL", "entities": [ "genistin" ], "offsets": [ [ 57, 65 ] ] }, { "pmid": "23333261", "text": "Contribution of single-minded 2 to hyperglycaemia-induced neurotoxicity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "Diabetes mellitus is associated to central nervous system damage, which results in impairment of brain functions and cognitive deficits and decline in memory.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "However, the mechanisms mediating the actions of glucose on the neurons remained elusive.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "23333261", "text": "Single-minded 2 (Sim2), a basic helix-loop-helix (bHLH)-PAS transcriptional repressor, is thought to be involved in some symptoms of Down syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "We hypothesized that Sim2 mediated hyperglycaemia-induced neuronal injury and impairment of learning and memory.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "It was found that expression of Sim2 protein in cortical neurons was increased in streptozotocin-induced diabetes mellitus rat model.", "type": "CHEMICAL", "entities": [ "streptozotocin" ], "offsets": [ [ 82, 96 ] ] }, { "pmid": "23333261", "text": "Drebrin, down-regulated by Sim2, was subsequently decreased as detected by confocal laser scanning microscopy and Western blot analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "The expression pattern of Sim2 and Drebrin correspond to 50mmol/L glucose (hyperglycaemia) was also found in primary cultured neurons.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 66, 73 ] ] }, { "pmid": "23333261", "text": "Curcumin, one neuroprotective agent, inhibited hyperglycaemia-induced neurotoxicity.", "type": "CHEMICAL", "entities": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23333261", "text": "Moreover, curcumin alleviated Sim2 expression, and reversely raised Drebrin expression in neurons treated with hyperglycaemia.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 10, 18 ] ] }, { "pmid": "23333261", "text": "Finally, we found that silencing Sim2 expression decreased hyperglycaemia-induced neuronal injury.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333261", "text": "In conclusion, Sim2 may mediate neurotoxicity during hyperglycaemia and thereby play a critical role in the development of hyperglycaemia-induced cognitive deficits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants.\n", "type": "CHEMICAL", "entities": [ "Cys", "His", "zinc" ], "offsets": [ [ 30, 33 ], [ 35, 38 ], [ 40, 44 ] ] }, { "pmid": "23471540", "text": "Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 10, 14 ] ] }, { "pmid": "23471540", "text": "A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 92, 96 ] ] }, { "pmid": "23471540", "text": "This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "We find that the characterized fingers can specify 47 of the 64 possible DNA triplets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23471540", "text": "To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 153, 157 ] ] }, { "pmid": "23471540", "text": "These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 81, 85 ] ] }, { "pmid": "20091113", "text": "Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of D-amphetamine: an exploratory pharmacogenetic study using healthy volunteers.\n", "type": "CHEMICAL", "entities": [ "dopamine", "D-amphetamine" ], "offsets": [ [ 17, 25 ], [ 88, 101 ] ] }, { "pmid": "20091113", "text": "Individuals vary in their subjective responses to stimulant drugs, and these differences are believed to be partially genetic in origin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20091113", "text": "We evaluated associations between mood, cognitive and cardiovascular responses to d-amphetamine and four polymorphisms in the dopamine transporter (SLC6A3): rs460000, rs3756450, rs37022 and rs6869645.", "type": "CHEMICAL", "entities": [ "d-amphetamine", "dopamine" ], "offsets": [ [ 82, 95 ], [ 126, 134 ] ] }, { "pmid": "20091113", "text": "Healthy Caucasian male and female volunteers (N = 152) participated in a double-blind, crossover design study in which they received placebo, 10 and 20 mg of d-amphetamine.", "type": "CHEMICAL", "entities": [ "d-amphetamine" ], "offsets": [ [ 158, 171 ] ] }, { "pmid": "20091113", "text": "We measured self-reported rating of mood, performance on the Digit Symbol Substitution Task, blood pressure and heart rate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20091113", "text": "Individuals with the C/C genotype at rs460000 (N = 83) reported approximately twofold higher ratings of stimulation and euphoria relative to the A/A+A/C (N = 69) genotype group, at both the 10 and 20 mg doses.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20091113", "text": "No other responses or SNPs showed significant effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20091113", "text": "rs460000 is in perfect LD with rs463379 (CEU: D' = 1; r (2) = 1), which was not studied here, but has been associated with etiology of Attention Deficit Hyperactivity Disorder (ADHD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20091113", "text": "These findings suggest a pleiotropic effect of this polymorphic locus on both ADHD and sensitivity to the subjective effects of amphetamine.", "type": "CHEMICAL", "entities": [ "amphetamine" ], "offsets": [ [ 128, 139 ] ] }, { "pmid": "23163726", "text": "The structure and properties of septin 3: a possible missing link in septin filament formation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "The human genome codes for 13 members of a family of filament-forming GTP-binding proteins known as septins.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 70, 73 ] ] }, { "pmid": "23163726", "text": "These have been divided into four different subgroups on the basis of sequence similarity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "The differences between the subgroups are believed to control their correct assembly into heterofilaments which have specific roles in membrane remodelling events.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "Many different combinations of the 13 proteins are theoretically possible and it is therefore important to understand the structural basis of specific filament assembly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "However, three-dimensional structures are currently available for only three of the four subgroups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "In the present study we describe the crystal structure of a construct of human SEPT3 which belongs to the outstanding subgroup.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "This construct (SEPT3-GC), which includes the GTP-binding and C-terminal domains, purifies as a nucleotide-free monomer, allowing for its characterization in terms of GTP-binding and hydrolysis.", "type": "CHEMICAL", "entities": [ "GTP", "C", "nucleotide", "GTP" ], "offsets": [ [ 46, 49 ], [ 62, 63 ], [ 96, 106 ], [ 167, 170 ] ] }, { "pmid": "23163726", "text": "In the crystal structure, SEPT3-GC forms foreshortened filaments which employ the same NC and G interfaces observed in the heterotrimeric complex of human septins 2, 6 and 7, reinforcing the notion of 'promiscuous' interactions described previously.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23163726", "text": "In the present study we describe these two interfaces and relate the structure to its tendency to form monomers and its efficiency in the hydrolysis of GTP.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 152, 155 ] ] }, { "pmid": "23163726", "text": "The relevance of these results is emphasized by the fact that septins from the SEPT3 subgroup may be important determinants of polymerization by occupying the terminal position in octameric units which themselves form the building blocks of at least some heterofilaments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23384446", "text": "The effect of inorganic arsenic on endothelium-dependent relaxation: Role of NADPH oxidase and hydrogen peroxide.\n", "type": "CHEMICAL", "entities": [ "arsenic", "NADPH", "hydrogen peroxide" ], "offsets": [ [ 24, 31 ], [ 77, 82 ], [ 95, 112 ] ] }, { "pmid": "23384446", "text": "Chronic arsenic ingestion predisposes to vascular disease, but underlying mechanisms are poorly understood.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 8, 15 ] ] }, { "pmid": "23384446", "text": "In the present study we have analyzed the effects of short-term arsenite exposure on vascular function and endothelium-dependent relaxation.", "type": "CHEMICAL", "entities": [ "arsenite" ], "offsets": [ [ 64, 72 ] ] }, { "pmid": "23384446", "text": "Endothelium-dependent relaxations, nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF)-type, were studied in rabbit iliac artery and aortic rings using the G protein-coupled receptor agonist acetylcholine (ACh) and by cyclopiazonic acid (CPA), which promotes store-operated Ca(2+) entry by inhibiting the endothelial SERCA pump.", "type": "CHEMICAL", "entities": [ "nitric oxide", "NO", "acetylcholine", "ACh", "cyclopiazonic acid", "CPA", "Ca(2+)" ], "offsets": [ [ 35, 47 ], [ 49, 51 ], [ 211, 224 ], [ 226, 229 ], [ 238, 256 ], [ 258, 261 ], [ 294, 300 ] ] }, { "pmid": "23384446", "text": "Production of reactive oxygen species (ROS) in the endothelium of rabbit aortic valve leaflets and endothelium-denuded RIA and aortic rings was assessed by imaging of dihydroethidium.", "type": "CHEMICAL", "entities": [ "oxygen", "dihydroethidium" ], "offsets": [ [ 23, 29 ], [ 167, 182 ] ] }, { "pmid": "23384446", "text": "In the iliac artery, exposure to 100μM arsenite for 30min potentiated EDHF-type relaxations evoked by both CPA and ACh.", "type": "CHEMICAL", "entities": [ "arsenite", "CPA", "ACh" ], "offsets": [ [ 39, 47 ], [ 107, 110 ], [ 115, 118 ] ] }, { "pmid": "23384446", "text": "Potentiation was prevented by catalase, the catalase/superoxide dismutase mimetic manganese porphyrin and the NADPH oxidase inhibitor apocynin.", "type": "CHEMICAL", "entities": [ "NADPH", "apocynin", "superoxide", "manganese porphyrin" ], "offsets": [ [ 109, 114 ], [ 133, 141 ], [ 52, 62 ], [ 81, 100 ] ] }, { "pmid": "23384446", "text": "By contrast in aortic rings, that exhibited negligible EDHF-type responses, endothelium-dependent NO-mediated relaxations evoked by CPA and ACh were unaffected by arsenite.", "type": "CHEMICAL", "entities": [ "NO", "CPA", "ACh", "arsenite" ], "offsets": [ [ 97, 99 ], [ 131, 134 ], [ 139, 142 ], [ 162, 170 ] ] }, { "pmid": "23384446", "text": "Arsenite induced apocynin-sensitive increases in ROS production in the aortic valve endothelium, but not in the media and adventitia of the iliac artery and aorta.", "type": "CHEMICAL", "entities": [ "apocynin" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "23384446", "text": "Our results suggest that arsenite can potentiate EDHF-type relaxations via a mechanism that is dependent on hydrogen peroxide, thus demonstrating that dismutation of the superoxide anion generated by NADPH oxidase can potentially offset loss of NO bioavailability under conditions of reduced eNOS activity.", "type": "CHEMICAL", "entities": [ "arsenite", "hydrogen peroxide", "superoxide", "NADPH", "NO" ], "offsets": [ [ 24, 32 ], [ 107, 124 ], [ 169, 179 ], [ 199, 204 ], [ 244, 246 ] ] }, { "pmid": "23384446", "text": "By contrast, selective increases in endothelial ROS production following exposure to arsenite failed to modify relaxations mediated by endogenous NO.", "type": "CHEMICAL", "entities": [ "arsenite", "NO" ], "offsets": [ [ 84, 92 ], [ 145, 147 ] ] }, { "pmid": "17570561", "text": "Anthocyanin, antioxidant activity and stress-induced gene expression in high CO2-treated table grapes stored at low temperature.\n", "type": "CHEMICAL", "entities": [ "Anthocyanin", "CO2" ], "offsets": [ [ 0, 11 ], [ 77, 80 ] ] }, { "pmid": "17570561", "text": "A pretreatment with 20kPa CO2+20 kPa O2+60 kPa N2 for 3 days proved effective in maintaining the fruit quality and controlling decay in table grapes (Vitis vinifera cv.", "type": "CHEMICAL", "entities": [ "CO2", "N2" ], "offsets": [ [ 26, 29 ], [ 47, 49 ] ] }, { "pmid": "17570561", "text": "Cardinal) stored at 0 degrees C. In the present work, we analyzed whether total anthocyanin content, the molecular mechanism implicated in their biosynthesis and antioxidant activity is related to the beneficial effect of this gaseous treatment.", "type": "CHEMICAL", "entities": [ "anthocyanin" ], "offsets": [ [ 80, 91 ] ] }, { "pmid": "17570561", "text": "We isolated partial cDNAs that codified for enzymes implicated in the anthocyanin biosynthesis such as l-phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS), and an antioxidant enzyme such as ascorbate peroxidase (APX).", "type": "CHEMICAL", "entities": [ "anthocyanin", "l-phenylalanine", "ammonia", "chalcone", "ascorbate" ], "offsets": [ [ 70, 81 ], [ 103, 118 ], [ 119, 126 ], [ 143, 151 ], [ 202, 211 ] ] }, { "pmid": "17570561", "text": "Low temperatures induced an accumulation of total anthocyanin content in the skin of both treated and non-treated grapes, although levels were lower in CO2-treated fruit.", "type": "CHEMICAL", "entities": [ "anthocyanin", "CO2" ], "offsets": [ [ 50, 61 ], [ 152, 155 ] ] }, { "pmid": "17570561", "text": "By contrast, antioxidant activity decreased during storage at 0 degrees C in non-treated grapes but did not change in CO2-treated grapes.", "type": "CHEMICAL", "entities": [ "CO2" ], "offsets": [ [ 118, 121 ] ] }, { "pmid": "17570561", "text": "The up-regulation of anthocyanin biosynthesis gene expression and VcAPX mRNA observed in non-treated grape is not enhanced in CO2-treated grapes, which presented low total decay.", "type": "CHEMICAL", "entities": [ "CO2", "anthocyanin" ], "offsets": [ [ 126, 129 ], [ 21, 32 ] ] }, { "pmid": "17570561", "text": "These results point out the ability of CO2-treated grapes to prevent the generation of reactive oxygen species rather than their inactivation by means of induction of studied defense systems.", "type": "CHEMICAL", "entities": [ "CO2", "oxygen" ], "offsets": [ [ 39, 42 ], [ 96, 102 ] ] }, { "pmid": "22580612", "text": "MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "Historically, much of the early work on MUC1 focused on the shed mucin subunit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3KAKT and mitogen-activated protein kinase kinase (MEK)extracellular signal-regulated kinase (ERK) pathways.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 88, 96 ] ] }, { "pmid": "22580612", "text": "MUC1-C also localizes to the nucleus where it activates the Wnt/β-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-κB RelA pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22580612", "text": "On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262035", "text": "Synthesis, crystal structure and antidiabetic activity of substituted (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one.\n", "type": "CHEMICAL", "entities": [ "(E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one" ], "offsets": [ [ 70, 126 ] ] }, { "pmid": "23262035", "text": "A novel series of substituted (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-onewere synthesized starting from 2-aminobenzothiazole and 1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-onesin the presence of a catalytic amount of sodium hydride in THF.", "type": "CHEMICAL", "entities": [ "2-aminobenzothiazole", "1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-ones", "sodium hydride", "THF", "(E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one" ], "offsets": [ [ 116, 136 ], [ 141, 189 ], [ 230, 244 ], [ 248, 251 ], [ 30, 85 ] ] }, { "pmid": "23262035", "text": "The synthesised compounds' structures were confirmed by IR, Mass spectrometry, (1)H NMR, (13)C NMR and HRMS spectral data.", "type": "CHEMICAL", "entities": [ "(1)H", "(13)C" ], "offsets": [ [ 79, 83 ], [ 89, 94 ] ] }, { "pmid": "23262035", "text": "These compounds were evaluated for their antidiabetic activity, and most of the derivatives of (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one displayed significant antidiabetic activity.", "type": "CHEMICAL", "entities": [ "(E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one" ], "offsets": [ [ 95, 150 ] ] }, { "pmid": "17884974", "text": "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.\n", "type": "CHEMICAL", "entities": [ "Acetaminophen", "paracetamol" ], "offsets": [ [ 0, 13 ], [ 15, 26 ] ] }, { "pmid": "17884974", "text": "For more than three decades, acetaminophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prostanoids.", "type": "CHEMICAL", "entities": [ "prostanoids", "acetaminophen", "INN", "paracetamol" ], "offsets": [ [ 132, 143 ], [ 29, 42 ], [ 44, 47 ], [ 49, 60 ] ] }, { "pmid": "17884974", "text": "Meanwhile, attempts to explain its action by inhibition of a central cyclooxygenase (COX)-3 have been rejected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17884974", "text": "The fact that acetaminophen acts functionally as a selective COX-2 inhibitor led us to investigate the hypothesis of whether it works via preferential COX-2 blockade.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 14, 27 ] ] }, { "pmid": "17884974", "text": "Ex vivo COX inhibition and pharmacokinetics of acetaminophen were assessed in 5 volunteers receiving single 1000 mg doses orally.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 47, 60 ] ] }, { "pmid": "17884974", "text": "Coagulation-induced thromboxane B(2) and lipopolysaccharide-induced prostaglandin E(2) were measured ex vivo and in vitro in human whole blood as indices of COX-1 and COX-2 activity.", "type": "CHEMICAL", "entities": [ "thromboxane B(2)", "prostaglandin E(2)" ], "offsets": [ [ 20, 36 ], [ 68, 86 ] ] }, { "pmid": "17884974", "text": "In vitro, acetaminophen elicited a 4.4-fold selectivity toward COX-2 inhibition (IC(50)=113.7 micromol/L for COX-1; IC(50)=25.8 micromol/L for COX-2).", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 10, 23 ] ] }, { "pmid": "17884974", "text": "Following oral administration of the drug, maximal ex vivo inhibitions were 56% (COX-1) and 83% (COX-2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17884974", "text": "Acetaminophen plasma concentrations remained above the in vitro IC(50) for COX-2 for at least 5 h postadministration.", "type": "CHEMICAL", "entities": [ "Acetaminophen" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "17884974", "text": "Ex vivo IC(50) values (COX-1: 105.2 micromol/L; COX-2: 26.3 micromol/L) of acetaminophen compared favorably with its in vitro IC(50) values.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 75, 88 ] ] }, { "pmid": "17884974", "text": "In contrast to previous concepts, acetaminophen inhibited COX-2 by more than 80%, i.e., to a degree comparable to nonsteroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 34, 47 ] ] }, { "pmid": "17884974", "text": "However, a >95% COX-1 blockade relevant for suppression of platelet function was not achieved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17884974", "text": "Our data may explain acetaminophen's analgesic and antiinflammatory action as well as its superior overall gastrointestinal safety profile compared with NSAIDs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17884974", "text": "In view of its substantial COX-2 inhibition, recently defined cardiovascular warnings for use of COX-2 inhibitors should also be considered for acetaminophen.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 144, 157 ] ] }, { "pmid": "17159811", "text": "Effect of galantamine on acetylcholinesterase and butyrylcholinesterase activities in the presence of L-carnitine in rat selected brain and peripheral tissues.\n", "type": "CHEMICAL", "entities": [ "L-carnitine", "galantamine" ], "offsets": [ [ 102, 113 ], [ 10, 21 ] ] }, { "pmid": "17159811", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17159811", "text": "The alkaloid galantamine (GAL), which exhibits a combined anticholinesterase and direct parasympathomimetic mechanism of action, is employed in conjunction with therapeutic interventions in the stimulation of central cholinergic transfer in cognitive diseases.", "type": "CHEMICAL", "entities": [ "galantamine", "GAL" ], "offsets": [ [ 13, 24 ], [ 26, 29 ] ] }, { "pmid": "17159811", "text": "We attempted to achieve pharmacologically-induced enhancement of the parasympathomimetic activity of GAL in the key areas of rat brain, using an interactive combination of the alkaloid with the transmembrane enhancer L-carnitine (CAR).", "type": "CHEMICAL", "entities": [ "GAL", "L-carnitine", "CAR" ], "offsets": [ [ 101, 104 ], [ 217, 228 ], [ 230, 233 ] ] }, { "pmid": "17159811", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17159811", "text": "We investigated activities of acetylcholinesterase (AChE) in brain areas (frontal cortex, basal ganglia, septum and hippocampus) and the hypophysis, and that of butyrylcholinesterase (BuChE) in plasma and liver.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17159811", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17159811", "text": "Following administration of the highest of the GAL doses used (2.5; 5; 10 mg/kg i.m.), AChE activity decreased mainly in the frontal cortex, hippocampus and hypophysis.", "type": "CHEMICAL", "entities": [ "GAL" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "17159811", "text": "In the interaction of GAL and CAR, AChE inhibition was stronger but without any statistical significance.", "type": "CHEMICAL", "entities": [ "GAL", "CAR" ], "offsets": [ [ 22, 25 ], [ 30, 33 ] ] }, { "pmid": "17159811", "text": "The peripheral inhibition of BuChE was found to be dose-dependent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17159811", "text": "Premedication by CAR led to a slight change in the values of the activities monitored.", "type": "CHEMICAL", "entities": [ "CAR" ], "offsets": [ [ 17, 20 ] ] }, { "pmid": "17159811", "text": "CONCLUSIONS: CAR in terms of positive modulation of GAL targeting to the central nervous system had no statistically significant effect.", "type": "CHEMICAL", "entities": [ "CAR", "GAL" ], "offsets": [ [ 13, 16 ], [ 52, 55 ] ] }, { "pmid": "23022324", "text": "Inhibition of neurite outgrowth and alteration of cytoskeletal gene expression by sodium arsenite.\n", "type": "CHEMICAL", "entities": [ "sodium arsenite" ], "offsets": [ [ 82, 97 ] ] }, { "pmid": "23022324", "text": "Arsenic compounds that are often found in drinking water increase the risk of developmental brain disorders.", "type": "CHEMICAL", "entities": [ "Arsenic" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23022324", "text": "In this study, we performed live imaging analyses of Neuro-2a cells expressing SCAT3, a caspase-3 cleavage peptide sequence linking two fluorescent proteins; enhanced cyan fluorescence protein (ECFP) and Venus, to determine whether sodium arsenite (NaAsO(2); 0, 1, 5, or 10 μM) affects both neurite outgrowth and/or induces apoptosis with the same doses and in the same cell cultures.", "type": "CHEMICAL", "entities": [ "sodium arsenite", "NaAsO(2)" ], "offsets": [ [ 232, 247 ], [ 249, 257 ] ] }, { "pmid": "23022324", "text": "We observed that the area ratio of neurite to cell body in SCAT3-expressing cells was significantly reduced by 5 and 10 μM NaAsO(2), but not by 1 μM, although the emission ratio of ECFP to Venus, an endpoint of caspase-3 activity, was not changed.", "type": "CHEMICAL", "entities": [ "NaAsO(2)" ], "offsets": [ [ 122, 130 ] ] }, { "pmid": "23022324", "text": "However, cytological assay using apoptotic and necrotic markers resulted in that apoptosis, but not necrosis, was significantly induced in Neuro-2a cells when NaAsO(2) exposure continued after the significant effects of NaAsO(2) on neurite outgrowth were found by live imaging.", "type": "CHEMICAL", "entities": [ "NaAsO(2)", "NaAsO(2)" ], "offsets": [ [ 156, 164 ], [ 217, 225 ] ] }, { "pmid": "23022324", "text": "These results suggested that neurite outgrowth was suppressed by NaAsO(2) prior to NaAsO(2)-induced apoptosis.", "type": "CHEMICAL", "entities": [ "NaAsO(2)", "NaAsO(2)" ], "offsets": [ [ 62, 70 ], [ 80, 88 ] ] }, { "pmid": "23022324", "text": "Next, we examined the effects of NaAsO(2) on cytoskeletal gene expression in Neuro-2a cells.", "type": "CHEMICAL", "entities": [ "NaAsO(2)" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "23022324", "text": "NaAsO(2) increased the mRNA levels of the light and medium subunits of neurofilament and decreased the mRNA levels of tau and tubulin in a dose-dependent manner; no significant effect was found in the mRNA levels of the heavy subunit of neurofilament, microtubule-associated protein 2, or actin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23022324", "text": "The changes in cytoskeletal gene expression are likely responsible for the inhibitory effects of NaAsO(2) on neurite outgrowth.", "type": "CHEMICAL", "entities": [ "NaAsO(2)" ], "offsets": [ [ 94, 102 ] ] }, { "pmid": "2855368", "text": "A naloxone-steroid hybrid azine with selective and long-acting opioid antagonism at delta receptors in vitro.\n", "type": "CHEMICAL", "entities": [ "naloxone-steroid hybrid azine" ], "offsets": [ [ 2, 31 ] ] }, { "pmid": "2855368", "text": "The interaction of naloxone estrone azine (N-EH) with various opioid receptor types was studied in vitro.", "type": "CHEMICAL", "entities": [ "naloxone estrone azine", "N-EH" ], "offsets": [ [ 19, 41 ], [ 43, 47 ] ] }, { "pmid": "2855368", "text": "Its potency as an antagonist of opioid effects was compared to that of naloxone on the electrically evoked contractions of mouse vas deferens (Mvd) and guinea pig ileum myenteric plexus longitudinal muscle (Gpi) preparations.", "type": "CHEMICAL", "entities": [ "naloxone" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "2855368", "text": "N-EH was found to be 9-fold more potent than naloxone in antagonizing the effects of D-Ala2-Leu5-enkephalin in the Mvd and 22-fold less potent in antagonizing normorphine in the Gpi.", "type": "CHEMICAL", "entities": [ "N-EH", "naloxone", "D-Ala2-Leu5-enkephalin", "normorphine" ], "offsets": [ [ 0, 4 ], [ 45, 53 ], [ 85, 107 ], [ 159, 170 ] ] }, { "pmid": "2855368", "text": "In the Mvd, the recovery half-time for N-EH was longer than 1000 min.", "type": "CHEMICAL", "entities": [ "N-EH" ], "offsets": [ [ 39, 43 ] ] }, { "pmid": "2855368", "text": "Neither compound showed agonism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2855368", "text": "The two compounds were also compared for their capacity to displace the binding of 3H-D-Ala2-Leu5-enkephalin, 3H-dihydromorphine, and 3H-ethylketocyclazocine to rat brain membranes under conditions where delta, mu, and kappa sites were labeled.", "type": "CHEMICAL", "entities": [ "3H-D-Ala2-Leu5-enkephalin", "3H-dihydromorphine", "3H-ethylketocyclazocine" ], "offsets": [ [ 83, 108 ], [ 110, 128 ], [ 134, 157 ] ] }, { "pmid": "2855368", "text": "The relative affinities were 0.70, 0.16, and 0.14 for N-EH and 0.05, 0.87, and 0.08 for naloxone, respectively.", "type": "CHEMICAL", "entities": [ "N-EH", "naloxone" ], "offsets": [ [ 54, 58 ], [ 88, 96 ] ] }, { "pmid": "2855368", "text": "Thus, compared to naloxone, which is mu selective, N-EH is a delta-selective antagonist.", "type": "CHEMICAL", "entities": [ "N-EH", "naloxone" ], "offsets": [ [ 51, 55 ], [ 18, 26 ] ] }, { "pmid": "18068977", "text": "Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin.\n", "type": "CHEMICAL", "entities": [ "atorvastatin" ], "offsets": [ [ 50, 62 ] ] }, { "pmid": "18068977", "text": "Dipeptidyl peptidase-IV (DPP-IV) is an enzyme responsible for the inactivation of the glucoregulatory incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18068977", "text": "In this report, we show that the hypolipidemic agent atorvastatin is a competitive inhibitor of porcine DPP-IV in vitro, with K(i)=57.8+/-2.3 microM.", "type": "CHEMICAL", "entities": [ "atorvastatin" ], "offsets": [ [ 53, 65 ] ] }, { "pmid": "18068977", "text": "These results may have implications in the development of novel DPP-IV inhibitors based on the use of atorvastatin as a lead compound for the treatment of type 2 diabetes.", "type": "CHEMICAL", "entities": [ "atorvastatin" ], "offsets": [ [ 102, 114 ] ] }, { "pmid": "23261590", "text": "Neoechinulin A suppresses amyloid-β oligomer-induced microglia activation and thereby protects PC-12 cells from inflammation-mediated toxicity.\n", "type": "CHEMICAL", "entities": [ "Neoechinulin A" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "23261590", "text": "A pathological hallmark of Alzheimer's disease (AD), aggregation and deposition of amyloid-β peptides, has been recognized as a potent activator of microglia-mediated neuroinflammation and neuronal dysfunction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261590", "text": "Therefore, downregulation of microglial activation has a significant therapeutic demand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23261590", "text": "In this study, focus was given to evaluate the ability of neoechinulin A, an indole alkaloid isolated from marine-derived Microsporum sp., to attenuate microglial activation by oligomeric amyloid-β 1-42 (Aβ42).", "type": "CHEMICAL", "entities": [ "neoechinulin A", "indole" ], "offsets": [ [ 56, 70 ], [ 75, 81 ] ] }, { "pmid": "23261590", "text": "Neoechinulin A treatment significantly inhibited the generation of reactive oxygen and nitrogen species in Aβ42-activated BV-2 microglia cells.", "type": "CHEMICAL", "entities": [ "oxygen", "nitrogen" ], "offsets": [ [ 72, 78 ], [ 83, 91 ] ] }, { "pmid": "23261590", "text": "In addition, we found that neoechinulin A significantly suppressed the production of neurotoxic inflammatory mediator tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in activated BV-2 cells.", "type": "CHEMICAL", "entities": [ "neoechinulin A", "prostaglandin E2", "PGE2" ], "offsets": [ [ 22, 36 ], [ 197, 213 ], [ 215, 219 ] ] }, { "pmid": "23261590", "text": "Moreover, the treatment downregulated the protein and gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β and IL-6.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 75, 87 ] ] }, { "pmid": "23261590", "text": "Further, activated microglia-mediated apoptosis of PC-12 pheochromocytoma cells was significantly repressed by neoechinulin A.", "type": "CHEMICAL", "entities": [ "neoechinulin A" ], "offsets": [ [ 100, 114 ] ] }, { "pmid": "23261590", "text": "The molecular mechanism studies suggested that neoechinulin A may block the phosphorylation of mitogen-activated protein kinase (MAPK) molecule p38, apoptosis signal-regulating kinase 1 (ASK-1) and nuclear translocation of nuclear factor-κB (NF-κB) p65 and p50 subunits.", "type": "CHEMICAL", "entities": [ "neoechinulin A" ], "offsets": [ [ 36, 50 ] ] }, { "pmid": "23261590", "text": "Regulation of these signalling pathways have most probably contributed to the anti-inflammatory activity of neoechinulin A. Collectively, these results suggest that with further studies neoechinulin A have a potential to be developed as a modulator of neuroinflammatory process in AD.", "type": "CHEMICAL", "entities": [ "neoechinulin A", "neoechinulin A" ], "offsets": [ [ 95, 109 ], [ 173, 187 ] ] }, { "pmid": "22370641", "text": "WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells.\n", "type": "CHEMICAL", "entities": [ "epirubicin" ], "offsets": [ [ 71, 81 ] ] }, { "pmid": "22370641", "text": "Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "However, the underlying molecular mechanisms are largely unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox).", "type": "CHEMICAL", "entities": [ "anthracycline", "epirubicin", "Epi", "doxorubicin", "Dox" ], "offsets": [ [ 134, 147 ], [ 166, 176 ], [ 178, 181 ], [ 187, 198 ], [ 200, 203 ] ] }, { "pmid": "22370641", "text": "Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of β-catenin to the proximal WNT6 promoter.", "type": "CHEMICAL", "entities": [ "Epi" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "22370641", "text": "Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22370641", "text": "In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy.", "type": "CHEMICAL", "entities": [ "Epi", "cisplatin", "5-fluorouracil" ], "offsets": [ [ 151, 154 ], [ 156, 165 ], [ 167, 181 ] ] }, { "pmid": "22370641", "text": "These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs.", "type": "CHEMICAL", "entities": [ "anthracycline" ], "offsets": [ [ 118, 131 ] ] }, { "pmid": "22370641", "text": "Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583884", "text": "2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced inflammatory activation is mediated by intracellular free calcium in microglial cells.\n", "type": "CHEMICAL", "entities": [ "2,3,7,8-Tetrachlorodibenzo-p-dioxin", "calcium" ], "offsets": [ [ 0, 35 ], [ 102, 109 ] ] }, { "pmid": "23583884", "text": "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues.", "type": "CHEMICAL", "entities": [ "2,3,7,8-Tetrachlorodibenzo-p-dioxin", "TCDD" ], "offsets": [ [ 0, 35 ], [ 37, 41 ] ] }, { "pmid": "23583884", "text": "However, the adverse effects of TCDD on the central nervous system (CNS) have not been entirely elucidated.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 32, 36 ] ] }, { "pmid": "23583884", "text": "In this study, using reverse transcriptase PCR (RT-PCR) and ELISA, we showed that TCDD up-regulated the expression and secretion of tumor necrosis factor-alpha (TNF-α) in a time-dependent manner in cultured HAPI microglial cells.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 82, 86 ] ] }, { "pmid": "23583884", "text": "TCDD also caused a fast (within 30min as judged by the increase in its mRNA level) activation of cytosolic phospholipase A2 (cPLA2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583884", "text": "This initial action was accompanied by up-regulation of cyclooxygenase-2 (COX-2), an important inflammation marker within 1h after TCDD treatment.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 130, 134 ] ] }, { "pmid": "23583884", "text": "These pro-inflammatory responses were inhibited by two types of Ca(2+) blockers, bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) and nifedipine, thus, indicating that the effects are triggered by initial increase in the intracellular concentration of free Ca(2+) ([Ca(2+)]i).", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)", "Ca(2+)", "bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester", "BAPTA-AM", "nifedipine" ], "offsets": [ [ 294, 300 ], [ 303, 309 ], [ 63, 69 ], [ 80, 155 ], [ 157, 165 ], [ 171, 181 ] ] }, { "pmid": "23583884", "text": "Further, TCDD exposure could induce phosphorylation- and ubiquitination-dependent degradation of IкBα, and the translocation of NF-κB p65 from the cytosol to the nucleus in this microglial cell line.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 8, 12 ] ] }, { "pmid": "23583884", "text": "Thus, the NF-κB signaling pathway can be activated after TCDD treatment.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "23583884", "text": "However, Ca(2+) blockers also obviously attenuated NF-κB activation and transnuclear transport induced by TCDD.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "TCDD" ], "offsets": [ [ 4, 10 ], [ 101, 105 ] ] }, { "pmid": "23583884", "text": "In concert with these results, we highlighted that the secretion of pro-inflammatory cytokine and NF-κB activation induced by TCDD can be mediated by elevation of [Ca(2+)]i in HAPI microglial cells.", "type": "CHEMICAL", "entities": [ "TCDD", "Ca(2+)" ], "offsets": [ [ 120, 124 ], [ 158, 164 ] ] }, { "pmid": "18093407", "text": "Introduction: The pharmacological profile of eprosartan--implications for cerebrovascular and cardiovascular risk reduction.\n", "type": "CHEMICAL", "entities": [ "eprosartan" ], "offsets": [ [ 45, 55 ] ] }, { "pmid": "18093407", "text": "Moderate elevations in blood pressure translate to significant increases in cardiovascular and cerebro vascular risk.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18093407", "text": "Beneficially, this relationship allows small decreases in blood pressure to be associated with risk reduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18093407", "text": "Both the renin-angiotensin system and the sympathetic nervous system are involved in hypertension, hence targeting these systems is likely to be of benefit in the treatment of hypertension.", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "18093407", "text": "Angiotensin II type 1 receptor blockers (ARBs) are used for controlling blood pressure and treating heart failure in a broad range of patients, including those with diabetes and the elderly.", "type": "CHEMICAL", "entities": [ "Angiotensin II" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "18093407", "text": "Not only have ARBs shown good efficacy and tolerability, they also appear to have a protective effect that goes beyond that expected from the reduction of blood pressure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18093407", "text": "The ARB eprosartan is a nonbiphenyl nontetrazole angiotensin II type 1 receptor (AT1) antagonist, which acts to decrease total peripheral resistance.", "type": "CHEMICAL", "entities": [ "eprosartan", "angiotensin II" ], "offsets": [ [ 8, 18 ], [ 49, 63 ] ] }, { "pmid": "18093407", "text": "Eprosartan acts at vascular AT1 receptors (postsynaptically) and at presynaptic AT1 receptors, where it inhibits noradrenaline release.", "type": "CHEMICAL", "entities": [ "noradrenaline", "Eprosartan" ], "offsets": [ [ 113, 126 ], [ 0, 10 ] ] }, { "pmid": "18093407", "text": "In clinical studies, eprosartan has been shown to significantly reduce cardiovascular and cerebrovascular events, whilst avoiding the persistent cough that commonly occurs with the use of angiotensin-converting enzyme inhibitors.", "type": "CHEMICAL", "entities": [ "eprosartan", "angiotensin" ], "offsets": [ [ 21, 31 ], [ 188, 199 ] ] }, { "pmid": "18093407", "text": "Eprosartan can also be differentiated from other ARBs due to its noradrenergic effects, which other ARBs used at therapeutic doses do not possess.", "type": "CHEMICAL", "entities": [ "Eprosartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18093407", "text": "Eprosartan, therefore, represents a useful therapeutic option in the management of patients with hypertension, including those with a history of stroke or with co-morbid type 2 diabetes mellitus.", "type": "CHEMICAL", "entities": [ "Eprosartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10401556", "text": "Analysis of alpha 1L-adrenoceptor pharmacology in rat small mesenteric artery.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "To illuminate the controversy on alpha 1A- or alpha 1L-adrenoceptor involvement in noradrenaline-mediated contractions of rat small mesenteric artery (SMA), we have studied the effects of subtype-selective alpha 1-adrenoceptor agonists and antagonists under different experimental conditions.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 83, 96 ] ] }, { "pmid": "10401556", "text": "2. The agonist potency order in rat SMA was: A61603 >>", "type": "CHEMICAL", "entities": [ "A61603" ], "offsets": [ [ 45, 51 ] ] }, { "pmid": "10401556", "text": "SKF89748-A > cirazoline > noradrenaline >", "type": "CHEMICAL", "entities": [ "SKF89748-A", "cirazoline", "noradrenaline" ], "offsets": [ [ 0, 10 ], [ 13, 23 ], [ 26, 39 ] ] }, { "pmid": "10401556", "text": "ST-587 > methoxamine.", "type": "CHEMICAL", "entities": [ "ST-587", "methoxamine" ], "offsets": [ [ 0, 6 ], [ 9, 20 ] ] }, { "pmid": "10401556", "text": "Prazosin antagonized all agonists with a low potency (pA2: 8.29-8.80) indicating the involvement of alpha 1L-rather than alpha 1A-adrenoceptors.", "type": "CHEMICAL", "entities": [ "Prazosin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "10401556", "text": "3. The putative alpha 1L-adrenoceptor antagonist JTH-601, but not the alpha 1B-adrenoceptor antagonist chloroethylclonidine (10 microM) antagonized noradrenaline-induced contractions of SMA.", "type": "CHEMICAL", "entities": [ "JTH-601", "chloroethylclonidine", "noradrenaline" ], "offsets": [ [ 49, 56 ], [ 103, 123 ], [ 148, 161 ] ] }, { "pmid": "10401556", "text": "The potency of the selective alpha 1D-adrenoceptor antagonist BMY 7378 against noradrenaline (pA2 = 6.16 +/- 0.13) and of the selective alpha 1A-adrenoceptor antagonist RS-17053 against noradrenaline (pKB = 8.35 +/- 0.10) and against the selective alpha 1A-adrenoceptor agonist A-61603 (pKB = 8.40 +/- 0.09) were too low to account for alpha 1D- and alpha 1A-adrenoceptor involvement.", "type": "CHEMICAL", "entities": [ "A-61603", "BMY 7378", "noradrenaline", "RS-17053", "noradrenaline" ], "offsets": [ [ 278, 285 ], [ 62, 70 ], [ 79, 92 ], [ 169, 177 ], [ 186, 199 ] ] }, { "pmid": "10401556", "text": "4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "The potency of RS-17053 (pKB/pA2's = 7.72-8.46) was not affected by lowering temperature, changing experimental protocol or inducing myogenic tone via KCl or U46619.", "type": "CHEMICAL", "entities": [ "RS-17053", "KCl", "U46619" ], "offsets": [ [ 15, 23 ], [ 151, 154 ], [ 158, 164 ] ] }, { "pmid": "10401556", "text": "5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "Selective protection of a putative alpha 1A-adrenoceptor population against the irreversible action of phenoxybenzamine also failed to increase the potency of RS-17053 (pA2 = 8.25 +/- 0.06 against A61603).", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "RS-17053" ], "offsets": [ [ 103, 119 ], [ 159, 167 ] ] }, { "pmid": "10401556", "text": "6.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "Combined concentration-ratio analysis demonstrated that tamsulosin, which does not discriminate between alpha 1A- and alpha 1L-adrenoceptors, and RS-17053 competed for binding at the same site in the SMA.", "type": "CHEMICAL", "entities": [ "tamsulosin", "RS-17053" ], "offsets": [ [ 56, 66 ], [ 146, 154 ] ] }, { "pmid": "10401556", "text": "7.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "In summary, data obtained in our experiments in rat SMA indicate that the alpha 1-adrenoceptor mediating noradrenaline-induced contraction displays a distinct alpha 1L-adrenoceptor pharmacology.", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 105, 118 ] ] }, { "pmid": "10401556", "text": "This study does not provide evidence for the hypothesis that alpha 1L-adrenoceptors represent an affinity state of the alpha 1A-adrenoceptor in functional assays.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10401556", "text": "Furthermore, there is no co-existing alpha 1A-adrenoceptor in the SMA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7768269", "text": "Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7768269", "text": "A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "7768269", "text": "It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 77, 85 ] ] }, { "pmid": "7768269", "text": "In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 156, 163 ] ] }, { "pmid": "7768269", "text": "Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine.", "type": "CHEMICAL", "entities": [ "Dimethocaine", "cocaine" ], "offsets": [ [ 0, 12 ], [ 72, 79 ] ] }, { "pmid": "7768269", "text": "Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg).", "type": "CHEMICAL", "entities": [ "dimethocaine", "cocaine", "cocaine", "dopamine", "SCH 39166", "(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine", "dopamine", "raclopride" ], "offsets": [ [ 9, 21 ], [ 38, 45 ], [ 103, 110 ], [ 153, 161 ], [ 185, 194 ], [ 196, 294 ], [ 304, 312 ], [ 336, 346 ] ] }, { "pmid": "7768269", "text": "SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection.", "type": "CHEMICAL", "entities": [ "SCH 39166", "cocaine", "dimethocaine", "cocaine", "raclopride", "cocaine" ], "offsets": [ [ 0, 9 ], [ 28, 35 ], [ 76, 88 ], [ 93, 100 ], [ 106, 116 ], [ 153, 160 ] ] }, { "pmid": "7768269", "text": "In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine.", "type": "CHEMICAL", "entities": [ "raclopride", "cocaine", "dimethocaine" ], "offsets": [ [ 42, 52 ], [ 61, 68 ], [ 114, 126 ] ] }, { "pmid": "7768269", "text": "In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects.", "type": "CHEMICAL", "entities": [ "procaine", "chloroprocaine", "cocaine" ], "offsets": [ [ 33, 41 ], [ 59, 73 ], [ 96, 103 ] ] }, { "pmid": "7768269", "text": "These results support a role for dopamine in the behavioral effects of some local anesthetics.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 33, 41 ] ] }, { "pmid": "11401111", "text": "Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction.", "type": "CHEMICAL", "entities": [ "carvedilol", "N" ], "offsets": [ [ 118, 128 ], [ 7, 8 ] ] }, { "pmid": "11401111", "text": "Australia-New Zealand Heart Failure Group.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo.", "type": "CHEMICAL", "entities": [ "N", "carvedilol", "amino", "N" ], "offsets": [ [ 110, 111 ], [ 300, 310 ], [ 49, 54 ], [ 56, 57 ] ] }, { "pmid": "11401111", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 113, 114 ] ] }, { "pmid": "11401111", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin).", "type": "CHEMICAL", "entities": [ "N", "carvedilol" ], "offsets": [ [ 7, 8 ], [ 125, 135 ] ] }, { "pmid": "11401111", "text": "The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]:", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 13, 14 ] ] }, { "pmid": "11401111", "text": "4.67", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "[2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "[1.3-4.5], respectively).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value.", "type": "CHEMICAL", "entities": [ "Carvedilol", "N" ], "offsets": [ [ 0, 10 ], [ 94, 95 ] ] }, { "pmid": "11401111", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11401111", "text": "In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 61, 62 ] ] }, { "pmid": "11401111", "text": "Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.", "type": "CHEMICAL", "entities": [ "Carvedilol", "N" ], "offsets": [ [ 0, 10 ], [ 92, 93 ] ] }, { "pmid": "23146690", "text": "Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells.\n", "type": "CHEMICAL", "entities": [ "resveratrol", "clofarabine" ], "offsets": [ [ 35, 46 ], [ 74, 85 ] ] }, { "pmid": "23146690", "text": "Dietary phytochemicals as adjuvants have been suggested to play important roles in enhancing chemotherapeutic potential owing to multitargeted chemopreventive properties and lack of substantial toxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146690", "text": "Here, we investigated the efficacy of the combined treatment of various phytochemicals with the anticancer drug clofarabine in malignant mesothelioma MSTO-211H cells and normal mesothelial MeT-5A cells.", "type": "CHEMICAL", "entities": [ "clofarabine" ], "offsets": [ [ 112, 123 ] ] }, { "pmid": "23146690", "text": "The combined treatment of resveratrol and clofarabine produced a synergistic antiproliferative effect in MSTO-211H cells, but not in MeT-5A cells.", "type": "CHEMICAL", "entities": [ "resveratrol", "clofarabine" ], "offsets": [ [ 26, 37 ], [ 42, 53 ] ] }, { "pmid": "23146690", "text": "In MSTO-211H cells, the nuclear accumulation of Sp1 and the levels of p-Akt, Sp1, c-Met, cyclin D1, and p21 were effectively decreased by the combined treatment of them.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23146690", "text": "In combination with clofarabine, the ability of resveratrol to reduce the contents of Sp1 and its target gene products was also evident in a time- and dose-dependent experiment.", "type": "CHEMICAL", "entities": [ "clofarabine", "resveratrol" ], "offsets": [ [ 20, 31 ], [ 48, 59 ] ] }, { "pmid": "23146690", "text": "The inhibition of phosphoinositide 3-kinase using Ly294002 augmented a decrease in the p21 level induced by their combination, but it showed no significant effects on expression of Sp1 and cyclin D1.", "type": "CHEMICAL", "entities": [ "phosphoinositide", "Ly294002" ], "offsets": [ [ 18, 34 ], [ 50, 58 ] ] }, { "pmid": "23146690", "text": "Taken together, the data provide evidence that the synergistic antiproliferative effect of resveratrol and clofarabine is linked to the inhibition of Akt and Sp1 activities, and suggest that this combination may have therapeutic value in treatment of malignant mesothelioma.", "type": "CHEMICAL", "entities": [ "resveratrol", "clofarabine" ], "offsets": [ [ 91, 102 ], [ 107, 118 ] ] }, { "pmid": "23122079", "text": "Phillyrin attenuates high glucose-induced lipid accumulation in human HepG2 hepatocytes through the activation of LKB1/AMP-activated protein kinase-dependent signalling.\n", "type": "CHEMICAL", "entities": [ "Phillyrin", "AMP", "glucose" ], "offsets": [ [ 0, 9 ], [ 119, 122 ], [ 26, 33 ] ] }, { "pmid": "23122079", "text": "Phillyrin, an active constituent found in many medicinal plants and certain functional foods, has anti-obesity activity in vivo.", "type": "CHEMICAL", "entities": [ "Phillyrin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23122079", "text": "The aim of our study was to provide new data on the molecular mechanism(s) underlying the role of phillyrin in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes.", "type": "CHEMICAL", "entities": [ "phillyrin", "glucose" ], "offsets": [ [ 98, 107 ], [ 134, 141 ] ] }, { "pmid": "23122079", "text": "We found that phillyrin suppressed high glucose-induced lipid accumulation in HepG2 cells.", "type": "CHEMICAL", "entities": [ "phillyrin", "glucose" ], "offsets": [ [ 14, 23 ], [ 40, 47 ] ] }, { "pmid": "23122079", "text": "Phillyrin strongly inhibited high glucose-induced fatty acid synthase (FAS) expression by modulating sterol regulatory element-binding protein-1c (SREBP-1c) activation.", "type": "CHEMICAL", "entities": [ "Phillyrin", "glucose", "fatty acid", "sterol" ], "offsets": [ [ 0, 9 ], [ 34, 41 ], [ 50, 60 ], [ 101, 107 ] ] }, { "pmid": "23122079", "text": "Moreover, use of the pharmacological AMP-activated protein kinase (AMPK) inhibitor compound C revealed that AMPK is essential for suppressing SREBP-1c expression in phillyrin-treated cells.", "type": "CHEMICAL", "entities": [ "AMP", "compound C", "phillyrin" ], "offsets": [ [ 37, 40 ], [ 83, 93 ], [ 165, 174 ] ] }, { "pmid": "23122079", "text": "Finally, we found that liver kinase B1 (LKB1) phosphorylation is required for the phillyrin-enhanced activation of AMPK in HepG2 hepatocytes.", "type": "CHEMICAL", "entities": [ "phillyrin" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "23122079", "text": "These results indicate that phillyrin prevents lipid accumulation in HepG2 cells by blocking the expression of SREBP-1c and FAS through LKB1/AMPK activation, suggesting that phillyrin is a novel AMPK activator with a role in the prevention and treatment of obesity.", "type": "CHEMICAL", "entities": [ "phillyrin", "phillyrin" ], "offsets": [ [ 174, 183 ], [ 28, 37 ] ] }, { "pmid": "15898717", "text": "Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEG-interferon-alpha2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2.\n", "type": "CHEMICAL", "entities": [ "PEG" ], "offsets": [ [ 77, 80 ] ] }, { "pmid": "15898717", "text": "Type-I Interferons exert antiviral and antiproliferative activities through the binding to a common cell surface receptor comprising two subunits, IFNAR1 and IFNAR2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "Human recombinant Interferon-alpha(2a) (IFNalpha(2a)) is a potent drug (Roferon-A) used to treat various cancers and viral diseases including Hepatitis B/C infections.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a).", "type": "CHEMICAL", "entities": [ "PEG", "lysine" ], "offsets": [ [ 12, 15 ], [ 139, 145 ] ] }, { "pmid": "15898717", "text": "Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "Our binding studies, using the surface plasmon resonance technique, show that the pegylation does not abolish the binding to the receptor, but significantly reduces the affinity mainly due to a change of the association rate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "The results are supported by modeling and simulation of the binding, using Self-Avoiding-Walk calculations for the polymer conformations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "A correlation between the structural parameters and the kinetic and thermodynamic parameters of the binding of the positional isomers could be established.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "For the Isomer-K31 and -K164, the PEG-polymer attachment point is located in proximity to the binding interface, and the isomers display affinity in the range 150-520 nM in an enthalpy-driven binding process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15898717", "text": "In contrast for the Isomer-K134, -K131, -K121, and -K70, the PEG-polymer is attached remotely from the binding interface, and the isomers exhibit a higher affinity (32-76 nM) in an entropy-driven binding process.", "type": "CHEMICAL", "entities": [ "PEG" ], "offsets": [ [ 61, 64 ] ] }, { "pmid": "15898717", "text": "This study constitutes an essential collection of knowledge on which the interaction of (40)PEG-IFNalpha(2a) and its positional isomers with its cellular receptors can be better understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositide-dependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis.", "type": "CHEMICAL", "entities": [ "phosphoinositide" ], "offsets": [ [ 118, 134 ] ] }, { "pmid": "22935616", "text": "While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473.", "type": "CHEMICAL", "entities": [ "Ser", "Ser" ], "offsets": [ [ 123, 126 ], [ 130, 133 ] ] }, { "pmid": "22935616", "text": "Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline.", "type": "CHEMICAL", "entities": [ "phospho" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "22935616", "text": "Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22935616", "text": "Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23642478", "text": "Carbonic anhydrase inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23642478", "text": "Benzenesulfonamides incorporating cyanoacrylamide moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase.\n", "type": "CHEMICAL", "entities": [ "Benzenesulfonamides", "cyanoacrylamide" ], "offsets": [ [ 0, 19 ], [ 34, 49 ] ] }, { "pmid": "23642478", "text": "A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA.", "type": "CHEMICAL", "entities": [ "benzenesulfonamides", "cyanoacrylamide", "tyrphostine" ], "offsets": [ [ 11, 30 ], [ 45, 60 ], [ 71, 82 ] ] }, { "pmid": "23642478", "text": "Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91-69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46-13.52 for inhibiting ScCA over hCA II.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23642478", "text": "The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged.", "type": "CHEMICAL", "entities": [ "azole" ], "offsets": [ [ 157, 162 ] ] }, { "pmid": "23642478", "text": "Indeed, some of these sulfonamides inhibited the growth of the yeast with CC50-s in the range of 0.73-6.54μM.", "type": "CHEMICAL", "entities": [ "sulfonamides" ], "offsets": [ [ 20, 32 ] ] }, { "pmid": "23063590", "text": "Artemisinic acid inhibits melanogenesis through downregulation of C/EBP α-dependent expression of HMG-CoA reductase gene.\n", "type": "CHEMICAL", "entities": [ "Artemisinic acid", "HMG-CoA" ], "offsets": [ [ 0, 16 ], [ 98, 105 ] ] }, { "pmid": "23063590", "text": "Cholesterol is associated with the regulation of melanogenesis which is the major physiological defense against solar irradiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23063590", "text": "The present study was designed to determine the effects of artemisinic acid on melanogenesis and its mechanisms of action in human epidermal melanocytes.", "type": "CHEMICAL", "entities": [ "artemisinic acid" ], "offsets": [ [ 58, 74 ] ] }, { "pmid": "23063590", "text": "In this study, we found that artemisinic acid inhibited melanin content.", "type": "CHEMICAL", "entities": [ "artemisinic acid" ], "offsets": [ [ 28, 44 ] ] }, { "pmid": "23063590", "text": "The mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were reduced by artemisinic acid treatment.", "type": "CHEMICAL", "entities": [ "artemisinic acid" ], "offsets": [ [ 171, 187 ] ] }, { "pmid": "23063590", "text": "Additionally, the mRNA levels of melanogenesis-related genes (c-KIT, stem cell factor (SCF), and macrophage migration inhibitory factor (MIF)) were down-regulated by artemisinic acid.", "type": "CHEMICAL", "entities": [ "artemisinic acid" ], "offsets": [ [ 165, 181 ] ] }, { "pmid": "23063590", "text": "Furthermore, cAMP production and protein kinase A (PKA) activity were suppressed by artemisinic acid.", "type": "CHEMICAL", "entities": [ "cAMP", "artemisinic acid" ], "offsets": [ [ 12, 16 ], [ 83, 99 ] ] }, { "pmid": "23063590", "text": "Moreover, attempts to elucidate a possible mechanism underlying the artemisinic acid-mediated effects revealed that artemisinic acid regulated melanogenesis by inhibiting cholesterol synthesis through downregulation of the hydroxymethylglutaryl CoA (HMG CoA) reductase gene, which was mediated through reduced expression of the CCAAT/enhancer-binding protein (C/EBP) α gene.", "type": "CHEMICAL", "entities": [ "cholesterol", "hydroxymethylglutaryl CoA", "HMG CoA", "artemisinic acid", "artemisinic acid" ], "offsets": [ [ 170, 181 ], [ 222, 247 ], [ 249, 256 ], [ 67, 83 ], [ 115, 131 ] ] }, { "pmid": "23063590", "text": "Taken together, these findings indicate that the inhibition of melanogenesis by artemisinic acid occurs through reduced expression of the HMG CoA reductase gene, which is mediated by C/EBP α inhibition and suggest that artemisinic acid may be useful as a hyperpigmentation inhibitor.", "type": "CHEMICAL", "entities": [ "artemisinic acid", "HMG CoA", "artemisinic acid" ], "offsets": [ [ 78, 94 ], [ 136, 143 ], [ 217, 233 ] ] }, { "pmid": "7711211", "text": "Norethisterone metabolites modulate the uteroglobin and progesterone receptor gene expression in prepubertal rabbits.\n", "type": "CHEMICAL", "entities": [ "Norethisterone", "progesterone" ], "offsets": [ [ 0, 14 ], [ 56, 68 ] ] }, { "pmid": "7711211", "text": "Norethisterone (NET) is a synthetic progestin, used as a contraceptive agent, that is biotransformed at target tissues into 5 alpha-NET and 3 beta,5 alpha-NET, which possess different pharmacological properties.", "type": "CHEMICAL", "entities": [ "Norethisterone", "5 alpha-NET", "3 beta,5 alpha-NET", "NET", "progestin" ], "offsets": [ [ 0, 14 ], [ 124, 135 ], [ 140, 158 ], [ 16, 19 ], [ 36, 45 ] ] }, { "pmid": "7711211", "text": "The effects of these metabolites on the expression of uteroglobin (UG) and progesterone receptor (PR) genes, both regulated by progesterone (P4), were evaluated in the uterus of prepubertal female rabbits that were simultaneously treated with P4 (1.0 mg) for 5 consecutive days.", "type": "CHEMICAL", "entities": [ "progesterone", "progesterone (P4)" ], "offsets": [ [ 75, 87 ], [ 127, 144 ] ] }, { "pmid": "7711211", "text": "As determined by Western and Northern blot analyses, 5 alpha-NET inhibited the P4-induced UG gene expression in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "5 alpha-NET" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "7711211", "text": "A similar inhibition was observed with the administration of RU-486.", "type": "CHEMICAL", "entities": [ "RU-486" ], "offsets": [ [ 61, 67 ] ] }, { "pmid": "7711211", "text": "The estrogenic agent 3 beta,5 alpha-NET and estradiol at a dose of 1.0 mg also inhibited the UG gene expression induced by P4.", "type": "CHEMICAL", "entities": [ "3 beta,5 alpha-NET", "estradiol" ], "offsets": [ [ 21, 39 ], [ 44, 53 ] ] }, { "pmid": "7711211", "text": "Both 5 alpha-NET and 3 beta,5 alpha-NET blocked the PR down-regulation induced by P4 as assessed by Western and Northern blot methods.", "type": "CHEMICAL", "entities": [ "5 alpha-NET", "3 beta,5 alpha-NET" ], "offsets": [ [ 5, 16 ], [ 21, 39 ] ] }, { "pmid": "7711211", "text": "The inhibition of UG synthesis and PR down-regulation by 5 alpha-NET and 3 beta,5 alpha-NET indicates that these NET metabolites possess antiprogestational properties.", "type": "CHEMICAL", "entities": [ "5 alpha-NET", "3 beta,5 alpha-NET", "NET" ], "offsets": [ [ 57, 68 ], [ 73, 91 ], [ 113, 116 ] ] }, { "pmid": "23552851", "text": "Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines.\n", "type": "CHEMICAL", "entities": [ "Dioscin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23552851", "text": "Our previous study has revealed that dioscin, a compound with anti-inflammatory, lipid-lowering, anticancer and hepatoprotective effects, may induce autophagy in hepatoma cells.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "23552851", "text": "Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552851", "text": "In this study, the role of autophagy and related signaling pathways during dioscin-induced apoptosis in human lung cancer cells was investigated.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "23552851", "text": "Results from 4'-6-diamidino-2-phenylindole and annexin-V/PI double-staining assay showed that caspase-3- and caspase-8-dependent, and dose-dependent apoptoses were detected after a 24-h dioscin treatment.", "type": "CHEMICAL", "entities": [ "4'-6-diamidino-2-phenylindole", "dioscin" ], "offsets": [ [ 13, 42 ], [ 186, 193 ] ] }, { "pmid": "23552851", "text": "Meanwhile, autophagy was detected as early as 12 h after an exposure to low-dose dioscin, as indicated by an up-regulated expression of LC3-II and beclin-1 proteins.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "23552851", "text": "Blockade of autophagy with bafilomycin A1 or 3-methyladenine sensitized the A549 and H1299 cells to apoptosis.", "type": "CHEMICAL", "entities": [ "bafilomycin A1", "3-methyladenine" ], "offsets": [ [ 26, 40 ], [ 44, 59 ] ] }, { "pmid": "23552851", "text": "Treatment of A549 and H1299 cells with dioscin caused a dose-dependent increase in ERK1/2 and JNK1/2 activity, accompanied with a decreased PI3K expression and decreased phosphorylation of Akt and mTOR.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 38, 45 ] ] }, { "pmid": "23552851", "text": "Taken together, this study demonstrated for the first time that autophagy occurred earlier than apoptosis during dioscin-induced human lung cancer cell line apoptosis.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 112, 119 ] ] }, { "pmid": "23552851", "text": "Dioscin-induced autophagy via ERK1/2 and JNK1/2 pathways may provide a protective mechanism for cell survival against dioscin-induced apoptosis to act as a cytoprotective reaction.", "type": "CHEMICAL", "entities": [ "dioscin" ], "offsets": [ [ 117, 124 ] ] }, { "pmid": "23550028", "text": "2-Hydroxy-3-methylanthraquinone from Hedyotis diffusa Willd induces apoptosis in human leukemic U937 cells through modulation of MAPK pathways.\n", "type": "CHEMICAL", "entities": [ "2-Hydroxy-3-methylanthraquinone" ], "offsets": [ [ 0, 31 ] ] }, { "pmid": "23550028", "text": "The herb of Hedyotis diffusa Willd (H. diffusa Willd), an annual herb distributed in northeastern Asia, has been known as a traditional oriental medicine for the treatment of cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550028", "text": "Recently, Chinese researchers have discovered that two anthraquinones isolated from a water extract of H. diffusa Willd showed apoptosis-inducing effects against cancer cells.", "type": "CHEMICAL", "entities": [ "anthraquinones" ], "offsets": [ [ 55, 69 ] ] }, { "pmid": "23550028", "text": "However, the cellular and molecular mechanisms responsible for this phenomenon are poorly understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23550028", "text": "The current study determines the role of mitogen-activated protein kinases (MAPK) in human leukemic U937 cells apoptosis induced by 2-hydroxy-3-methylanthraquinone from H. diffusa.", "type": "CHEMICAL", "entities": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 132, 163 ] ] }, { "pmid": "23550028", "text": "Our results showed that 2-hydroxy-3-methylanthraquinone decreased phosphorylation-ERK1/2 (p-ERK1/2), and increased p-p38MAPK, but did not affect expressions of p-JNK1/2 in U937 cells.", "type": "CHEMICAL", "entities": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 24, 55 ] ] }, { "pmid": "23550028", "text": "Moreover, treatment of U937 cells with 2-hydroxy-3-methylanthraquinone resulted in activation of caspase-3.", "type": "CHEMICAL", "entities": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 39, 70 ] ] }, { "pmid": "23550028", "text": "Furthermore, PD98059 (ERK1/2 inhibitor) significantly enhanced 2-hydroxy-3-methylanthraquinone-induced apoptosis in U937 cells, whereas caspase-3 inhibitor or SB203580 (p-p38MAPK inhibitor), decreased apoptosis in U937 cells.", "type": "CHEMICAL", "entities": [ "SB203580", "PD98059", "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 159, 167 ], [ 13, 20 ], [ 63, 94 ] ] }, { "pmid": "23550028", "text": "Taken together, our study for the first time suggests that 2-hydroxy-3-methylanthraquinone is able to enhance apoptosis of U937 cells, at least in part, through activation of p-p38MAPK and downregulation of p-ERK1/2.", "type": "CHEMICAL", "entities": [ "2-hydroxy-3-methylanthraquinone" ], "offsets": [ [ 59, 90 ] ] }, { "pmid": "23550028", "text": "Moreover, the triggering of caspase-3 activation mediated apoptotic induction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20541672", "text": "Hormonal therapy of prostate cancer.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20541672", "text": "Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 161, 169 ] ] }, { "pmid": "20541672", "text": "A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues.", "type": "CHEMICAL", "entities": [ "testosterone", "testosterone" ], "offsets": [ [ 44, 56 ], [ 99, 111 ] ] }, { "pmid": "20541672", "text": "Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood.", "type": "CHEMICAL", "entities": [ "testosterone", "dehydroepiandrosterone", "DHEA" ], "offsets": [ [ 65, 77 ], [ 91, 113 ], [ 115, 119 ] ] }, { "pmid": "20541672", "text": "Consequently, after castration, the 95-97% fall in serum testosterone does not reflect the 40-50% testosterone (testo) and dihydrotestosterone (DHT) made locally in the prostate from DHEA of adrenal origin.", "type": "CHEMICAL", "entities": [ "testosterone", "testosterone", "testo", "dihydrotestosterone", "DHT", "DHEA" ], "offsets": [ [ 57, 69 ], [ 98, 110 ], [ 112, 117 ], [ 123, 142 ], [ 144, 147 ], [ 183, 187 ] ] }, { "pmid": "20541672", "text": "In fact, while elimination of testicular androgens by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure anti-androgen has been the first treatment shown to prolong life.", "type": "CHEMICAL", "entities": [ "gonadotropin-releasing hormone", "GnRH", "androgen", "androgens" ], "offsets": [ [ 193, 223 ], [ 225, 229 ], [ 257, 265 ], [ 41, 50 ] ] }, { "pmid": "20541672", "text": "Most importantly, when applied at the localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of the disease in more than 90% of cases.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 73, 81 ] ] }, { "pmid": "20541672", "text": "Obviously, since prostate cancer usually grows and metastasizes without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to diagnose prostate cancer at an 'early' stage before metastasis occurs and the cancer becomes non-curable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20541672", "text": "While the role of androgens was believed to have become non-significant in cancer progressing under any form of androgen blockade, recent data have shown increased expression of the androgen receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade.", "type": "CHEMICAL", "entities": [ "androgens", "androgen", "androgen", "androgen" ], "offsets": [ [ 18, 27 ], [ 112, 120 ], [ 182, 190 ], [ 262, 270 ] ] }, { "pmid": "20541672", "text": "Since the available anti-androgens have low affinity for AR and cannot block androgen action completely, especially in the presence of increased AR levels, it becomes important to discover more potent and purely antagonistic blockers of AR.", "type": "CHEMICAL", "entities": [ "androgens", "androgen" ], "offsets": [ [ 25, 34 ], [ 77, 85 ] ] }, { "pmid": "20541672", "text": "The data obtained with compounds under development are promising.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20541672", "text": "While waiting for this (these) new anti-androgen(s), combined treatment with castration and a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease with the optimal chance of success and even cure in localized disease.", "type": "CHEMICAL", "entities": [ "androgen(s)", "androgen", "bicalutamide", "flutamide", "nilutamide" ], "offsets": [ [ 40, 51 ], [ 104, 112 ], [ 114, 126 ], [ 128, 137 ], [ 141, 151 ] ] }, { "pmid": "16281286", "text": "Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM).", "type": "CHEMICAL", "entities": [ "Cobalamin", "methylmalonyl CoA" ], "offsets": [ [ 0, 9 ], [ 169, 186 ] ] }, { "pmid": "16281286", "text": "To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Sequence analysis identified mutations in 96% of disease alleles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "A total of 116 different mutations, 68 of which were novel, were identified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Sixty-one of the mutations have only been identified in one family.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Two mutations were seen only in Asian patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16281286", "text": "Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "Resistant variants of the human leukaemic line K562 were developed using selection with the deoxynucleoside analogues cytosine arabinoside, 2-chlorodeoxyadenosine, fludarabine and gemcitabine.", "type": "CHEMICAL", "entities": [ "cytosine arabinoside", "2-chlorodeoxyadenosine", "fludarabine", "gemcitabine" ], "offsets": [ [ 118, 138 ], [ 140, 162 ], [ 164, 175 ], [ 180, 191 ] ] }, { "pmid": "10444166", "text": "The resistant lines displayed a high degree of cross resistance to all deoxynucleoside analogues, with little or no cross resistance to other agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "There was a profound accumulation defect of all nucleoside analogues in the resistant variants but no significant defect in nucleoside transport in any of the variants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "5' nucleotidase activity was strongly increased and deoxycytidine kinase activity was moderately reduced in all of the resistant variants, resulting in reduced accumulation of triphosphate analogues.", "type": "CHEMICAL", "entities": [ "deoxycytidine", "triphosphate" ], "offsets": [ [ 52, 65 ], [ 176, 188 ] ] }, { "pmid": "10444166", "text": "In addition a deletion in one of the alleles of the deoxycytidine kinase was detected in the fludarabine-resistant line.", "type": "CHEMICAL", "entities": [ "deoxycytidine", "fludarabine" ], "offsets": [ [ 52, 65 ], [ 93, 104 ] ] }, { "pmid": "10444166", "text": "Ribonucleotide reductase activity was found to be strongly increased in the gemcitabine-selected line and purine nucleoside phosphorylase was increased in the 2-chlorodeoxyadenosine-selected line.", "type": "CHEMICAL", "entities": [ "gemcitabine", "2-chlorodeoxyadenosine" ], "offsets": [ [ 76, 87 ], [ 159, 181 ] ] }, { "pmid": "10444166", "text": "Free nucleotide pools were increased in the 2-chlorodeoxyadenosine-selected line.", "type": "CHEMICAL", "entities": [ "nucleotide", "2-chlorodeoxyadenosine" ], "offsets": [ [ 5, 15 ], [ 44, 66 ] ] }, { "pmid": "10444166", "text": "There was no expression of the mdr1 gene by the resistant lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "Karyotypic analysis and FISH experiments using a 6q21 specific probe showed alterations in the 6(q16-q22) region which contains the 5'-nucleotidase gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10444166", "text": "Early events in the activation and degradation of deoxynucleoside analogues appear to constitute common mechanisms of resistance to these compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23466232", "text": "A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors.\n", "type": "CHEMICAL", "entities": [ "N2-substituted-5-(p-toluenesulfonylamino)phthalimide" ], "offsets": [ [ 16, 68 ] ] }, { "pmid": "23466232", "text": "Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated.", "type": "CHEMICAL", "entities": [ "sugar", "5-(p-toluenesulfonylamino)phthalimide" ], "offsets": [ [ 38, 43 ], [ 85, 122 ] ] }, { "pmid": "23466232", "text": "The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23466232", "text": "Almost all the compounds had strong inhibitory activities against yeast α-glycosidase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23466232", "text": "Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23466232", "text": "Structure-activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities.", "type": "CHEMICAL", "entities": [ "5-(p-toluenesulfonylamino)phthalimide" ], "offsets": [ [ 48, 85 ] ] }, { "pmid": "22865292", "text": "The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "Vacuolar H(+) -ATPase", "type": "CHEMICAL", "entities": [ "H(+)" ], "offsets": [ [ 9, 13 ] ] }, { "pmid": "22865292", "text": "(V-ATPase), a multisubunit enzyme located at the ruffled border and in lysosomes of osteoclasts, is necessary for bone resorption.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "We previously showed that heterozygous mice with an R740S mutation in the a3 subunit of V-ATPase (+/R740S) have mild osteopetrosis resulting from an ∼90% reduction in proton translocation across osteoclast membranes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "Here we show that lysosomal pH is also higher in +/R740S compared with wild-type (+/+) osteoclasts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "Both osteoclast number and size were decreased in cultures of +/R740S compared with +/+ bone marrow cells, with concomitant decreased expression of key osteoclast markers (TRAP, cathepsin K, OSCAR, DC-STAMP, and NFATc1), suggesting that low lysosomal pH plays an important role in osteoclastogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "To elucidate the molecular mechanism of this inhibition, NFATc1 activation was assessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "NFATc1 nuclear translocation was significantly reduced in +/R740S compared with +/+ cells; however, this was not because of impaired enzymatic activity of calcineurin, the phosphatase responsible for NFATc1 dephosphorylation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "Protein and RNA expression levels of regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of NFATc1 activation and a protein degraded in lysosomes, were not significantly different between +/R740S and +/+ osteoclasts, but the RCAN1/NFATc1 ratio was significantly higher in +/R740S versus +/+ cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22865292", "text": "The lysosomal inhibitor chloroquine significantly increased RCAN1 accumulation in +/+ cells, consistent with the hypothesis that higher lysosomal pH impairs RCAN1 degradation, leading to a higher RCAN1/NFATc1 ratio and consequently NFATc1 inhibition.", "type": "CHEMICAL", "entities": [ "chloroquine" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "22865292", "text": "Our data indicate that increased lysosomal pH in osteoclasts leads to decreased NFATc1 signaling and nuclear translocation, resulting in a cell autonomous impairment of osteoclastogenesis in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23539296", "text": "p38 Mitogen Activated Protein Kinase Regulates the Nuclear Receptor CAR to Activate the CYP2B6 Gene.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23539296", "text": "The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes such as cytochrome P450 (CYP) and certain transferases.", "type": "CHEMICAL", "entities": [ "androstane" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "23539296", "text": "p38 mitogen activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell-lines including HepG2 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23539296", "text": "Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23539296", "text": "Here, we have now found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes.", "type": "CHEMICAL", "entities": [ "anisomycin" ], "offsets": [ [ 55, 65 ] ] }, { "pmid": "23539296", "text": "siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA.", "type": "CHEMICAL", "entities": [ "anisomycin" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "23539296", "text": "In addition to CYP2B6, anisomycin co-treatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs.", "type": "CHEMICAL", "entities": [ "anisomycin", "UDP" ], "offsets": [ [ 23, 33 ], [ 116, 119 ] ] }, { "pmid": "23539296", "text": "Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug metabolizing enzymes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23539296", "text": "Our present results suggest that CAR-mediated induction of these enzymes can not be understood by ligand binding alone because the specificity and magnitude of induction are co-determined by a given cell signaling such as p38 MAPK; both physiological and pathophysiological states of cell signaling may have a strong impact in hepatic drug metabolizing capability during therapeutic treatments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Parnaparin, a low-molecular-weight heparin (LMWH), prevents platelet activation and interaction with polymorphonuclear leukocyte (PMN) in a washed cell system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "The in-vitro effect of parnaparin was studied here on platelet-PMN aggregates formed with more physiologic approaches in whole blood, in parallel with unfractionated heparin and enoxaparin, another LMWH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Citrated blood from healthy subjects was stimulated: i) from passage through the \"Platelet Function Analyzer\" (PFA-100), a device that exposes blood to standardized high shear flow through collagen/ADP cartridges; ii) by collagen and ADP (2 and 50 mug/ml, respectively) added in combination under stirring in an aggregometer cuvette; iii) with recombinant Tissue Factor, to generate thrombin concentrations able to activate platelets without inducing blood clotting, or iv) the Thrombin Receptor Activating Peptide-6 (TRAP-6).", "type": "CHEMICAL", "entities": [ "ADP", "ADP" ], "offsets": [ [ 198, 201 ], [ 234, 237 ] ] }, { "pmid": "17549299", "text": "Platelet P-selectin and platelet-PMN aggregates were measured by flow cytometry upon stimulation of blood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Fibrinogen binding to platelets and markers of PMN activation were also detected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Platelet P-selectin expression and platelet-PMN aggregate formation were induced in all four activation conditions tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Parnaparin prevented in a concentration-dependent manner (0.3-0.8 IUaXa/ml) the expression of P-selectin and the formation of mixed aggregates, while the two reference heparin preparations had a much weaker effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "Platelet fibrinogen binding and PMN activation markers (fibrinogen binding, CD11b and CD40) were also prevented by parnaparin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "These data extend in more physiological systems of platelet activation, the anti-inflammatory profile of parnaparin, previously reported in washed cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17549299", "text": "The greater effect of parnaparin, as compared to the reference heparins, could be due to chemico-physical differences possibly unrelated to their anticoagulant effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23505146", "text": "Diverse effects of macromolecular crowding on the sequential glycan-processing pathway involved in glycoprotein quality control.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23505146", "text": "Compared with in vitro conditions, the intracellular environment is highly crowded with biomolecules; this has numerous effects on protein functions, including enzymatic activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23505146", "text": "We examined the effects of macromolecular crowding on glycan processing of N-glycoprotein in the endoplasmic reticulum as a model sequential metabolic pathway.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 75, 76 ] ] }, { "pmid": "23505146", "text": "Experiments with synthetic substrates of physiological glycan structure clearly showed that the first half of the pathway (glucose trimming) was accelerated, whereas the second (mannose trimming) was decelerated under molecular crowding conditions.", "type": "CHEMICAL", "entities": [ "glucose", "mannose" ], "offsets": [ [ 123, 130 ], [ 178, 185 ] ] }, { "pmid": "23505146", "text": "Furthermore, calreticulin, a lectin-like molecular chaperone, bound more strongly to a glycan-processing intermediate under these conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23505146", "text": "This study demonstrates the diverse effects of molecular crowding on sequential enzymatic processing, and the importance of the effects of macromolecular crowding on in vitro assays for understanding sequential metabolic pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631374", "text": "X-ray structure analysis of a solid solution of milbemycins A3 and A4.\n", "type": "CHEMICAL", "entities": [ "milbemycins A3 and A4" ], "offsets": [ [ 48, 69 ] ] }, { "pmid": "23631374", "text": "Milbemycins A3 and A4 are pharmaceutically and agriculturally useful macrolides isolated from Streptomyces species.", "type": "CHEMICAL", "entities": [ "Milbemycins A3 and A4" ], "offsets": [ [ 0, 21 ] ] }, { "pmid": "23631374", "text": "The molecular structures of the title compounds were unambiguously established by a single crystal X-ray analysis of the solid solution of both compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631374", "text": "The crystals present trigonal system, space group P32 with Z = 3, unit cell dimensions:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631374", "text": "a = 12.2211(4), c = 17.5372(7) Å; V = 2268.4(1) Å(3), μ = 0.082 mm(- 1);", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631374", "text": "d = 1.183 g cm(- 3).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23631374", "text": "An interesting system of intramolecular hydrogen bonds and weak intermolecular CH…O type hydrogen bond was observed in the solid state.", "type": "CHEMICAL", "entities": [ "hydrogen", "CH", "O", "hydrogen" ], "offsets": [ [ 18, 26 ], [ 57, 59 ], [ 60, 61 ], [ 67, 75 ] ] }, { "pmid": "23609606", "text": "In vitro exploration of potential mechanisms of toxicity of the human hepatotoxic drug fenclozic acid.\n", "type": "CHEMICAL", "entities": [ "fenclozic acid" ], "offsets": [ [ 87, 101 ] ] }, { "pmid": "23609606", "text": "The carboxylic acid NSAID fenclozic acid exhibited an excellent preclinical safety profile and promising clinical efficacy, yet was withdrawn from clinical development in 1971 due to hepatotoxicity observed in clinical trials.", "type": "CHEMICAL", "entities": [ "fenclozic acid", "carboxylic acid" ], "offsets": [ [ 26, 40 ], [ 4, 19 ] ] }, { "pmid": "23609606", "text": "A variety of modern in vitro approaches have been used to explore potential underlying mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609606", "text": "Covalent binding studies were undertaken with [(14)C]-fenclozic acid to investigate the possible role of reactive metabolites.", "type": "CHEMICAL", "entities": [ "[(14)C]-fenclozic acid" ], "offsets": [ [ 46, 68 ] ] }, { "pmid": "23609606", "text": "Time-dependent covalent binding to protein was observed in NADPH-supplemented liver microsomes, although no metabolites were detected in these incubations or in reactive metabolite trapping experiments.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 59, 64 ] ] }, { "pmid": "23609606", "text": "In human hepatocytes, covalent binding was observed at lower levels than in microsomes and a minor uncharacterizable metabolite was also observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609606", "text": "In addition, covalent binding was observed in incubations undertaken with dog and rat hepatocytes, where a taurine conjugate of the drug was detected.", "type": "CHEMICAL", "entities": [ "taurine" ], "offsets": [ [ 107, 114 ] ] }, { "pmid": "23609606", "text": "Although an acyl glucuronide metabolite was detected when liver microsomes from human, rat and dog were supplemented with UDPGA, there was no detectable UDPGA-dependent covalent binding.", "type": "CHEMICAL", "entities": [ "UDPGA", "UDPGA", "acyl glucuronide" ], "offsets": [ [ 122, 127 ], [ 153, 158 ], [ 12, 28 ] ] }, { "pmid": "23609606", "text": "No effects were observed when fenclozic acid was assessed for P450-dependent and P450-independent cytotoxicity to THLE cell lines, time-dependent inhibition of five major human cytochrome P450 enzymes, inhibition of the biliary efflux transporters BSEP and MRP2 or mitochondrial toxicity to THLE or HepG2 cells.", "type": "CHEMICAL", "entities": [ "fenclozic acid" ], "offsets": [ [ 30, 44 ] ] }, { "pmid": "23609606", "text": "These data suggest that Phase 1 bioactivation plays a role in the hepatotoxicity of fenclozic acid and highlight the unique insight into mechanisms of human drug toxicity that can be provided by investigations of biotransformation and covalent binding to proteins.", "type": "CHEMICAL", "entities": [ "fenclozic acid" ], "offsets": [ [ 84, 98 ] ] }, { "pmid": "14529460", "text": "Mechanism of organophosphates (nerve gases and pesticides) and antidotes: electron transfer and oxidative stress.\n", "type": "CHEMICAL", "entities": [ "organophosphates" ], "offsets": [ [ 13, 29 ] ] }, { "pmid": "14529460", "text": "Evidence indicates that nerve gas toxins operate in ways in addition to inhibition of acetylcholine esterase.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "14529460", "text": "Alternative bioactivities are discussed with focus on electron transfer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14529460", "text": "The main class, including pralidoxime (2-PAM), incorporates conjugated iminium and oxime moieties that are electron affinic.", "type": "CHEMICAL", "entities": [ "pralidoxime", "2-PAM", "iminium", "oxime" ], "offsets": [ [ 26, 37 ], [ 39, 44 ], [ 71, 78 ], [ 83, 88 ] ] }, { "pmid": "14529460", "text": "Various physiological properties of iminium and oxime species are reviewed.", "type": "CHEMICAL", "entities": [ "iminium", "oxime" ], "offsets": [ [ 36, 43 ], [ 48, 53 ] ] }, { "pmid": "14529460", "text": "The organophosphates encompass both nerve gases and insecticides, possessing similar properties, but different activities.", "type": "CHEMICAL", "entities": [ "organophosphates" ], "offsets": [ [ 4, 20 ] ] }, { "pmid": "14529460", "text": "Toxic manifestations are apparently due, in part, to oxidative stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14529460", "text": "Alkylation of DNA takes place which may lead to generation of reactive oxygen species.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 71, 77 ] ] }, { "pmid": "14529460", "text": "Structure-activity relationships are examined, including reduction potentials and the captodative effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034761", "text": "Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4.\nToll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses.", "type": "CHEMICAL", "entities": [ "Auranofin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17034761", "text": "TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034761", "text": "Auranofin, an Au(I) compound, is a well-known and long-used anti-rheumatic drug.", "type": "CHEMICAL", "entities": [ "Auranofin", "Au(I)" ], "offsets": [ [ 0, 9 ], [ 14, 19 ] ] }, { "pmid": "17034761", "text": "However, the mechanism as to how auranofin relieves the symptom of rheumatoid arthritis has not been fully clarified.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 33, 42 ] ] }, { "pmid": "17034761", "text": "Our results demonstrated that auranofin suppressed TLR4-mediated activation of transcription factors, NF-kappaB and IRF3, and expression of COX-2, a pro-inflammatory enzyme.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "17034761", "text": "This suppression was well correlated with the inhibitory effect of auranofin on the homodimerization of TLR4 induced by an agonist.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "17034761", "text": "Furthermore, auranofin inhibited NF-kappaB activation induced by MyD88-dependent downstream signaling components of TLR4, MyD88, IKKbeta, and p65.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "17034761", "text": "IRF3 activation induced by MyD88-independent signaling components, TRIF and TBK1, was also downregulated by auranofin.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 108, 117 ] ] }, { "pmid": "17034761", "text": "Our results first demonstrate that auranofin suppresses the multiple steps in TLR4 signaling, especially the homodimerization of TLR4.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 35, 44 ] ] }, { "pmid": "17034761", "text": "The results suggest that the suppression of TLR4 activity by auranofin may be the molecular mechanism through which auranofin exerts anti-rheumatic activity.", "type": "CHEMICAL", "entities": [ "auranofin", "auranofin" ], "offsets": [ [ 61, 70 ], [ 116, 125 ] ] }, { "pmid": "9094999", "text": "Differential binding of fibroblast growth factor-2 and -7 to basement membrane heparan sulfate: comparison of normal and abnormal human tissues.\n", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 87, 94 ] ] }, { "pmid": "9094999", "text": "Fibroblast growth factors (FGFs) play multiple roles during development and in adult tissues as paracrine regulators of growth and differentiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9094999", "text": "FGFs signal through transmembrane receptor tyrosine kinases, but heparan sulfate is also required for signaling by members of the FGF family.", "type": "CHEMICAL", "entities": [ "tyrosine", "sulfate" ], "offsets": [ [ 43, 51 ], [ 73, 80 ] ] }, { "pmid": "9094999", "text": "In addition, heparan sulfate may be involved in determining tissue distribution of FGFs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9094999", "text": "Using biotinylated FGF-2 and FGF-7 (KGF) as probes, we have identified specific interactions between FGFs and heparan sulfates in human tissues.", "type": "CHEMICAL", "entities": [ "sulfates" ], "offsets": [ [ 118, 126 ] ] }, { "pmid": "9094999", "text": "Both FGF species bind to tissue mast cells and to epithelial cell membranes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9094999", "text": "Binding to basement membrane heparan sulfate is tissue source dependent and specific.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "9094999", "text": "Although FGF-2 strongly binds to basement membrane heparan sulfate in skin and most other tissue sites examined, FGF-7 fails to bind to basement membrane heparan sulfate in most locations.", "type": "CHEMICAL", "entities": [ "sulfate", "sulfate" ], "offsets": [ [ 59, 66 ], [ 162, 169 ] ] }, { "pmid": "9094999", "text": "However, in subendothelial matrix in blood vessels and in the basement membrane of a papillary renal cell carcinoma, strong FGF-7 binding is seen.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9094999", "text": "In summary, distinct and specific affinities of heparan sulfates for different FGFs were identified that may affect growth factor activation and local distribution.", "type": "CHEMICAL", "entities": [ "sulfates" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "9094999", "text": "Heparan sulfate may have a gatekeeper function to either restrict or permit diffusion of heparin-binding growth factors across the basement membrane.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 8, 15 ] ] }, { "pmid": "23584948", "text": "Vandetanib: opening a new treatment practice in advanced medullary thyroid carcinoma.\n", "type": "CHEMICAL", "entities": [ "Vandetanib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23584948", "text": "Medullary thyroid cancer (MTC) is frequently diagnosed in a locally advanced or metastatic stage, and 10-year survival rates in these cases are below 20 %.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584948", "text": "Cytotoxic chemotherapy has no significant impact on overall or progression-free survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584948", "text": "Vandetanib (Caprelsa(®), AstraZeneca) is a once-daily oral tyrosine kinase inhibitor that selectively inhibits signalling mediated by growth-factor receptor tyrosine kinase RET (constitutively activated in roughly 60 % of all MTCs), vascular endothelial growth-factor receptors 2 and 3, and epidermal growth-factor receptors.", "type": "CHEMICAL", "entities": [ "Caprelsa", "tyrosine", "tyrosine" ], "offsets": [ [ 11, 19 ], [ 58, 66 ], [ 156, 164 ] ] }, { "pmid": "23584948", "text": "It is the first systemic drug with demonstrated anti-tumor benefits in advanced MTC, and it has recently been approved for locally advanced or metastatic MTC by the United States Food and Drug Administration (April 2011) and the European Medicines Agency (February 2012).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584948", "text": "This review, starting from the phases II and III efficacy and safety data that led to these approvals, explores important issues related to dosing, patient selection, and strategies for managing the substantial risk of toxicity associated with the drug (including life-threatening cardiac events that are the subject of a black-box warning in the United States).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584948", "text": "All these issues still remain to be defined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23584948", "text": "Vandetanib is becoming a standard of care for symptomatic, progressive, metastatic MTCs, to be used selectively in those patients who are likely to benefit from it.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23521080", "text": "Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic Acid.\n", "type": "CHEMICAL", "entities": [ "tranexamic Acid" ], "offsets": [ [ 96, 111 ] ] }, { "pmid": "23521080", "text": "Protein-protein interfaces provide an important class of drug targets currently receiving increased attention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23521080", "text": "The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23521080", "text": "One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin.", "type": "CHEMICAL", "entities": [ "tranexamic acid", "TXA", "lysine" ], "offsets": [ [ 17, 32 ], [ 34, 37 ], [ 52, 58 ] ] }, { "pmid": "23521080", "text": "However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties.", "type": "CHEMICAL", "entities": [ "TXA" ], "offsets": [ [ 27, 30 ] ] }, { "pmid": "23521080", "text": "In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA.", "type": "CHEMICAL", "entities": [ "TXA" ], "offsets": [ [ 122, 125 ] ] }, { "pmid": "23521080", "text": "Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders.", "type": "CHEMICAL", "entities": [ "5-(4-piperidyl)-3-isoxazolol", "4-PIOL" ], "offsets": [ [ 91, 119 ], [ 121, 127 ] ] }, { "pmid": "23521080", "text": "Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA.", "type": "CHEMICAL", "entities": [ "4-PIOL", "TXA" ], "offsets": [ [ 12, 18 ], [ 78, 81 ] ] }, { "pmid": "16835395", "text": "Gene deletion reveals roles for annexin A1 in the regulation of lipolysis and IL-6 release in epididymal adipose tissue.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "In this study, epididymal adipose tissue from male annexin 1 (ANXA1)-null and wild-type control mice were used to explore the potential role of ANXA1 in adipocyte biology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "ANXA1 was detected by Western blot analysis in wild-type tissue and localized predominantly to the stromal-vascular compartment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "Epididymal fat pad mass was reduced by ANXA1 gene deletion, but adipocyte size was unchanged, suggesting that ANXA1 is required for the maintenance of adipocyte and/or preadipocyte cell number.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "Epididymal tissue from wild-type mice responded in vitro to noradrenaline and isoprenaline with increased glycerol release, reduced IL-6 release, and increased cAMP accumulation.", "type": "CHEMICAL", "entities": [ "noradrenaline", "isoprenaline", "glycerol", "cAMP" ], "offsets": [ [ 60, 73 ], [ 78, 90 ], [ 106, 114 ], [ 160, 164 ] ] }, { "pmid": "16835395", "text": "Qualitatively similar but significantly attenuated responses to the catecholamines were observed in tissue from ANXA1-null mice, an effect that was not associated with changes in beta-adrenoceptor mRNA expression.", "type": "CHEMICAL", "entities": [ "catecholamines" ], "offsets": [ [ 68, 82 ] ] }, { "pmid": "16835395", "text": "Lipopolysaccharide (LPS) also stimulated lipolysis in vitro, but its effects were muted by ANXA1 gene deletion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "By contrast, LPS failed to influence IL-6 release from wild-type tissue but stimulated the release of the cytokine from tissue from ANXA1-null mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "ANXA1 gene deletion did not affect glucocorticoid receptor expression or the ability of dexamethasone to suppress catecholamine-induced lipolysis.", "type": "CHEMICAL", "entities": [ "dexamethasone", "catecholamine" ], "offsets": [ [ 88, 101 ], [ 114, 127 ] ] }, { "pmid": "16835395", "text": "It did, however, augment IL-6 expression and modify the inhibitory effects of glucocorticoids on IL-6 release.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16835395", "text": "Collectively, these studies suggest that ANXA1 supports aspects of adipose tissue mass and alters the sensitivity of epididymal adipose tissue to catecholamines, glucocorticoids, and LPS, thereby modulating lipolysis and IL-6 release.", "type": "CHEMICAL", "entities": [ "catecholamines" ], "offsets": [ [ 146, 160 ] ] }, { "pmid": "10207608", "text": "Phospholipase A2 inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes.\n", "type": "CHEMICAL", "entities": [ "p-bromophenacyl bromide", "arachidonyl trifluoromethyl ketone" ], "offsets": [ [ 28, 51 ], [ 56, 90 ] ] }, { "pmid": "10207608", "text": "Phospholipase A2 (PLA2) has been postulated to play a role in the regulation of cytokine expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10207608", "text": "Therefore, the objective of the present study was to investigate the effects of PLA2 inhibitors p-bromophenacyl bromide (BPB) and arachidonyl trifluoromethyl ketone (AACOCF3) on interleukin-2 (IL-2) expression in murine primary splenocytes.", "type": "CHEMICAL", "entities": [ "p-bromophenacyl bromide", "BPB", "arachidonyl trifluoromethyl ketone", "AACOCF3" ], "offsets": [ [ 96, 119 ], [ 121, 124 ], [ 130, 164 ], [ 166, 173 ] ] }, { "pmid": "10207608", "text": "Pretreatment of the splenocytes with both BPB and AACOCF3 suppressed phorbol 12-myristate 13-acetate plus ionomycin-induced IL-2 secretion in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "BPB", "AACOCF3", "phorbol 12-myristate 13-acetate" ], "offsets": [ [ 42, 45 ], [ 50, 57 ], [ 69, 100 ] ] }, { "pmid": "10207608", "text": "Inhibition > 90% of IL-2 secretion was observed at 1 microM BPB and 10 microM AACOCF3 compared to the respective vehicle control.", "type": "CHEMICAL", "entities": [ "BPB", "AACOCF3" ], "offsets": [ [ 60, 63 ], [ 78, 85 ] ] }, { "pmid": "10207608", "text": "Likewise, IL-2 steady-state mRNA expression was inhibited by both PLA2 inhibitors in a concentration-dependent fashion with > 90% inhibition at 1 microM BPB and 20 microM AACOCF3.", "type": "CHEMICAL", "entities": [ "BPB", "AACOCF3" ], "offsets": [ [ 153, 156 ], [ 171, 178 ] ] }, { "pmid": "10207608", "text": "Taken together, these data demonstrated that PLA2 inhibitors BPB and AACOCF3 are robust inhibitors of IL-2 expression at both the mRNA and protein levels in murine splenocytes.", "type": "CHEMICAL", "entities": [ "BPB", "AACOCF3" ], "offsets": [ [ 61, 64 ], [ 69, 76 ] ] }, { "pmid": "10207608", "text": "Moreover, these findings suggest that drugs and chemicals which inhibit PLA2 may have marked effects on T-cell function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127916", "text": "Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy.\n", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 164, 172 ] ] }, { "pmid": "23127916", "text": "The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST.", "type": "CHEMICAL", "entities": [ "tyrosine", "imatinib" ], "offsets": [ [ 115, 123 ], [ 93, 101 ] ] }, { "pmid": "23127916", "text": "Response to imatinib mainly depends from KIT and PDGFRα mutational status.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 12, 20 ] ] }, { "pmid": "23127916", "text": "Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 128, 136 ] ] }, { "pmid": "23127916", "text": "This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127916", "text": "We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy.", "type": "CHEMICAL", "entities": [ "imatinib", "imatinib" ], "offsets": [ [ 108, 116 ], [ 178, 186 ] ] }, { "pmid": "23127916", "text": "Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and -3A5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127916", "text": "Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127916", "text": "Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127916", "text": "In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 152, 160 ] ] }, { "pmid": "23127916", "text": "Further investigations are required in an attempt to further personalize GIST therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "Acute Macrovascular Dysfunction in Patients With Type 2 Diabetes Induced by Ingestion of Advanced Glycated β-Lactoglobulins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "OBJECTIVE Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified β-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "RESEARCH DESIGN AND METHODS In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "We measured macrovascular", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "[brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T180) min. RESULTS Following the AGE-BLG, FMD decreased at T90 by 80% from baseline and remained decreased by 42% at T180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "By comparison, following C-BLG, FMD decreased by 27% at T90 and 51% at T180 (P < 0.05 vs. baseline at T180).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG.", "type": "CHEMICAL", "entities": [ "nitrite", "nitrate", "N(ε)-carboxymethyllisine" ], "offsets": [ [ 24, 31 ], [ 43, 50 ], [ 104, 128 ] ] }, { "pmid": "23238657", "text": "There was no change in microvascular function caused by either beverage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238657", "text": "CONCLUSIONS In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 188, 200 ] ] }, { "pmid": "23238657", "text": "These AGE-related changes were independent of heat treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23477570", "text": "In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23477570", "text": "In situ forming reduction-sensitive degradable nanogels were designed and developed based on poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) (PEG-P(HEMA-co-AC))", "type": "CHEMICAL", "entities": [ "PEG-P(HEMA-co-AC)", "poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate)" ], "offsets": [ [ 176, 193 ], [ 93, 174 ] ] }, { "pmid": "23477570", "text": "block copolymers for efficient loading as well as triggered intracellular release of proteins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23477570", "text": "PEG-P(HEMA-co-AC) copolymers were prepared with controlled Mn of 9.1, 9.5, and 9.9 kg/mol and varying numbers of AC units per molecule of 7, 9 and 11, respectively (denoted as copolymer 1, 2, and 3) by reversible addition-fragmentation chain transfer copolymerization.", "type": "CHEMICAL", "entities": [ "PEG-P(HEMA-co-AC)" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "23477570", "text": "These copolymers were freely soluble in phosphate buffer but formed disulfide-cross-linked nanogels with defined sizes ranging from 72.5 to 124.1 nm in the presence of cystamine via ring-opening reaction with cyclic carbonate groups.", "type": "CHEMICAL", "entities": [ "phosphate", "disulfide", "cystamine", "cyclic carbonate" ], "offsets": [ [ 40, 49 ], [ 68, 77 ], [ 168, 177 ], [ 209, 225 ] ] }, { "pmid": "23477570", "text": "The sizes of nanogels decreased with increasing AC units as a result of increased cross-linking density.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23477570", "text": "Dynamic light scattering studies showed that these nanogels though stable at physiological conditions were rapidly dissociated in response to 10 mM dithiothreitol (DTT).", "type": "CHEMICAL", "entities": [ "dithiothreitol", "DTT" ], "offsets": [ [ 148, 162 ], [ 164, 167 ] ] }, { "pmid": "23477570", "text": "Interestingly, FITC-labeled cytochrome C (FITC-CC) could be readily loaded into nanogels with remarkable loading efficiencies (up to 98.2%) and loading contents (up to 48.2 wt.%).", "type": "CHEMICAL", "entities": [ "FITC", "FITC" ], "offsets": [ [ 15, 19 ], [ 42, 46 ] ] }, { "pmid": "23477570", "text": "The in vitro release studies showed that release of FITC-CC was minimal under physiological conditions but significantly enhanced under reductive conditions in the presence of 10 mM DTT with about 96.8% of FITC-CC released in 22 h from nanogel 1.", "type": "CHEMICAL", "entities": [ "FITC", "DTT", "FITC" ], "offsets": [ [ 52, 56 ], [ 182, 185 ], [ 206, 210 ] ] }, { "pmid": "23477570", "text": "In contrast, protein release from 1,4-butanediamine cross-linked nanogels (reduction-insensitive control) remained low under otherwise the same conditions.", "type": "CHEMICAL", "entities": [ "1,4-butanediamine" ], "offsets": [ [ 34, 51 ] ] }, { "pmid": "23477570", "text": "MTT assays showed that these nanogels were nontoxic to HeLa cells up to a tested concentration of 2 mg/mL. Confocal microscopy results showed that nanogel 1 delivered and released FITC-CC into the perinuclei region of HeLa cells following 8 h incubation.", "type": "CHEMICAL", "entities": [ "MTT", "FITC" ], "offsets": [ [ 0, 3 ], [ 180, 184 ] ] }, { "pmid": "23477570", "text": "CC-loaded reductively degradable nanogels demonstrated apparently better apoptotic activity than free CC as well as reduction-insensitive controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23477570", "text": "These in situ forming, surfactant and oil-free, and reduction-sensitive degradable nanogels are highly promising for targeted protein therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "Brugada syndrome.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility to ventricular tachyarrhythmia and sudden cardiac death has been described by Brugada et al. in 1992.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "This disease is now frequently called \"Brugada syndrome\" (BrS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "The prevalence of BrS in the general population is unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "Syncope, typically occurring at rest or during sleep (in individuals in their third or fourth decades of life) is a common presentation of BrS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "In some cases, tachycardia does not terminate spontaneously and it may degenerate into ventricular fibrillation and lead to sudden death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 123, 129 ] ] }, { "pmid": "16972995", "text": "Since the use of the implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest, the identification of high-risk subjects is one of the major goals in the clinical decision-making process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16972995", "text": "Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients with multiple recurrences.", "type": "CHEMICAL", "entities": [ "Quinidine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22878908", "text": "Thiazolidinediones (TZDs) affect osteoblast viability and biomarkers independently of the TZD effects on aromatase.\n", "type": "CHEMICAL", "entities": [ "Thiazolidinediones", "TZDs", "TZD" ], "offsets": [ [ 0, 18 ], [ 20, 24 ], [ 90, 93 ] ] }, { "pmid": "22878908", "text": "Thiazolidinediones (TZDs) are insulin sensitizers used for treatment of diabetes.", "type": "CHEMICAL", "entities": [ "Thiazolidinediones", "TZDs" ], "offsets": [ [ 0, 18 ], [ 20, 24 ] ] }, { "pmid": "22878908", "text": "We have previously reported that TZDs reduce estrogen synthesis by inhibiting aromatase activity in human granulosa cells (HGC).", "type": "CHEMICAL", "entities": [ "TZDs", "estrogen" ], "offsets": [ [ 33, 37 ], [ 45, 53 ] ] }, { "pmid": "22878908", "text": "Multiple clinical trials demonstrated that TZDs increase the risk of fractures in postmenopausal women with type 2 diabetes.", "type": "CHEMICAL", "entities": [ "TZDs" ], "offsets": [ [ 43, 47 ] ] }, { "pmid": "22878908", "text": "We studied mouse osteoblasts alone or in a co-culture with HGC to determine whether TZD inhibition of aromatase plays a role in their effects on bone metabolism.", "type": "CHEMICAL", "entities": [ "TZD" ], "offsets": [ [ 84, 87 ] ] }, { "pmid": "22878908", "text": "Mouse osteoblasts were cultured with and without HGC, and incubated in a medium with or without testosterone, pioglitazone or rosiglitazone.", "type": "CHEMICAL", "entities": [ "testosterone", "pioglitazone", "rosiglitazone" ], "offsets": [ [ 96, 108 ], [ 110, 122 ], [ 126, 139 ] ] }, { "pmid": "22878908", "text": "Cell growth, oleic acid uptake, alkaline phosphatase activity, and osteocalcin production were measured.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22878908", "text": "TZDs inhibited estradiol production by up to 84% in HGC/mouse osteoblast co-cultures.", "type": "CHEMICAL", "entities": [ "TZDs", "estradiol" ], "offsets": [ [ 0, 4 ], [ 15, 24 ] ] }, { "pmid": "22878908", "text": "TZDs induced mouse osteoblast death and increased oleic acid uptake.", "type": "CHEMICAL", "entities": [ "TZDs", "oleic acid" ], "offsets": [ [ 0, 4 ], [ 50, 60 ] ] }, { "pmid": "22878908", "text": "TZDs also inhibited alkaline phosphatase activity (58-75%, p<0.046) and osteocalcin production (52-75%, p<0.031).", "type": "CHEMICAL", "entities": [ "TZDs" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "22878908", "text": "For all the parameters, there were no significant differences between the osteoblast cultures alone and the HCG/osteoblast co-cultures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22878908", "text": "TZD effects on osteoblast viability, oleic acid uptake, alkaline phosphatase and osteocalcin production are independent of their effects on aromatase.", "type": "CHEMICAL", "entities": [ "TZD" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "15199474", "text": "P2Y12, a new platelet ADP receptor, target of clopidogrel.\n", "type": "CHEMICAL", "entities": [ "ADP", "clopidogrel" ], "offsets": [ [ 22, 25 ], [ 46, 57 ] ] }, { "pmid": "15199474", "text": "Clopidogrel is a potent antithrombotic drug that inhibits ADP-induced platelet aggregation.", "type": "CHEMICAL", "entities": [ "Clopidogrel", "ADP" ], "offsets": [ [ 0, 11 ], [ 58, 61 ] ] }, { "pmid": "15199474", "text": "The results of large clinical trials have demonstrated an overall benefit of clopidogrel over aspirin in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease.", "type": "CHEMICAL", "entities": [ "clopidogrel", "aspirin" ], "offsets": [ [ 77, 88 ], [ 94, 101 ] ] }, { "pmid": "15199474", "text": "The antiaggregating effect of clopidogrel is attributed to an irreversible inhibition of ADP binding to a purinergic receptor present at the platelet surface.", "type": "CHEMICAL", "entities": [ "clopidogrel", "ADP" ], "offsets": [ [ 30, 41 ], [ 89, 92 ] ] }, { "pmid": "15199474", "text": "Clopidogrel is not active in vitro and can be considered a precursor of an active metabolite formed in the liver.", "type": "CHEMICAL", "entities": [ "Clopidogrel" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15199474", "text": "The chemical structure of this active metabolite and its biological activity have been described recently.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15199474", "text": "Several purinergic receptors have been described on platelets; P2X (1), a calcium channel, and P2Y1 a Gq-coupled seven-transmembrane domain receptor, have been found not to be antagonized by clopidogrel.", "type": "CHEMICAL", "entities": [ "calcium", "clopidogrel" ], "offsets": [ [ 74, 81 ], [ 191, 202 ] ] }, { "pmid": "15199474", "text": "Another Gi (2)-coupled receptor (named P2Y12) has been recently cloned and stably expressed in CHO cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15199474", "text": "These cells displayed a strong affinity for (33)P-2MeS-ADP, a stable analogue of ADP, the binding characteristics of which corresponded in all points to those observed on platelets.", "type": "CHEMICAL", "entities": [ "(33)P-2MeS-ADP", "ADP" ], "offsets": [ [ 44, 58 ], [ 81, 84 ] ] }, { "pmid": "15199474", "text": "The binding of (33)P-2MeS-ADP to these cells was strongly inhibited by the active metabolite of clopidogrel with a potency that was consistent with that observed for this compound on platelets.", "type": "CHEMICAL", "entities": [ "(33)P-2MeS-ADP", "clopidogrel" ], "offsets": [ [ 15, 29 ], [ 96, 107 ] ] }, { "pmid": "15199474", "text": "In these transfected CHO cells, as in platelets, ADP and 2MeS-ADP induced adenylyl cyclase downregulation, an effect that was inhibited by the active metabolite of clopidogrel.", "type": "CHEMICAL", "entities": [ "ADP", "2MeS-ADP", "adenylyl", "clopidogrel" ], "offsets": [ [ 49, 52 ], [ 57, 65 ], [ 74, 82 ], [ 164, 175 ] ] }, { "pmid": "15199474", "text": "These results demonstrate that this receptor corresponds to the previously called \"P2t\" platelet receptor and show that the active metabolite of clopidogrel binds in a covalent manner to this receptor, thus explaining how it blocks the aggregating effect of ADP on platelets.", "type": "CHEMICAL", "entities": [ "clopidogrel", "ADP" ], "offsets": [ [ 145, 156 ], [ 258, 261 ] ] }, { "pmid": "15155769", "text": "Redesign of carnitine acetyltransferase specificity by protein engineering.\n", "type": "CHEMICAL", "entities": [ "carnitine" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "15155769", "text": "In eukaryotes, L-carnitine is involved in energy metabolism by facilitating beta-oxidation of fatty acids.", "type": "CHEMICAL", "entities": [ "L-carnitine", "fatty acids" ], "offsets": [ [ 15, 26 ], [ 94, 105 ] ] }, { "pmid": "15155769", "text": "Carnitine acetyltransferases (CrAT) catalyze the reversible conversion of acetyl-CoA and carnitine to acetylcarnitine and free CoA.", "type": "CHEMICAL", "entities": [ "Carnitine", "acetyl-CoA", "carnitine", "acetylcarnitine" ], "offsets": [ [ 0, 9 ], [ 74, 84 ], [ 89, 98 ], [ 102, 117 ] ] }, { "pmid": "15155769", "text": "To redesign the specificity of rat CrAT toward its substrates, we mutated Met564.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15155769", "text": "The M564G mutated CrAT showed higher activity toward longer chain acyl-CoAs: activity toward myristoyl-CoA was 1250-fold higher than that of the wild-type CrAT, and lower activity toward its natural substrate, acetyl-CoA. Kinetic constants of the mutant CrAT showed modification in favor of longer acyl-CoAs as substrates.", "type": "CHEMICAL", "entities": [ "acyl-CoAs", "myristoyl-CoA", "acetyl-CoA", "acyl-CoAs" ], "offsets": [ [ 66, 75 ], [ 93, 106 ], [ 210, 220 ], [ 298, 307 ] ] }, { "pmid": "15155769", "text": "In the reverse case, mutation of the orthologous glycine (Gly553) to methionine in carnitine octanoyltransferase (COT) decreased activity toward its natural substrates, medium- and long-chain acyl-CoAs, and increased activity toward short-chain acyl-CoAs.", "type": "CHEMICAL", "entities": [ "glycine", "methionine", "carnitine", "acyl-CoAs", "acyl-CoAs" ], "offsets": [ [ 49, 56 ], [ 69, 79 ], [ 83, 92 ], [ 192, 201 ], [ 245, 254 ] ] }, { "pmid": "15155769", "text": "Another CrAT mutant, M564A, was prepared and tested in the same way, with similar results.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15155769", "text": "We conclude that Met564 blocks the entry of medium- and long-chain acyl-CoAs to the catalytic site of CrAT.", "type": "CHEMICAL", "entities": [ "acyl-CoAs" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "15155769", "text": "Three-dimensional models of wild-type and mutated CrAT and COT support this hypothesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15155769", "text": "We show for the first time that a single amino acid is able to determine the substrate specificity of CrAT and COT.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 41, 51 ] ] }, { "pmid": "2226440", "text": "Cooperative homotropic interaction of L-noradrenaline with the catalytic site of phenylalanine 4-monooxygenase.\nCatecholamines (adrenaline, noradrenaline and dopamine) are potent inhibitors of phenylalanine 4-monooxygenase (phenylalanine hydroxylase, EC 1.14.16.1).", "type": "CHEMICAL", "entities": [ "Catecholamines", "phenylalanine", "adrenaline", "noradrenaline", "dopamine", "phenylalanine", "L-noradrenaline", "phenylalanine" ], "offsets": [ [ 112, 126 ], [ 224, 237 ], [ 128, 138 ], [ 140, 153 ], [ 158, 166 ], [ 193, 206 ], [ 38, 53 ], [ 81, 94 ] ] }, { "pmid": "2226440", "text": "The amines bind to the enzyme by a direct coordination to the high-spin (S = 5/2) Fe(III) at the active site (charge transfer interaction), as seen by resonance Raman and EPR spectroscopy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2226440", "text": "Experimental evidence is presented that a group with an apparent pKa value of about 5.1 (20 degrees C) is involved in the interaction between the catecholamine and the enzyme.", "type": "CHEMICAL", "entities": [ "catecholamine" ], "offsets": [ [ 146, 159 ] ] }, { "pmid": "2226440", "text": "The high-affinity binding of L-noradrenaline to phenylalanine hydroxylase, as studied by equilibrium microdialysis (anaerobically) and ultrafiltration (aerobically), shows positive cooperativity (h = 1.9); at pH 7.2 and 20 degrees C the rat enzyme binds about 0.5 mol L-noradrenaline/mol subunit with a half-maximal binding (S50) at 0.25 microM L-noradrenaline.", "type": "CHEMICAL", "entities": [ "L-noradrenaline", "phenylalanine", "L-noradrenaline", "L-noradrenaline" ], "offsets": [ [ 29, 44 ], [ 48, 61 ], [ 268, 283 ], [ 345, 360 ] ] }, { "pmid": "2226440", "text": "No binding to the ferrous form of the enzyme was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2226440", "text": "The affinity decreases with decreasing pH, by phosphorylation and by preincubation of the enzyme with the substrate L-phenylalanine, while it increases after alkylation of the enzyme with the activator N-ethylmaleimide.", "type": "CHEMICAL", "entities": [ "L-phenylalanine", "N-ethylmaleimide" ], "offsets": [ [ 116, 131 ], [ 202, 218 ] ] }, { "pmid": "2226440", "text": "Preincubation of the enzyme with L-phenylalanine also leads to a complete loss of the cooperativity of L-noradrenaline binding (h = 1.0).", "type": "CHEMICAL", "entities": [ "L-phenylalanine", "L-noradrenaline" ], "offsets": [ [ 33, 48 ], [ 103, 118 ] ] }, { "pmid": "2226440", "text": "The many similarities in binding properties of the inhibitor L-noradrenaline and the activator/substrate L-phenylalanine makes it likely that the cooperative interactions of these effectors are due to their binding to the same site.", "type": "CHEMICAL", "entities": [ "L-noradrenaline", "L-phenylalanine" ], "offsets": [ [ 61, 76 ], [ 105, 120 ] ] }, { "pmid": "2226440", "text": "The high-affinity of catecholamines to phenylalanine hydroxylase is a valuable probe to study the active site of this enzyme and is also relevant for the homologous enzyme tyrosine hydroxylase, which is purified as a stable catecholamine-Fe(III) complex.", "type": "CHEMICAL", "entities": [ "catecholamines", "phenylalanine", "tyrosine", "catecholamine", "Fe(III)" ], "offsets": [ [ 21, 35 ], [ 39, 52 ], [ 172, 180 ], [ 224, 237 ], [ 238, 245 ] ] }, { "pmid": "23640283", "text": "The design and realization of a large-area flexible nanofiber-based mat for pollutant degradation: an application in photocatalysis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640283", "text": "This work demonstrates a novel multifunctional nanofibrous mat for photocatalytic applications based on TiO2 nanocables functionalized by Ag nanoparticles and coated with a thin (∼2 nm) graphitic shell.", "type": "CHEMICAL", "entities": [ "TiO2", "Ag", "graphitic" ], "offsets": [ [ 104, 108 ], [ 138, 140 ], [ 186, 195 ] ] }, { "pmid": "23640283", "text": "In this mat, which was realized by an electrospinning technique, each component serves a unique function: the carbon coating acts as both an adsorption material for capturing pollutants and as a charge-transfer material, the Ag nanoparticles act as a visible-light sensitizing agent and also as a charge-transfer material, finally the TiO2 nanocable mat acts as a UV sensitive photocatalytic matrix and as the flexible substrate for the other functional components.", "type": "CHEMICAL", "entities": [ "carbon", "Ag", "TiO2" ], "offsets": [ [ 108, 114 ], [ 223, 225 ], [ 333, 337 ] ] }, { "pmid": "23640283", "text": "This multicomponent nanocable mat exhibits excellent photocatalytic activity under simulated solar irradiation for the degradation of model pollutants including RhB and phenol.", "type": "CHEMICAL", "entities": [ "RhB", "phenol" ], "offsets": [ [ 159, 162 ], [ 167, 173 ] ] }, { "pmid": "23640283", "text": "The significant photocatalytic properties are attributed to the synergetic effect of the three functional components and the unique charge transport \"freeway\" property of the nanofibrous mat.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640283", "text": "In addition, the porous carbon coating infiltrated into the nanocable matrix endows the mat with excellent flexibility and enables robust, large-area (10 × 10 cm) fabrication, representing a significant advantage over previous brittle ceramic nanofibrous mat photocatalyst substrates.", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 22, 28 ] ] }, { "pmid": "23640283", "text": "This study provides new insight into the design and preparation of an advanced, yet commercially practical and scaleable photocatalytic composite membrane material.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640283", "text": "The as-prepared photocatalytic mat might also be of interest in solar cell, catalysis, separation technology, biomedical engineering, and nanotechnology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "The effects of kisspeptin in human reproductive function - therapeutic implications.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "23256725", "text": "Evidence suggests that this system is a key regulator of mammalian and human reproduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "Animal studies have shown that GPR54-deficient mice have abnormal sexual development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect.", "type": "CHEMICAL", "entities": [ "gonadotrophin releasing hormone", "GnRH" ], "offsets": [ [ 140, 171 ], [ 173, 177 ] ] }, { "pmid": "23256725", "text": "In humans, inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females particularly in the preovulatatory phase of the menstrual cycle.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 212, 224 ] ] }, { "pmid": "23256725", "text": "In infertility due to hypothalamic amenorrhoea acute administration of kisspeptin results in stimulation of reproductive hormones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "Hence kisspeptin has potential as a novel tool for the manipulation of the HPG axis and treatment of infertility in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256725", "text": "This review discusses the evidence highlighting kisspeptin's key role in human reproduction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "Species-specific differences in the glucocorticoid receptor transactivation function upon binding with betamethasone-esters.\n", "type": "CHEMICAL", "entities": [ "betamethasone-esters" ], "offsets": [ [ 103, 123 ] ] }, { "pmid": "12188035", "text": "Glucocorticoids (GCs) are the most effective drugs for anti-inflammatory diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "A number of adverse side effects, however, limit chronic treatment with GCs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "To improve their therapeutic usefulness, attempts have been made to dissociate the two main actions of the glucocorticoid receptor (GR), transactivation and transrepression, which are believed to be responsible for the side effects and anti-inflammatory effects, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "We report here species-specific differences in the transactivation response mediated by GR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "Dexamethasone (DEX), betamethasone (BM), and their esterified-derivatives had full transrepression agonistic activity in a reporter assay using CV-1 cells transfected with either human or rat GR.", "type": "CHEMICAL", "entities": [ "Dexamethasone", "DEX", "betamethasone", "BM" ], "offsets": [ [ 0, 13 ], [ 15, 18 ], [ 21, 34 ], [ 36, 38 ] ] }, { "pmid": "12188035", "text": "These GCs also had full transactivation agonistic activity in CV-1 cells transfected with human GR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "The esterified-BM, however, had only partial transactivation agonistic activity in cells transfected with rat GR, whereas BM and esterified-DEX had full transactivation agonistic activity.", "type": "CHEMICAL", "entities": [ "BM", "BM", "DEX" ], "offsets": [ [ 15, 17 ], [ 122, 124 ], [ 140, 143 ] ] }, { "pmid": "12188035", "text": "Moreover, in rat hepatoma H4-II-E cells, the esterified-BM failed to induce tyrosine aminotransferase, which is regulated by GR-mediated transactivation activity.", "type": "CHEMICAL", "entities": [ "BM", "tyrosine" ], "offsets": [ [ 56, 58 ], [ 76, 84 ] ] }, { "pmid": "12188035", "text": "There were no significant differences between the binding affinity of these GCs to human and rat GR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12188035", "text": "Consistent with the weak transactivation activity of esterified-BM mediated by rat GR, there were few side effects, evaluated by thymus involution and body weight loss, in an antigen-induced asthmatic model in rats.", "type": "CHEMICAL", "entities": [ "BM" ], "offsets": [ [ 64, 66 ] ] }, { "pmid": "12188035", "text": "These results suggest that the potency of esterified-BM to induce transactivation activity is different between species and that this difference is not due to differences in receptor binding.", "type": "CHEMICAL", "entities": [ "BM" ], "offsets": [ [ 53, 55 ] ] }, { "pmid": "1322791", "text": "Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II.\n", "type": "CHEMICAL", "entities": [ "Amsacrine", "etoposide" ], "offsets": [ [ 0, 9 ], [ 14, 23 ] ] }, { "pmid": "1322791", "text": "Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid-borne TOP2 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide (VP-16).", "type": "CHEMICAL", "entities": [ "amsacrine", "etoposide", "VP-16" ], "offsets": [ [ 196, 205 ], [ 210, 219 ], [ 221, 226 ] ] }, { "pmid": "1322791", "text": "This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both RAD52+ repair-proficient strains and rad52 mutants that are defective in the repair of double-stranded breaks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1322791", "text": "These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II, and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "Characterization of insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 1, 2, and 3 in human prostate epithelial cells: potential roles for IGFBP-rP1 and 2 in senescence of the prostatic epithelium.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "Insulin-like growth factor (IGF)-binding protein (IGFBP)-related proteins (IGFBP-rPs) are newly described cysteine-rich proteins that share significant aminoterminal structural similarity with the conventional IGFBPs and are involved in a diversity of biological functions, including growth regulation.", "type": "CHEMICAL", "entities": [ "cysteine" ], "offsets": [ [ 106, 114 ] ] }, { "pmid": "11089538", "text": "IGFBP-rP1 (MAC25/Angiomodulin/prostacyclin-stimulating factor) is a potential tumor-suppressor gene that is differentially expressed in meningiomas, mammary and prostatic cancers, compared with their malignant counterparts.", "type": "CHEMICAL", "entities": [ "prostacyclin" ], "offsets": [ [ 30, 42 ] ] }, { "pmid": "11089538", "text": "We have previously shown that IGFBP-rP1 is preferentially produced by primary cultures of human prostate epithelial cells (HPECs) and by poorly tumorigenic P69SV40T cells, compared with the cancerous prostatic LNCaP, DU145, PC-3, and M12 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "We now show that IGFBP-rP1 increases during senescence of HPEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "IGFBP-rP2 (also known as connective tissue growth factor), a downstream effector of transforming growth factor (TGF)-beta and modulator of growth for both fibroblasts and endothelial cells, was detected in most of the normal and malignant prostatic epithelial cells tested, with a marked up-regulation of IGFBP-rP2 during senescence of HPEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "Moreover, IGFBP-rP2 noticeably increased in response to TGF-beta1 and all-trans retinoic acid (atRA) in HPEC and PC-3 cells, and it decreased in response to IGF-I in HPEC.", "type": "CHEMICAL", "entities": [ "all-trans retinoic acid", "atRA" ], "offsets": [ [ 70, 93 ], [ 95, 99 ] ] }, { "pmid": "11089538", "text": "IGFBP-rP3", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "[nephroblastoma overexpressed (NOV)], the protein product of the NOV protooncogene, was not detected in HPEC but was expressed in the tumorigenic DU145 and PC-3 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "It was also synthesized by the SV40-T antigen-transformed P69 and malignant M12 cells, where it was down-regulated by atRA.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 118, 122 ] ] }, { "pmid": "11089538", "text": "These observations suggest biological roles of IGFBP-rPs in the human prostate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "IGFBP-rP1 and IGFBP-rP2 are likely to negatively regulate growth, because they seem to increase during senescence of the prostate epithelium and in response to growth inhibitors (TGF-beta1 and atRA).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11089538", "text": "Although the data collected on IGFBP-rP3 in prostate are modest, its role as a growth stimulator and/or protooncogene is supported by its preferential expression in cancerous cells and its down-regulation by atRA.", "type": "CHEMICAL", "entities": [ "atRA" ], "offsets": [ [ 208, 212 ] ] }, { "pmid": "15921304", "text": "[Disorders with eosinophilia, treatment of hypereosinophilic syndrome].\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15921304", "text": "Eosinophilia may be associated with reactive conditions and with clonal disorders of the hematopoietic cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15921304", "text": "The hypereosinophilic syndrome takes an intermedier place in this group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15921304", "text": "In this disease a sustained eosinophilia with end organ damage can occur.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15921304", "text": "The author summarized the diagnostic procedures and differential diagnosis in the group of these diseases focusing on characteristics and treatment of hypereosinophilic syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15921304", "text": "The treatment has been varied and included steroids, hydroxyurea, interferon-alpha, and in some cases chemotherapy.", "type": "CHEMICAL", "entities": [ "steroids", "hydroxyurea" ], "offsets": [ [ 43, 51 ], [ 53, 64 ] ] }, { "pmid": "15921304", "text": "On the basis of FIP1L1-PDGFRa fusion gene hypereosinophilic syndrome would be classified as a clonal disease and in the FIP1L1-PDGFRa positive cases the tyrosine kinase inhibitor imatinib mesylate (Glivec) would be effective.", "type": "CHEMICAL", "entities": [ "tyrosine", "imatinib mesylate" ], "offsets": [ [ 153, 161 ], [ 179, 196 ] ] }, { "pmid": "23327877", "text": "Transport by OATP1B1 and OATP1B3 enhances the cytotoxicity of epigallocatechin 3-O-gallate and several quercetin derivatives.\n", "type": "CHEMICAL", "entities": [ "quercetin", "epigallocatechin 3-O-gallate" ], "offsets": [ [ 103, 112 ], [ 62, 90 ] ] }, { "pmid": "23327877", "text": "Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327877", "text": "OATP1B3 is also expressed in certain cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327877", "text": "Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs.", "type": "CHEMICAL", "entities": [ "Flavonoids", "catechins", "quercetin glycosides" ], "offsets": [ [ 0, 10 ], [ 29, 38 ], [ 43, 63 ] ] }, { "pmid": "23327877", "text": "In the present study, the extent to which six substituted quercetin derivatives (1-6) affected the function of OATP1B1 and OATP1B3 was investigated.", "type": "CHEMICAL", "entities": [ "quercetin" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "23327877", "text": "Uptake of the radiolabeled model substrates estradiol 17β-glucuronide, estrone 3-sulfate, and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds 1-6 using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3.", "type": "CHEMICAL", "entities": [ "estradiol 17β-glucuronide", "estrone 3-sulfate", "dehydroepiandrosterone sulfate", "DHEAS" ], "offsets": [ [ 44, 69 ], [ 71, 88 ], [ 94, 124 ], [ 126, 131 ] ] }, { "pmid": "23327877", "text": "Several of compounds 1-6 inhibited OATP-mediated uptake of all three model substrates, suggesting that they could also be potential substrates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327877", "text": "Compound 6 stimulated OATP1B3-mediated estradiol 17β-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate.", "type": "CHEMICAL", "entities": [ "estradiol 17β-glucuronide" ], "offsets": [ [ 38, 63 ] ] }, { "pmid": "23327877", "text": "Cytotoxicity assays demonstrated that epigallocatechin 3-O-gallate (EGCG) and most of compounds 1-6 killed preferentially OATP-expressing CHO cells.", "type": "CHEMICAL", "entities": [ "epigallocatechin 3-O-gallate", "EGCG" ], "offsets": [ [ 36, 64 ], [ 66, 70 ] ] }, { "pmid": "23327877", "text": "EGCG, 1, and 3 were the most potent cytotoxic compounds, with EGCG and 3 selectively killing OATP1B3-expressing cells.", "type": "CHEMICAL", "entities": [ "EGCG" ], "offsets": [ [ 60, 64 ] ] }, { "pmid": "23327877", "text": "Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs.", "type": "CHEMICAL", "entities": [ "EGCG", "quercetin" ], "offsets": [ [ 50, 54 ], [ 71, 80 ] ] }, { "pmid": "23192350", "text": "Silencing α1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "Leukocyte adhesion during inflammation is initiated by the binding of sialofucosylated carbohydrates expressed on leukocytes to endothelial E/P-selectin.", "type": "CHEMICAL", "entities": [ "carbohydrates" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "23192350", "text": "Although the glycosyltransferases (glycoTs) constructing selectin-ligands have largely been identified using knock-out mice, important differences may exist between humans and mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "To address this, we developed a systematic lentivirus-based shRNA delivery workflow to create human leukocytic HL-60 cell lines that lack up to three glycoTs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "Using this, the contributions of all three myeloid α1,3-fucosyltransferases (FUT4, FUT7, and FUT9) to selectin-ligand biosynthesis were evaluated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "The cell adhesion properties of these modified cells to L-, E-, and P-selectin under hydrodynamic shear were compared with bone marrow-derived neutrophils from Fut4(-/-)Fut7(-/-) dual knock-out mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "Results demonstrate that predominantly FUT7, and to a lesser extent FUT4, forms the selectin-ligand at the N terminus of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) in humans and mice.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 105, 106 ] ] }, { "pmid": "23192350", "text": "Here, 85% reduction in leukocyte interaction was observed in human FUT4(-)7(-) dual knockdowns on P/L-selectin substrates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "Unlike Fut4(-/-)Fut7(-/-) mouse neutrophils, however, human knockdowns lacking FUT4 and FUT7 only exhibited partial reduction in rolling interaction on E-selectin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "In this case, the third α1,3-fucosyltransferase FUT9 played an important role because leukocyte adhesion was reduced by 50-60% in FUT9-HL-60, 70-80% in dual knockdown FUT7(-)9(-) cells, and ∼85% in FUT4(-)7(-)9(-) triple knockdowns.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "Gene silencing results are in agreement with gain-of-function experiments where all three fucosyltransferases conferred E-selectin-mediated rolling in HEK293T cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "This study advances new tools to study human glycoT function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23192350", "text": "It suggests a species-specific role for FUT9 during the biosynthesis of human E-selectin ligands.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "Optimization of frozen sour cherries vacuum drying process.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "The objective of this research was to optimize the vacuum-drying of frozen sour cherries in order to preserve health-beneficial phytochemicals, as well as textural characteristics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "Investigated range of temperature was 46-74°C and, of pressure, 17-583mbar, in a new design of vacuum-dryer equipment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "The total solids, a(w) value, total phenolics, vitamin C, antioxidant activity, anthocyanin content, total colour change and firmness were used as quality indicators of dried sour cherry.", "type": "CHEMICAL", "entities": [ "phenolics", "vitamin C", "anthocyanin" ], "offsets": [ [ 35, 44 ], [ 46, 55 ], [ 79, 90 ] ] }, { "pmid": "23017392", "text": "Within the experimental range of studied variables, the optimum conditions of 54.03°C and 148.16mbar were established for vacuum drying of sour cherry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "Separate validation experiments were conducted, under optimum conditions, to verify predictions and adequacy of the second-order polynomial models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "Under these optimal conditions, the predicted amount of total phenolics was 744mg CAE/100 dw, vitamin C 1.44mg/100g per dry weight (g dw), anthocyanin content 125mg/100g dw, IC(50)", "type": "CHEMICAL", "entities": [ "phenolics", "vitamin C", "anthocyanin" ], "offsets": [ [ 60, 69 ], [ 92, 101 ], [ 137, 148 ] ] }, { "pmid": "23017392", "text": "3.23mg/ml, total solids 70.72%, a(w) value 0.646, total colour change 52.61 and firmness 3395.4g.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23017392", "text": "The investigated parameters had a significant effect on the quality of the dried sour cherries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8242725", "text": "Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?\n", "type": "CHEMICAL", "entities": [ "Dopamine", "ergotamine", "123I-iodobenzamide", "ergotamine" ], "offsets": [ [ 0, 8 ], [ 105, 115 ], [ 34, 52 ], [ 88, 98 ] ] }, { "pmid": "8242725", "text": "Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123I-3-iodo-6-methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal.", "type": "CHEMICAL", "entities": [ "123I-3-iodo-6-methoxybenzamide", "123I-IBZM", "ergotamine", "dopamine" ], "offsets": [ [ 104, 134 ], [ 136, 145 ], [ 154, 164 ], [ 62, 70 ] ] }, { "pmid": "8242725", "text": "Results were compared with 15 healthy controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8242725", "text": "Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 142, 150 ] ] }, { "pmid": "8242725", "text": "No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine.", "type": "CHEMICAL", "entities": [ "123I-IBZM", "ergotamine" ], "offsets": [ [ 48, 57 ], [ 115, 125 ] ] }, { "pmid": "8242725", "text": "Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.", "type": "CHEMICAL", "entities": [ "ergotamine", "dopamine" ], "offsets": [ [ 35, 45 ], [ 70, 78 ] ] }, { "pmid": "16633143", "text": "Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: a double-blind, fixed-dosage, controlled trial.\n", "type": "CHEMICAL", "entities": [ "Reboxetine", "fluvoxamine" ], "offsets": [ [ 0, 10 ], [ 18, 29 ] ] }, { "pmid": "16633143", "text": "BACKGROUND: Motor vehicle accidents (MVAs) are a leading cause of posttraumatic stress disorder (PTSD) in the general population.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "Alterations in norepinephrine and serotonin systems have been proposed as mechanisms involved in the pathophysiology of the condition, with treatment directed at these neurotransmitter systems.", "type": "CHEMICAL", "entities": [ "norepinephrine", "serotonin" ], "offsets": [ [ 15, 29 ], [ 34, 43 ] ] }, { "pmid": "16633143", "text": "Reboxetine, a selective norepinephrine reuptake inhibitor, exhibits high affinity and selectivity for the human norepinephrine transporter.", "type": "CHEMICAL", "entities": [ "Reboxetine", "norepinephrine", "norepinephrine" ], "offsets": [ [ 0, 10 ], [ 24, 38 ], [ 112, 126 ] ] }, { "pmid": "16633143", "text": "Inasmuch as PTSD may be associated with dysregulation of noradrenergic activity, the present double-blind randomized clinical trial intended to evaluate reboxetine's efficacy in the management of MVA-related PTSD and to compare its efficacy with a medication commonly used in PTSD, the selective serotonin reuptake inhibitor fluvoxamine.", "type": "CHEMICAL", "entities": [ "serotonin", "fluvoxamine" ], "offsets": [ [ 296, 305 ], [ 325, 336 ] ] }, { "pmid": "16633143", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "Forty patients with MVA-related PTSD attending a local community mental health outpatient clinic were randomized to receive a fixed dose of either reboxetine (8 mg/d) or fluvoxamine (150 mg/d) in a double-blind fashion for a period of 8 weeks.", "type": "CHEMICAL", "entities": [ "reboxetine", "fluvoxamine" ], "offsets": [ [ 147, 157 ], [ 170, 181 ] ] }, { "pmid": "16633143", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "At baseline and at study end point, the 2 subgroups demonstrated no statistical differences in scores on PTSD, depression, and anxiety rating scales.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "Both medications led to significant improvements in all clinical scales measured.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "Nine patients receiving reboxetine and 3 receiving fluvoxamine withdrew from the study because of side effects.", "type": "CHEMICAL", "entities": [ "reboxetine", "fluvoxamine" ], "offsets": [ [ 24, 34 ], [ 51, 62 ] ] }, { "pmid": "16633143", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16633143", "text": "Study observations indicate comparable efficacy of reboxetine and fluvoxamine in the management of MVA-related PTSD despite reboxetine's selective noradrenergic activity.", "type": "CHEMICAL", "entities": [ "reboxetine", "fluvoxamine" ], "offsets": [ [ 51, 61 ], [ 66, 77 ] ] }, { "pmid": "16633143", "text": "Reboxetine appears to be at least as effective as fluvoxamine and may offer an alternative management option in this often difficult-to-treat and disabling condition.", "type": "CHEMICAL", "entities": [ "Reboxetine", "fluvoxamine" ], "offsets": [ [ 0, 10 ], [ 50, 61 ] ] }, { "pmid": "16633143", "text": "A lower and flexible reboxetine dosing schedule will be recommended for future research to improve its tolerability in PTSD patients.", "type": "CHEMICAL", "entities": [ "reboxetine" ], "offsets": [ [ 21, 31 ] ] }, { "pmid": "22820907", "text": "Current understanding of TRPM7 pharmacology and drug development for stroke.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22820907", "text": "The initial excitement and countless efforts to find a pharmacological agent that disrupts the excitotoxic pathway of ischemic neuronal death have only led to disappointing clinical trials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22820907", "text": "Currently, a thrombolytic agent called recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment available for patients with acute ischemic stroke in most countries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22820907", "text": "Even though its efficacy has been confirmed repeatedly, rt-PA is considerably underused due to reasons including a short therapeutic window and repeated complications associated with its use.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22820907", "text": "A search for alternative mechanisms that may operate dependently or independently with the well-established excitotoxic mechanism has led researchers to the discovery of newly described non-glutamate mechanisms.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 190, 199 ] ] }, { "pmid": "22820907", "text": "Among the latter, transient receptor potential melastatin 7 (TRPM7) is one of the important nonglutamate mechanisms in stroke, which has been evaluated in both in-vitro and in-vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22820907", "text": "In this review, we will discuss the current state of pharmacological treatments of ischemic stroke and provide evidence that TRPM7 is a promising therapeutic target of stroke.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17616291", "text": "Analgesic and anti-inflammatory activities of aqueous extract from Glycine tomentella root in mice.\n", "type": "CHEMICAL", "entities": [ "Glycine" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "17616291", "text": "In the present study, we have investigated the analgesic effect of the aqueous extract of the root of Glycine tomentella (AGT) using models of acetic acid-induced writhing response and formalin test, the anti-inflammatory effect of AGT using model of lambda-carrageenan-induced paw edema.", "type": "CHEMICAL", "entities": [ "Glycine", "acetic acid", "formalin" ], "offsets": [ [ 102, 109 ], [ 143, 154 ], [ 185, 193 ] ] }, { "pmid": "17616291", "text": "In order to investigate the anti-inflammatory mechanism of AGT, we have detected the activities of glutathione peroxidase (GPx) and glutathione reductase (GRx) in the liver and the levels of malondialdehyde (MDA) and NO in the edema paw.", "type": "CHEMICAL", "entities": [ "glutathione", "glutathione", "malondialdehyde", "MDA", "NO" ], "offsets": [ [ 99, 110 ], [ 132, 143 ], [ 191, 206 ], [ 208, 211 ], [ 217, 219 ] ] }, { "pmid": "17616291", "text": "In the analgesic test, AGT (0.5 and 1.0 g/kg) decreased the acetic acid-induced writhing response and the licking time on the late phase in the formalin test.", "type": "CHEMICAL", "entities": [ "acetic acid", "formalin" ], "offsets": [ [ 60, 71 ], [ 144, 152 ] ] }, { "pmid": "17616291", "text": "In the anti-inflammatory test, AGT (0.5 and 1.0 g/kg) decreased the paw edema at the third, fourth, fifth and sixth hour after lambda-carrageenan administration, and increased the activities of SOD, GPx and GRx in the liver tissue and decreased the MDA level in the edema paw at the third hour after lambda-carrageenan injection.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 249, 252 ] ] }, { "pmid": "17616291", "text": "However, AGT could not affect the NO level which induced by lambda-carrageenan.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 34, 36 ] ] }, { "pmid": "17616291", "text": "These results suggested that AGT possessed analgesic and anti-inflammatory effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17616291", "text": "The anti-inflammatory mechanism of AGT might be related to the decrease in the level of MDA in the edema paw via increasing the activities of SOD, GPx and GRx in the liver.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 88, 91 ] ] }, { "pmid": "23560442", "text": "Enhancing Raman Scattering without Plasmons:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23560442", "text": "Unprecedented Sensitivity Achieved by TiO2 Shell-Based Resonators.\n", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 38, 42 ] ] }, { "pmid": "23560442", "text": "A remarkable enhancement of Raman scattering is achieved by TiO2 shell-based spherical resonators in the absence of plasmonic enhancers.", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 60, 64 ] ] }, { "pmid": "23560442", "text": "This effect is ascribed to the synergistic combination of high refractive index of the shell layer, multiple light scattering through the spheres, and related geometrical factors and can be exploited to fabricate a new generation of self-diagnostic, recyclable SERS-active substrates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23473681", "text": "Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA.\n", "type": "CHEMICAL", "entities": [ "MAC13243", "thiourea" ], "offsets": [ [ 15, 23 ], [ 68, 76 ] ] }, { "pmid": "23473681", "text": "The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23473681", "text": "We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea.", "type": "CHEMICAL", "entities": [ "MAC13243", "MAC13243", "S-(4-chlorobenzyl)isothiourea" ], "offsets": [ [ 87, 95 ], [ 213, 221 ], [ 247, 276 ] ] }, { "pmid": "23473681", "text": "Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively.", "type": "CHEMICAL", "entities": [ "MAC13243", "thiourea" ], "offsets": [ [ 187, 195 ], [ 204, 212 ] ] }, { "pmid": "23473681", "text": "We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a Kd of ~150 μM.", "type": "CHEMICAL", "entities": [ "thiourea", "MAC13243" ], "offsets": [ [ 83, 91 ], [ 115, 123 ] ] }, { "pmid": "23473681", "text": "Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.", "type": "CHEMICAL", "entities": [ "thiourea" ], "offsets": [ [ 36, 44 ] ] }, { "pmid": "14767264", "text": "Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "We provide a comprehensive overview of the role of alpha1-adrenergic receptors (alpha1ARs) as critical mediators of lower urinary tract symptoms (LUTS) and pathophysiology in benign prostatic hyperplasia (BPH), and we review the pharmacological antagonists of alpha1ARs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "MATERIALS AND METHODS: A review was performed of pertinent studies in the literature relating to the pathophysiology of LUTS and BPH, focusing on the role of alpha1ARs, and of clinical trial and practice data evaluating the different agents that inhibit these receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "Further characterization of the alpha1AR gene family indicates that 3 receptor subtypes exist in humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "Their different distribution between urinary tract and cardiovascular tissues has provided a strategy for the development of improved therapeutic agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "Since excessive activity of the alpha1aAR and alpha1dAR subtypes appears to be a common feature in symptomatic BPH and alpha1aARs are enriched in prostatic tissue, drugs that demonstrate high alpha1aAR selectivity have attracted attention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "Tamsulosin, which has high affinity for alpha1aAR and alpha1dAR subtypes but not for alpha1bAR, shows efficacy similar to the nonsubtype selective agents terazosin and doxazosin.", "type": "CHEMICAL", "entities": [ "Tamsulosin", "terazosin", "doxazosin" ], "offsets": [ [ 0, 10 ], [ 154, 163 ], [ 168, 177 ] ] }, { "pmid": "14767264", "text": "It is associated with fewer cardiovascular side effects, although it has some ejaculatory side effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "The nonsubtype selective agent alfuzosin also demonstrates efficacy and offers an enhanced side effect profile, particularly minimizing hypotension.", "type": "CHEMICAL", "entities": [ "alfuzosin" ], "offsets": [ [ 31, 40 ] ] }, { "pmid": "14767264", "text": "Other agents with super selective specificity for the alpha1aAR subtype are under investigation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14767264", "text": "Further advances in the treatment of LUTS associated with BPH may depend not only on receptor subtype selectivity, but also on other pharmacokinetic and pharmacodynamic factors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391485", "text": "Effect of low dose Bisphenol A on the early differentiation of human embryonic stem cells into mammary epithelial cells.\n", "type": "CHEMICAL", "entities": [ "Bisphenol A" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23391485", "text": "It has been previously reported that Bisphenol A (BPA) can disturb the development of mammary structure and increase the risk of breast cancer in experimental animals.", "type": "CHEMICAL", "entities": [ "Bisphenol A", "BPA" ], "offsets": [ [ 37, 48 ], [ 50, 53 ] ] }, { "pmid": "23391485", "text": "In this study, an in vitro model of human embryonic stem cell (hESC) differentiation into mammary epithelial cells was applied to investigate the effect of low dose BPA on the early stages of mammogenesis.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 165, 168 ] ] }, { "pmid": "23391485", "text": "A newly established hESC line was directionally differentiated into mammary epithelial cells by a well-established three-dimensional (3D) culture system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391485", "text": "The differentiated mammary epithelial cells were characterized by immunofluorescence and western blotting assay, and were called induced differentiated mammary epithelial cells (iDMECs) based on these data.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23391485", "text": "The hESCs were treated with low doses of BPA range 10(-9)-10(-6)M during the differentiation process, with DMSO as the solvent control and 17-β-estrodiol (E2) as the estrogen-positive control.", "type": "CHEMICAL", "entities": [ "BPA", "DMSO", "17-β-estrodiol" ], "offsets": [ [ 41, 44 ], [ 107, 111 ], [ 139, 153 ] ] }, { "pmid": "23391485", "text": "Our results showed that low dose BPA and E2 could influence the mammosphere area of iDMECs and upregulate the expression level of Oct4 and Nanog proteins, while only BPA could downregulate the expression of E-cadherin protein.", "type": "CHEMICAL", "entities": [ "BPA", "BPA" ], "offsets": [ [ 165, 168 ], [ 32, 35 ] ] }, { "pmid": "23391485", "text": "Taken together, this study provides some insights into the effects of low dose BPA on the early differentiation stage of mammary epithelial cells and suggests an easier canceration status of iDMECs under the effect of low dose BPA during its early differentiation stage.", "type": "CHEMICAL", "entities": [ "BPA", "BPA" ], "offsets": [ [ 78, 81 ], [ 226, 229 ] ] }, { "pmid": "23473804", "text": "Absence of correlation between oxysterol accumulation in lipid raft microdomains, calcium increase, and apoptosis induction on 158N murine oligodendrocytes.\n", "type": "CHEMICAL", "entities": [ "oxysterol", "calcium" ], "offsets": [ [ 31, 40 ], [ 82, 89 ] ] }, { "pmid": "23473804", "text": "There is some evidence that oxidized derivatives of cholesterol, 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC), are increased in the plasma of patients with neurodegenerative diseases associated with demyelinization of the central nervous system (CNS).", "type": "CHEMICAL", "entities": [ "7βOHC", "cholesterol", "7-ketocholesterol", "7KC", "7β-hydroxycholesterol" ], "offsets": [ [ 116, 121 ], [ 52, 63 ], [ 65, 82 ], [ 84, 87 ], [ 93, 114 ] ] }, { "pmid": "23473804", "text": "It was therefore of interest to investigate the effects of these oxysterols on oligodendrocytes, the myelin-forming cells in the CNS.", "type": "CHEMICAL", "entities": [ "oxysterols" ], "offsets": [ [ 63, 73 ] ] }, { "pmid": "23473804", "text": "To this end, 158N murine oligodendrocytes were treated with 7KC or 7βOHC inducing an apoptotic mode of cell death characterized by condensation/fragmentation of the nuclei, dephosphorylation of Akt and GSK3, mitochondrial depolarization involving Mcl-1, and caspase-3 activation.", "type": "CHEMICAL", "entities": [ "7KC", "7βOHC" ], "offsets": [ [ 58, 61 ], [ 65, 70 ] ] }, { "pmid": "23473804", "text": "In contrast, under treatment with 27-hydroxycholesterol (27OHC), no cell death was observed.", "type": "CHEMICAL", "entities": [ "27-hydroxycholesterol" ], "offsets": [ [ 31, 52 ] ] }, { "pmid": "23473804", "text": "When the cells were stained with Fura-2, no significant Ca(2+) rise was found with the different oxysterols, whereas strong signals were detected with ionomycin used as positive control.", "type": "CHEMICAL", "entities": [ "Fura-2", "Ca(2+)", "oxysterols", "ionomycin" ], "offsets": [ [ 30, 36 ], [ 53, 59 ], [ 94, 104 ], [ 148, 157 ] ] }, { "pmid": "23473804", "text": "At concentrations which induced apoptosis, 7KC but not 7βOHC accumulated in lipid rafts.", "type": "CHEMICAL", "entities": [ "7KC", "7βOHC" ], "offsets": [ [ 40, 43 ], [ 52, 57 ] ] }, { "pmid": "23473804", "text": "Although not cytotoxic, 27OHC was mainly detected in lipid rafts.", "type": "CHEMICAL", "entities": [ "27OHC" ], "offsets": [ [ 20, 25 ] ] }, { "pmid": "23473804", "text": "It is noteworthy that α-tocopherol (but not ellagic acid and resveratrol) was able to counteract 7KC- and 7βOHC-induced apoptosis and to decrease the accumulation of 7KC and 27OHC in lipid rafts.", "type": "CHEMICAL", "entities": [ "α-tocopherol", "ellagic acid", "resveratrol", "7KC", "7βOHC", "7KC", "27OHC" ], "offsets": [ [ 18, 30 ], [ 40, 52 ], [ 57, 68 ], [ 93, 96 ], [ 102, 107 ], [ 162, 165 ], [ 170, 175 ] ] }, { "pmid": "23473804", "text": "Thus, in 158N cells, the ability of oxysterols to trigger a mode of cell death by apoptosis involving GSK-3 and caspase-3 activation is independent of the increase in the Ca(2+) level and of their accumulation in lipid raft microdomains.", "type": "CHEMICAL", "entities": [ "oxysterols", "Ca(2+)" ], "offsets": [ [ 30, 40 ], [ 165, 171 ] ] }, { "pmid": "22991330", "text": "Can peripheral blood γδ T cells predict osteonecrosis of the jaw?", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22991330", "text": "An immunological perspective on the adverse drug effects of aminobisphosphonate therapy.\n", "type": "CHEMICAL", "entities": [ "aminobisphosphonate" ], "offsets": [ [ 58, 77 ] ] }, { "pmid": "22991330", "text": "Nitrogen-bisphosphonates (n-BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility.", "type": "CHEMICAL", "entities": [ "n-BP", "aminobisphosphonates" ], "offsets": [ [ 24, 28 ], [ 52, 72 ] ] }, { "pmid": "22991330", "text": "However, long-term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate-associated osteonecrosis of the jaw (BAONJ).", "type": "CHEMICAL", "entities": [ "bisphosphonate" ], "offsets": [ [ 108, 122 ] ] }, { "pmid": "22991330", "text": "n-BP use is known to unintentionally activate a subset of innate T cells called Vγ9Vδ2 T cells, but the consequence of this chronic immune stimulation has remained unexplored.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22991330", "text": "The primary objectives of this study were to 1) determine the fate of Vγ9Vδ2 T cells in osteoporotic patients on n-BP therapy as a function of time and type of therapy; 2) evaluate the proportion of Vγ9Vδ2 T cells in patients who had recently experienced n-BP-associated ONJ.", "type": "CHEMICAL", "entities": [ "n-BP", "n-BP" ], "offsets": [ [ 109, 113 ], [ 251, 255 ] ] }, { "pmid": "22991330", "text": "We found there is a notable loss of Vγ9Vδ2 T cells over time in osteoporotic patients on n-BP therapy, particularly those on intravenous (iv) therapy (Spearman r = -0.55, p < 0.0001 iv; r = -0.3, p < 0.03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes.", "type": "CHEMICAL", "entities": [ "n-BP" ], "offsets": [ [ 81, 85 ] ] }, { "pmid": "22991330", "text": "Importantly, the observed negative effect on Vγ9Vδ2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22991330", "text": "Patients (n = 6) who had experienced BAONJ were all found to be significantly deficient in Vγ9Vδ2 T cells (median = 0.07%) in comparison to age- and sex-matched treatment-naïve controls (N = 11; median = 2.40%), U = 0, p = 0.001; this was the only consistent difference in the leukocytes assessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22991330", "text": "All BAONJ cases had an underlying condition that further contributed to impaired immunity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22991330", "text": "We propose Vγ9Vδ2 T cells show a strong potential to serve as harbingers of possible adverse immune effects of n-BP therapy, particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ.", "type": "CHEMICAL", "entities": [ "n-BP" ], "offsets": [ [ 52, 56 ] ] }, { "pmid": "15121646", "text": "A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone.\n", "type": "CHEMICAL", "entities": [ "ziprasidone", "dopamine", "serotonin" ], "offsets": [ [ 131, 142 ], [ 15, 23 ], [ 31, 40 ] ] }, { "pmid": "15121646", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15121646", "text": "Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro.", "type": "CHEMICAL", "entities": [ "5-HT", "Ziprasidone", "dopamine", "serotonin" ], "offsets": [ [ 89, 93 ], [ 0, 11 ], [ 121, 129 ], [ 79, 88 ] ] }, { "pmid": "15121646", "text": "The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.", "type": "CHEMICAL", "entities": [ "ziprasidone" ], "offsets": [ [ 16, 27 ] ] }, { "pmid": "15121646", "text": "METHOD:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15121646", "text": "The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range.", "type": "CHEMICAL", "entities": [ "[(11)C]raclopride", "5-HT", "[(18)F]setoperone", "ziprasidone" ], "offsets": [ [ 68, 85 ], [ 91, 95 ], [ 116, 133 ], [ 285, 296 ] ] }, { "pmid": "15121646", "text": "PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15121646", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15121646", "text": "The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively).", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 9, 13 ] ] }, { "pmid": "15121646", "text": "The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy.", "type": "CHEMICAL", "entities": [ "ziprasidone" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "15121646", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15121646", "text": "These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies.", "type": "CHEMICAL", "entities": [ "ziprasidone", "ziprasidone" ], "offsets": [ [ 23, 34 ], [ 199, 210 ] ] }, { "pmid": "15121646", "text": "The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine.", "type": "CHEMICAL", "entities": [ "ziprasidone", "risperidone", "clozapine", "quetiapine" ], "offsets": [ [ 89, 100 ], [ 120, 131 ], [ 185, 194 ], [ 199, 209 ] ] }, { "pmid": "15121646", "text": "Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.", "type": "CHEMICAL", "entities": [ "ziprasidone", "ziprasidone" ], "offsets": [ [ 6, 17 ], [ 289, 300 ] ] }, { "pmid": "12566304", "text": "Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells.\n", "type": "CHEMICAL", "entities": [ "Sulindac sulfide" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "12566304", "text": "Colorectal cancer is the second leading cause of cancer death in the United States.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12566304", "text": "Nonsteroidal anti-inflammatory drugs including sulindac are promising chemopreventive agents for colorectal cancer.", "type": "CHEMICAL", "entities": [ "sulindac" ], "offsets": [ [ 47, 55 ] ] }, { "pmid": "12566304", "text": "Sulindac and selective cyclooxygenase (COX)-2 inhibitors cause regression of colonic polyps in familial polyposis patients.", "type": "CHEMICAL", "entities": [ "Sulindac" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12566304", "text": "Sulindac induces apoptotic cell death in cancer cells in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Sulindac" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12566304", "text": "In tumor cells, activation of extracellular-regulated kinase (ERK) 1/2 results in phosphorylation of several ERK1/2 effectors, including the proapoptotic protein Bad. Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 186, 189 ] ] }, { "pmid": "12566304", "text": "Sulindac metabolites and other nonsteroidal anti-inflammatory drugs selectively inhibit ERK1/2 phosphorylation in human colon cancer cells.", "type": "CHEMICAL", "entities": [ "Sulindac" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12566304", "text": "In this study we show that epidermal growth factor (EGF) strongly induces phosphorylation of ERK1/2 and Bad in HT29 colon cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12566304", "text": "EGF-stimulated phosphorylation of ERK and Bad is blocked by pretreatment with U0126, a selective MAP kinase kinase (MKK)1/2 inhibitor.", "type": "CHEMICAL", "entities": [ "U0126" ], "offsets": [ [ 78, 83 ] ] }, { "pmid": "12566304", "text": "Similarly, pretreatment with sulindac sulfide blocks the ability of EGF to induce ERK1/2 and Bad phosphorylation, but also down-regulates total Bad but not ERK1/2 protein levels.", "type": "CHEMICAL", "entities": [ "sulindac sulfide" ], "offsets": [ [ 29, 45 ] ] }, { "pmid": "12566304", "text": "The ability of sulindac to block ERK1/2 signaling by the EGF receptor may account for at least part of its potent growth-inhibitory effects against cancer cells.", "type": "CHEMICAL", "entities": [ "sulindac" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "23590386", "text": "Fibrillar Morphology of Derivatives of Poly(3-alkylthiophene)s by Solvent Vapor Annealing: Effects of Conformational Transition and Conjugate Length.\n", "type": "CHEMICAL", "entities": [ "Poly(3-alkylthiophene)s" ], "offsets": [ [ 39, 62 ] ] }, { "pmid": "23590386", "text": "A fibrillar morphology was obtained, compared to the featherless pristine films, via solvent annealing the films of a series of derivatives of poly(3-alkylthiophene)s (P3ATs): poly(3-dodecylthiophene) (P3DDT), poly(3,3‴-didodecyl-quaterthiophene) (PQT12), and poly(2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene) (pBTTT12).", "type": "CHEMICAL", "entities": [ "poly(3-alkylthiophene)s", "P3ATs", "poly(3-dodecylthiophene)", "P3DDT", "poly(3,3‴-didodecyl-quaterthiophene)", "PQT12", "poly(2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene)", "pBTTT12" ], "offsets": [ [ 143, 166 ], [ 168, 173 ], [ 176, 200 ], [ 202, 207 ], [ 210, 246 ], [ 248, 253 ], [ 260, 319 ], [ 321, 328 ] ] }, { "pmid": "23590386", "text": "Among the solvents used, including dichloromethane, chloroform, tetrahydrofuran, and carbon disulfide (CS2), CS2 was the best to induce fibril formation because its solubility parameter is closest to those of the P3AT derivatives.", "type": "CHEMICAL", "entities": [ "dichloromethane", "chloroform", "tetrahydrofuran", "carbon disulfide", "CS2", "CS2", "P3AT" ], "offsets": [ [ 33, 48 ], [ 50, 60 ], [ 62, 77 ], [ 83, 99 ], [ 101, 104 ], [ 107, 110 ], [ 211, 215 ] ] }, { "pmid": "23590386", "text": "It was found that higher critical CS2 vapor pressures were needed to form crystal nuclei with increasing conjugation length and molecular weight of the P3AT derivatives; i.e., the critical vapor pressures for P3DDT 13.9k and PQT12 15.5k were 59.0% and 80.7%, respectively, and there were no nuclei of fibrils for pBTTT12 15.6k with the highest conjugation length, even at a CS2 vapor pressure of 98.3%.", "type": "CHEMICAL", "entities": [ "CS2", "P3AT", "P3DDT", "PQT12", "pBTTT12", "CS2" ], "offsets": [ [ 32, 35 ], [ 150, 154 ], [ 207, 212 ], [ 223, 228 ], [ 311, 318 ], [ 372, 375 ] ] }, { "pmid": "23590386", "text": "Meanwhile, at the highest vapor pressure, the fibril density decreased with increasing conjugation length and molecular weight of the P3AT derivatives.", "type": "CHEMICAL", "entities": [ "P3AT" ], "offsets": [ [ 132, 136 ] ] }, { "pmid": "23590386", "text": "This is attributed to the rod-like conformation prevailing for polymers with larger conjugation length and higher molecular weight during solvent annealing, making the conformational transition toward coils more difficult and hindering diffusion of molecules.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590386", "text": "The results presented here are expected to be helpful for the design and processing of conjugated semiconductor polymers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines.\n", "type": "CHEMICAL", "entities": [ "Histamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20573261", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Histamine H4 receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma.", "type": "CHEMICAL", "entities": [ "Histamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20573261", "text": "We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "In addition, effects on Th2 mediated lung dysfunction were also determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Mice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison.", "type": "CHEMICAL", "entities": [ "JNJ 7777120" ], "offsets": [ [ 76, 87 ] ] }, { "pmid": "20573261", "text": "Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20573261", "text": "The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "Research on the preparation of antioxidant peptides derived from egg white with assisting of high-intensity pulsed electric field.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "Egg white protein powder, one of the main egg products, was hydrolysed by Alcalase, Trypsin, and Pepsin respectively to prepare antioxidant peptides.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "All hydrolysates were assayed by determination of reducing power (RP) ability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "Three kinds of hydrolysates were prepared under optimal enzymatic parameters that were obtained from the preliminary one-factor-at-a-time (OFAT) and response surface methodology (RSM) experiments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "The results showed that the Alcalase hydrolysates exerted the best RP ability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "Thereafter, the Alcalase hydrolysates were sequentially fractionated by ultra filtration membranes in cut-off molecular weight (MW) of 30, 10, and 1kDa, and tested their antioxidant activities in terms of RP ability, DPPH radical scavenging ability, ABTS radical scavenging ability, and FRAP assay.", "type": "CHEMICAL", "entities": [ "DPPH", "ABTS" ], "offsets": [ [ 217, 221 ], [ 250, 254 ] ] }, { "pmid": "23561109", "text": "Effects of high intensity pulsed electric field treatment were further investigated on antioxidant peptides to improve their activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "The results showed that Alcalase hydrolysates possessed the strongest antioxidant ability compared with the other two hydrolysates, particularly for the Fraction-3 with MW <1kDa.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23561109", "text": "After PEF treatment, this fraction showed a significant improvement of RP ability within 5h (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17197042", "text": "Development and validation of a non-radioactive DNA polymerase assay for studying cytomegalovirus resistance to foscarnet.\n", "type": "CHEMICAL", "entities": [ "foscarnet" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "17197042", "text": "Phenotypic characterisation of the human cytomegalovirus (HCMV) pUL54 DNA polymerase is a useful tool for testing for mutations in the UL54 gene thought to render HCMV resistant to foscarnet.", "type": "CHEMICAL", "entities": [ "foscarnet" ], "offsets": [ [ 181, 190 ] ] }, { "pmid": "17197042", "text": "In this study, an in-house non-isotopic method for assessing polymerase enzymatic activity in the presence and absence of foscarnet was developed and its utility for HCMV polymerase phenotyping evaluated.", "type": "CHEMICAL", "entities": [ "foscarnet" ], "offsets": [ [ 122, 131 ] ] }, { "pmid": "17197042", "text": "Polymerase activity was assessed by monitoring the incorporation of digoxigenin-labelled nucleotides into the growing DNA chain and foscarnet concentrations inhibiting enzymatic activity by 50% were determined.", "type": "CHEMICAL", "entities": [ "digoxigenin", "foscarnet" ], "offsets": [ [ 68, 79 ], [ 132, 141 ] ] }, { "pmid": "17197042", "text": "HCMV DNA polymerases were synthesised in vitro by expression of UL54 under the control of the T7 promoter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17197042", "text": "Mutations of interest were introduced into the wild-type UL54 gene by site-directed mutagenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17197042", "text": "Mutated polymerases and polymerases from HCMV reference strains were studied.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17197042", "text": "The activity of polymerases containing mutations known to confer resistance to foscarnet (V715M, T700A and N495K) was inhibited by concentrations of foscarnet eight to 14 times higher than those required to inhibit wild-type polymerases.", "type": "CHEMICAL", "entities": [ "foscarnet", "foscarnet" ], "offsets": [ [ 149, 158 ], [ 79, 88 ] ] }, { "pmid": "17197042", "text": "Our in-house non-radioactive phenotypic assay was sensitive and reproducible.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17197042", "text": "It is also easy to perform and could provide a convenient method for characterising mutations conferring resistance to foscarnet in HCMV.", "type": "CHEMICAL", "entities": [ "foscarnet" ], "offsets": [ [ 119, 128 ] ] }, { "pmid": "23291323", "text": "In vitro study of intestinal transport of fluoride using the Caco-2 cell line.\n", "type": "CHEMICAL", "entities": [ "fluoride" ], "offsets": [ [ 42, 50 ] ] }, { "pmid": "23291323", "text": "Water and food are the main sources of fluoride exposure and therefore it is necessary to study intestinal absorption in order to make a correct evaluation of the risk/benefit associated with exposure to fluoride.", "type": "CHEMICAL", "entities": [ "fluoride", "fluoride" ], "offsets": [ [ 204, 212 ], [ 39, 47 ] ] }, { "pmid": "23291323", "text": "The present study characterizes intestinal transport of fluoride, using the Caco-2 cell line as a model of the intestinal epithelium, and evaluates the coefficients of apparent permeability and intracellular accumulation in various conditions (pH, temperature, opening of cell junctions, presence of anions).", "type": "CHEMICAL", "entities": [ "fluoride" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "23291323", "text": "The results indicate that fluoride is an element with moderate absorption (<70%) in both directions (absorptive and secretory).", "type": "CHEMICAL", "entities": [ "fluoride" ], "offsets": [ [ 26, 34 ] ] }, { "pmid": "23291323", "text": "Both in absorption (apical-basolateral) and in secretion (basolateral-apical) there is transport by the paracellular pathway, which may be considered predominant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291323", "text": "Absorption and secretion of fluoride increase at acid pH levels, possibly because of its non-ionized state at these pHs", "type": "CHEMICAL", "entities": [ "fluoride" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "23291323", "text": "and/or because of participation of a F(-)/H(+) cotransporter or a F(-)/OH(-) antiporter.", "type": "CHEMICAL", "entities": [ "F(-)", "OH(-)", "F(-)", "H(+)" ], "offsets": [ [ 66, 70 ], [ 71, 76 ], [ 37, 41 ], [ 42, 46 ] ] }, { "pmid": "23291323", "text": "The results also suggest transcellular participation of mechanisms involved in transport of Cl(-) and of an active transport in the secretory direction.", "type": "CHEMICAL", "entities": [ "Cl(-)" ], "offsets": [ [ 92, 97 ] ] }, { "pmid": "23291323", "text": "The present study extend the knowledge on the cellular transport of fluoride and provide the basis for future studies aimed at identifying potential transporters involved in human fluoride absorption.", "type": "CHEMICAL", "entities": [ "fluoride", "fluoride" ], "offsets": [ [ 68, 76 ], [ 180, 188 ] ] }, { "pmid": "23265892", "text": "Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase", "type": "CHEMICAL", "entities": [ "tricyclic bispyran sulfone" ], "offsets": [ [ 43, 69 ] ] }, { "pmid": "23265892", "text": "inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265892", "text": "An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "SCH 900229", "sulfone" ], "offsets": [ [ 121, 131 ], [ 81, 88 ] ] }, { "pmid": "23265892", "text": "Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a.", "type": "CHEMICAL", "entities": [ "4-CF(3)", "4-Br", "arylsulfone" ], "offsets": [ [ 12, 19 ], [ 24, 28 ], [ 41, 52 ] ] }, { "pmid": "23265892", "text": "On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.", "type": "CHEMICAL", "entities": [ "sulfone" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "12388748", "text": "Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12388748", "text": "Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia.", "type": "CHEMICAL", "entities": [ "alcoholic", "nonalcoholic" ], "offsets": [ [ 135, 144 ], [ 160, 172 ] ] }, { "pmid": "12388748", "text": "Mice fed long term with griseofulvin are an animal model of MB formation.", "type": "CHEMICAL", "entities": [ "griseofulvin" ], "offsets": [ [ 24, 36 ] ] }, { "pmid": "12388748", "text": "However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12388748", "text": "Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA.", "type": "CHEMICAL", "entities": [ "griseofulvin" ], "offsets": [ [ 28, 40 ] ] }, { "pmid": "12388748", "text": "Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death.", "type": "CHEMICAL", "entities": [ "rhodamine B" ], "offsets": [ [ 159, 170 ] ] }, { "pmid": "12388748", "text": "The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12388748", "text": "Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12388748", "text": "In contrast, an NH(2)-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression.", "type": "CHEMICAL", "entities": [ "NH(2)" ], "offsets": [ [ 16, 21 ] ] }, { "pmid": "12388748", "text": "Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580316", "text": "Anti-Ulcerative Colitis Activity of Compounds from Euphorbia granuleta Forssk.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580316", "text": "The aim of the present study was to evaluate the anti-ulcerative colitis (UC) activity of the total alcohol extracts of Euphorbia granuleta Forssk.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "23580316", "text": "(Euphorpiaceae), isolate and identify the active compounds that could be responsible for the activity, in addition to determination of the possible mechanism of action.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580316", "text": "Six compounds were isolated and identified from this plant: three phenolic compounds (kampferol, kampferol-3-glucoside and kampferol-3-galactoside) in addition to three steroidal compounds (1-ethoxypentacosane, heptacosan-1-ol and β-sitosterol).", "type": "CHEMICAL", "entities": [ "phenolic", "kampferol", "kampferol-3-glucoside", "kampferol-3-galactoside", "1-ethoxypentacosane", "heptacosan-1-ol", "β-sitosterol" ], "offsets": [ [ 66, 74 ], [ 86, 95 ], [ 97, 118 ], [ 123, 146 ], [ 190, 209 ], [ 211, 226 ], [ 231, 243 ] ] }, { "pmid": "23580316", "text": "Three compounds (heptacosan-1-ol, β-sitosterol and kampferol-3-galactoside) were found to be responsible for the anti-UC activity of E. granuleta extract.", "type": "CHEMICAL", "entities": [ "heptacosan-1-ol", "β-sitosterol", "kampferol-3-galactoside" ], "offsets": [ [ 16, 31 ], [ 33, 45 ], [ 50, 73 ] ] }, { "pmid": "23580316", "text": "The anti-UC activity of these compounds may be explained by reducing the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), in addition to reduction of colonic malondialdehyde (MDA) contents.", "type": "CHEMICAL", "entities": [ "malondialdehyde", "MDA" ], "offsets": [ [ 170, 185 ], [ 187, 190 ] ] }, { "pmid": "23580316", "text": "No side effects were reported on liver and kidney functions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580316", "text": "The active compounds reduced both serum TNF-α and mucosal MDA levels.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 55, 58 ] ] }, { "pmid": "23580316", "text": "Copyright ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580316", "text": " 2013 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12398910", "text": "MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities.\n", "type": "CHEMICAL", "entities": [ "MDMA", "p-chlorophenylalanine", "5-HT", "serotonin" ], "offsets": [ [ 0, 4 ], [ 10, 31 ], [ 53, 57 ], [ 85, 94 ] ] }, { "pmid": "12398910", "text": "Low levels of serotonin may reduce the density of the serotonin transporter (SERT) by either increasing trafficking or reducing synthesis; a \"neuroadaptive response\".", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin" ], "offsets": [ [ 14, 23 ], [ 54, 63 ] ] }, { "pmid": "12398910", "text": "To determine whether 3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in SERT density could be related to such a mechanism, p-chlorophenylalanine or MDMA was administered to rats, and brain serotonin and SERT density were measured.", "type": "CHEMICAL", "entities": [ "3,4-methylenedioxymethamphetamine", "MDMA", "p-chlorophenylalanine", "MDMA", "serotonin" ], "offsets": [ [ 21, 54 ], [ 56, 60 ], [ 135, 156 ], [ 160, 164 ], [ 201, 210 ] ] }, { "pmid": "12398910", "text": "As expected, both treatments led to serotonin depletion 1, 7 and 14 days later.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "12398910", "text": "However, only MDMA reduced SERT density.", "type": "CHEMICAL", "entities": [ "MDMA" ], "offsets": [ [ 14, 18 ] ] }, { "pmid": "12398910", "text": "This observation suggests that MDMA-induced reductions in SERT density do not represent neuroadaptive responses to decreased levels of brain serotonin, but may occur in response to some other stimulus or to the neurotoxic effects of MDMA.", "type": "CHEMICAL", "entities": [ "MDMA", "serotonin", "MDMA" ], "offsets": [ [ 31, 35 ], [ 141, 150 ], [ 233, 237 ] ] }, { "pmid": "23250811", "text": "Curcumin improves TNBS-induced colitis in rats by inhibiting IL-27 expression via the TLR4/NF-κB signaling pathway.\n", "type": "CHEMICAL", "entities": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23250811", "text": "Curcumin is a widely used spice with anti-inflammatory and anticancer properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23250811", "text": "It has been reported to have beneficial effects in experimental colitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23250811", "text": "This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 27, 35 ] ] }, { "pmid": "23250811", "text": "After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week.", "type": "CHEMICAL", "entities": [ "2,4,6-trinitrobenzene sulfonic acid", "curcumin", "sulfasalazine" ], "offsets": [ [ 30, 65 ], [ 112, 120 ], [ 124, 137 ] ] }, { "pmid": "23250811", "text": "Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23250811", "text": "Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23250811", "text": "Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05).", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 44, 52 ] ] }, { "pmid": "23250811", "text": "TLR4 mRNA expression did not differ between groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23250811", "text": "Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05).", "type": "CHEMICAL", "entities": [ "curcumin", "sulfasalazine" ], "offsets": [ [ 48, 56 ], [ 83, 96 ] ] }, { "pmid": "23250811", "text": "There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups.", "type": "CHEMICAL", "entities": [ "curcumin", "sulfasalazine" ], "offsets": [ [ 83, 91 ], [ 104, 117 ] ] }, { "pmid": "23250811", "text": "Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine.", "type": "CHEMICAL", "entities": [ "2,4,6-trinitrobenzene sulfonic acid", "sulfasalazine" ], "offsets": [ [ 44, 79 ], [ 119, 132 ] ] }, { "pmid": "23250811", "text": "The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 27, 35 ] ] }, { "pmid": "16916952", "text": "Bovine and ovine gonadotropin-releasing hormone (GnRH)-II ligand precursors and type II GnRH receptor genes are functionally inactivated.\n", "type": "CHEMICAL", "entities": [ "gonadotropin-releasing hormone", "(GnRH)-II" ], "offsets": [ [ 17, 47 ], [ 48, 57 ] ] }, { "pmid": "16916952", "text": "The decapeptide sequence of GnRH-II is conserved in all jawed vertebrate species studied to date.", "type": "CHEMICAL", "entities": [ "GnRH-II" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "16916952", "text": "New data for cattle (Bos taurus) indicates a gene encoding GnRH-II decapeptide possessing arginine (codon: CGG) rather than tryptophan (TGG) at position three in the mature peptide.", "type": "CHEMICAL", "entities": [ "GnRH-II", "arginine", "CGG", "tryptophan", "TGG" ], "offsets": [ [ 59, 66 ], [ 90, 98 ], [ 107, 110 ], [ 124, 134 ], [ 136, 139 ] ] }, { "pmid": "16916952", "text": "This substitution is unique.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16916952", "text": "We confirmed the DNA sequence after cloning part of the bovine prepro-GnRH-II gene.", "type": "CHEMICAL", "entities": [ "GnRH-II" ], "offsets": [ [ 70, 77 ] ] }, { "pmid": "16916952", "text": "Bovine GnRH-II peptide was synthesized and pharmacologically characterized.", "type": "CHEMICAL", "entities": [ "GnRH-II" ], "offsets": [ [ 7, 14 ] ] }, { "pmid": "16916952", "text": "It did not bind to mammalian GnRH receptors expressed in different types of cell nor did it exhibit agonist or antagonist properties on types I or II GnRH receptors expressed in COS-7 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16916952", "text": "Bovine primers facilitated cloning of ovine GnRH-II DNA.", "type": "CHEMICAL", "entities": [ "GnRH-II" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "16916952", "text": "A premature stop codon (TGA) replaces the expected tryptophan codon at position seven of GnRH-II in sheep DNA.", "type": "CHEMICAL", "entities": [ "tryptophan", "GnRH-II" ], "offsets": [ [ 51, 61 ], [ 89, 96 ] ] }, { "pmid": "16916952", "text": "Thus, both species possess prepro-GnRH-II genes encoding inactive peptides, as previously described for chimpanzee GnRH-II.", "type": "CHEMICAL", "entities": [ "GnRH-II", "GnRH-II" ], "offsets": [ [ 34, 41 ], [ 115, 122 ] ] }, { "pmid": "16916952", "text": "The updated bovine type II GnRH receptor gene sequence revealed inactivation by frame shifts, premature stop codons, and nucleotide changes specifying nonconservative replacement of amino acid residues, similar to inactivation of sheep type II GnRH receptor.", "type": "CHEMICAL", "entities": [ "nucleotide", "amino acid" ], "offsets": [ [ 121, 131 ], [ 182, 192 ] ] }, { "pmid": "16916952", "text": "Spliced RNA transcripts from the disrupted receptor gene were not detected in bovine pituitary.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16916952", "text": "In contrast, bovine prepro-GnRH-I and type I GnRH receptor genes are intact, encoding well-conserved protein sequences.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16916952", "text": "These findings, and previous descriptions of inactivation of the human type II GnRH receptor and deletions of prepro-GnRH-II and type II GnRH receptor in laboratory rodents, suggest the GnRH-II system has been replaced by the GnRH-I system or is redundant in certain mammals.", "type": "CHEMICAL", "entities": [ "GnRH-II", "GnRH-II" ], "offsets": [ [ 117, 124 ], [ 186, 193 ] ] }, { "pmid": "12761285", "text": "Biosynthetic regulation and intracellular transport of phosphatidylserine in mammalian cells.\n", "type": "CHEMICAL", "entities": [ "phosphatidylserine" ], "offsets": [ [ 55, 73 ] ] }, { "pmid": "12761285", "text": "In mammalian cells, phosphatidylserine (PtdSer) is synthesized through the action of the endoplasmic reticulum enzymes, PtdSer synthase 1 and 2, and the decarboxylation of PtdSer accounts for the majority of phosphatidylethanolamine (PtdEtn) synthesis.", "type": "CHEMICAL", "entities": [ "PtdSer", "phosphatidylserine", "phosphatidylethanolamine", "PtdEtn", "PtdSer" ], "offsets": [ [ 120, 126 ], [ 20, 38 ], [ 208, 232 ], [ 234, 240 ], [ 40, 46 ] ] }, { "pmid": "12761285", "text": "PtdSer decarboxylation for PtdEtn formation occurs in the mitochondria.", "type": "CHEMICAL", "entities": [ "PtdSer", "PtdEtn" ], "offsets": [ [ 0, 6 ], [ 27, 33 ] ] }, { "pmid": "12761285", "text": "In addition, the transport of PtdSer from the endoplasmic reticulum to the mitochondria is probably a rate limiting step for PtdEtn synthesis through the decarboxylation pathway.", "type": "CHEMICAL", "entities": [ "PtdSer", "PtdEtn" ], "offsets": [ [ 30, 36 ], [ 125, 131 ] ] }, { "pmid": "12761285", "text": "Therefore, the regulation of PtdSer synthesis and its intracellular transport appear to be essential events for the maintenance of normal cellular PtdSer and PtdEtn levels.", "type": "CHEMICAL", "entities": [ "PtdSer", "PtdSer", "PtdEtn" ], "offsets": [ [ 29, 35 ], [ 147, 153 ], [ 158, 164 ] ] }, { "pmid": "12761285", "text": "Here we describe the current understanding of the regulation of PtdSer biosynthesis and the transport of PtdSer from the ER to the mitochondria in mammalian cells.", "type": "CHEMICAL", "entities": [ "PtdSer", "PtdSer" ], "offsets": [ [ 64, 70 ], [ 105, 111 ] ] }, { "pmid": "15931605", "text": "Use of nitisinone in patients with alkaptonuria.\n", "type": "CHEMICAL", "entities": [ "nitisinone" ], "offsets": [ [ 7, 17 ] ] }, { "pmid": "15931605", "text": "Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA).", "type": "CHEMICAL", "entities": [ "homogentisate", "homogentisic acid", "HGA" ], "offsets": [ [ 104, 117 ], [ 220, 237 ], [ 239, 242 ] ] }, { "pmid": "15931605", "text": "Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria.", "type": "CHEMICAL", "entities": [ "4-hydroxyphenylpyruvate", "HGA" ], "offsets": [ [ 39, 62 ], [ 120, 123 ] ] }, { "pmid": "15931605", "text": "We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months.", "type": "CHEMICAL", "entities": [ "HGA", "nitisinone" ], "offsets": [ [ 35, 38 ], [ 61, 71 ] ] }, { "pmid": "15931605", "text": "Each patient received nitisinone in incremental doses, 0.35", "type": "CHEMICAL", "entities": [ "nitisinone" ], "offsets": [ [ 22, 32 ] ] }, { "pmid": "15931605", "text": "mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15931605", "text": "Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001).", "type": "CHEMICAL", "entities": [ "Nitisinone", "HGA" ], "offsets": [ [ 0, 10 ], [ 27, 30 ] ] }, { "pmid": "15931605", "text": "The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001).", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 19, 27 ] ] }, { "pmid": "15931605", "text": "During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints.", "type": "CHEMICAL", "entities": [ "tyrosine", "nitisinone" ], "offsets": [ [ 118, 126 ], [ 215, 225 ] ] }, { "pmid": "15931605", "text": "Weekly ophthalmologic examinations showed no signs of corneal toxicity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15931605", "text": "Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15931605", "text": "We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria.", "type": "CHEMICAL", "entities": [ "nitisinone", "HGA" ], "offsets": [ [ 26, 36 ], [ 65, 68 ] ] }, { "pmid": "15931605", "text": "Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.", "type": "CHEMICAL", "entities": [ "nitisinone" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "17418819", "text": "Functional and molecular characterization of multiple K-Cl cotransporter isoforms in corneal epithelial cells.\n", "type": "CHEMICAL", "entities": [ "K-Cl" ], "offsets": [ [ 54, 58 ] ] }, { "pmid": "17418819", "text": "The dependence of regulatory volume decrease (RVD) activity on potassium-chloride cotransporter (KCC) isoform expression was characterized in corneal epithelial cells (CEC).", "type": "CHEMICAL", "entities": [ "potassium-chloride" ], "offsets": [ [ 63, 81 ] ] }, { "pmid": "17418819", "text": "During exposure to a 50% hypotonic challenge, the RVD response was larger in SV40-immortalized human CEC (HCEC) than in SV40-immortalized rabbit CEC (RCEC).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "A KCC inhibitor-[(dihydroindenyl)oxy] alkanoic acid (DIOA)-blocked RVD more in HCEC than RCEC.", "type": "CHEMICAL", "entities": [ "[(dihydroindenyl)oxy] alkanoic acid", "DIOA" ], "offsets": [ [ 16, 51 ], [ 53, 57 ] ] }, { "pmid": "17418819", "text": "Under isotonic conditions, N-ethylmaleimide (NEM) produced KCC activation and transient cell shrinkage.", "type": "CHEMICAL", "entities": [ "N-ethylmaleimide", "NEM" ], "offsets": [ [ 27, 43 ], [ 45, 48 ] ] }, { "pmid": "17418819", "text": "Both of these changes were greater in HCEC than in RCEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "Immunoblot analysis of HCEC, RCEC, primary human CEC (pHCEC), and primary bovine CEC (BCEC) plasma membrane enriched fractions revealed KCC1, KCC3, and KCC4 isoform expression, whereas KCC2 was undetectable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "During a hypotonic challenge, KCC1 membrane content increased more rapidly in HCEC than in RCEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "Such a challenge induced a larger increase and more transient p44/42MAPK activation in HCEC than RCEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "On the other hand, HCEC and RCEC p38MAPK phosphorylation reached peak activations at 2.5 and 15 min, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "Only in HCEC, pharmacological manipulation of KCC activity modified the hypotonicity-induced activation of p44/42MAPK, whereas p38MAPK phosphorylation was insensitive to such procedures in both cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "Larger increases in HCEC KCC1 membrane protein content correlated with their ability to undergo faster and more complete RVD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "Furthermore, pharmacological activation of KCC increased p44/42MAPK phosphorylation in HCEC but not in RCEC, presumably a reflection of low KCC1 membrane expression in RCEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17418819", "text": "These findings suggest that KCC1 plays a role in (i) maintaining isotonic steady-state cell volume homeostasis, (ii) recovery of isotonic cell volume after a hypotonic challenge through RVD, and (iii) regulating hypotonicity-induced activation of the p44/42MAPK signaling pathway required for cell proliferation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435358", "text": "Changes in morphometry and association between whole-body fatty acids and steroid hormone profiles in relation to bioaccumulation patterns in salmon larvae exposed to perfluorooctane sulfonic or perfluorooctane carboxylic acids.\n", "type": "CHEMICAL", "entities": [ "perfluorooctane sulfonic or perfluorooctane carboxylic acids", "fatty acids", "steroid" ], "offsets": [ [ 167, 227 ], [ 58, 69 ], [ 74, 81 ] ] }, { "pmid": "23435358", "text": "In the present study, we have used salmon embryos whose continuous exposure to waterborne PFOA or PFOS at 100 μg/L started as freshly fertilized eggs, and lasted for a total of 52 days.", "type": "CHEMICAL", "entities": [ "PFOA", "PFOS" ], "offsets": [ [ 90, 94 ], [ 98, 102 ] ] }, { "pmid": "23435358", "text": "PFOS and PFOA were dissolved in methanol (carrier vehicle) whose concentration never exceeded 0.01% of total tank volume.", "type": "CHEMICAL", "entities": [ "PFOA", "methanol" ], "offsets": [ [ 8, 12 ], [ 31, 39 ] ] }, { "pmid": "23435358", "text": "Samples were collected at day 21, 28, 35, 52, 49 and 56 after the start of the exposure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435358", "text": "Note that days 49 and 56 represent end of exposure and 1 week after a recovery period, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435358", "text": "Tissue bioaccumulations were determined by HPLC/MS/MS, steroid hormones, fatty acids (FAs) and lipids were determined by GC-MS, while mRNA expression levels of genes were determined by qPCR in whole body homogenate.", "type": "CHEMICAL", "entities": [ "steroid", "fatty acids", "FAs" ], "offsets": [ [ 54, 61 ], [ 72, 83 ], [ 85, 88 ] ] }, { "pmid": "23435358", "text": "We observed that PFOS and PFOA showed a steady increase in whole body burden during the exposure period, with a slight decrease after the recovery period.", "type": "CHEMICAL", "entities": [ "PFOS", "PFOA" ], "offsets": [ [ 16, 20 ], [ 25, 29 ] ] }, { "pmid": "23435358", "text": "Calculated somatic indexes showed that PFOA produced increases in heart-, thymus-, liver- and kidney somatic indexes (HSI, TSI, LSI and KSI).", "type": "CHEMICAL", "entities": [ "PFOA" ], "offsets": [ [ 38, 42 ] ] }, { "pmid": "23435358", "text": "PFOA and PFOS exposure produced significant decreases in whole body dehydroepiandrosterone (DHEA), estrone and testosterone at sampling day 21 and a strong increase of cortisol and cholesterol at the end of recovery period (day 56).", "type": "CHEMICAL", "entities": [ "PFOS", "dehydroepiandrosterone", "DHEA", "testosterone", "cortisol", "cholesterol" ], "offsets": [ [ 8, 12 ], [ 67, 89 ], [ 91, 95 ], [ 110, 122 ], [ 167, 175 ], [ 180, 191 ] ] }, { "pmid": "23435358", "text": "PFOA and PFOS effects differed with DHEA and estrone.", "type": "CHEMICAL", "entities": [ "PFOS", "DHEA", "estrone" ], "offsets": [ [ 8, 12 ], [ 35, 39 ], [ 44, 51 ] ] }, { "pmid": "23435358", "text": "While PFOS decreased DHEA levels, PFOA produced an increase at day 49, and while PFOS decreased estrone, PFOA produced a slight increase at day 56.", "type": "CHEMICAL", "entities": [ "PFOS", "DHEA", "PFOA", "PFOS", "estrone", "PFOA" ], "offsets": [ [ 5, 9 ], [ 20, 24 ], [ 33, 37 ], [ 80, 84 ], [ 95, 102 ], [ 104, 108 ] ] }, { "pmid": "23435358", "text": "We observed changes in FA composition that predominantly involved increases in FA methyl esters (FAMEs), mono- and poly-unsaturated FA (MUFA and PUFA) and a decrease in n-3/n-6 PUFA ratio by both PFOA and PFOS.", "type": "CHEMICAL", "entities": [ "FA methyl esters", "FAMEs", "mono- and poly-unsaturated FA", "MUFA", "PUFA", "PUFA", "PFOA", "PFOS" ], "offsets": [ [ 78, 94 ], [ 96, 101 ], [ 104, 133 ], [ 135, 139 ], [ 144, 148 ], [ 176, 180 ], [ 195, 199 ], [ 204, 208 ] ] }, { "pmid": "23435358", "text": "Particularly, an increase in - pentadecenoic MUFA (15:1), two n-3 PUFAs α-linolenic acid", "type": "CHEMICAL", "entities": [ "pentadecenoic MUFA", "PUFAs", "α-linolenic acid" ], "offsets": [ [ 30, 48 ], [ 65, 70 ], [ 71, 87 ] ] }, { "pmid": "23435358", "text": "[ALA: 18:3 n3] and eicosapentaenoic acid", "type": "CHEMICAL", "entities": [ "eicosapentaenoic acid" ], "offsets": [ [ 17, 38 ] ] }, { "pmid": "23435358", "text": "[EPA: 20:5 n-3] and n-6 PUFA: arachidonic acid", "type": "CHEMICAL", "entities": [ "PUFA", "arachidonic acid" ], "offsets": [ [ 22, 26 ], [ 28, 44 ] ] }, { "pmid": "23435358", "text": "[ARA: 20:4 n6], docosapentaenoic acid (DPA) by PFOA and PFOS were observed.", "type": "CHEMICAL", "entities": [ "docosapentaenoic acid", "DPA", "PFOA", "PFOS" ], "offsets": [ [ 14, 35 ], [ 37, 40 ], [ 45, 49 ], [ 54, 58 ] ] }, { "pmid": "23435358", "text": "These effects were associated with changes in mRNA expression of FA elongase (FAE), Δ5-desaturase (FAD5) and Δ6-desaturase (FAD6) genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435358", "text": "In summary, the changes in hormonal and FA profiles may represent cellular and/or physiological adaptation to continuous PFOS and PFOA exposure by increasing membrane fluidity, and/or overt developmental effects.", "type": "CHEMICAL", "entities": [ "PFOS", "PFOA" ], "offsets": [ [ 117, 121 ], [ 126, 130 ] ] }, { "pmid": "23435358", "text": "The present findings provide some potential insights and basis for a better understanding on the possible mechanisms of PFCs toxicity in fish.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Drugs in Development for Relapsing Multiple Sclerosis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market?", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Are they safer or better tolerated?", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Do they offer any practical advantages over current treatments?", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route.", "type": "CHEMICAL", "entities": [ "Fingolimod" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23609782", "text": "However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Other monoclonal antibodies are in various phases of development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Its once-yearly administration, however, seems particularly advantageous.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "There are new oral drugs in development, and it is likely that BG-12 will be licensed this year.", "type": "CHEMICAL", "entities": [ "BG-12" ], "offsets": [ [ 62, 67 ] ] }, { "pmid": "23609782", "text": "This has been licensed for psoriasis so there are good safety data in humans that may also hold true in MS; however, its three times daily dosage will probably impact on patient compliance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "Laquinimod has lower efficacy than BG-12 but appears safe and could find a place as a first-line agent.", "type": "CHEMICAL", "entities": [ "BG-12" ], "offsets": [ [ 34, 39 ] ] }, { "pmid": "23609782", "text": "Teriflunomide has just been licensed by the US FDA and may challenge the current injectable first-line therapies as it has a similar efficacy but the advantage of being taken orally.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "However, risk of teratogenicity may caution against its use in some women of child-bearing potential.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609782", "text": "This review will examine drugs that have been recently approved as well as those that are in late phase 2 or 3 development as treatment for relapsing MS, highlighting their mechanism of action as well as the clinical trial and safety data before discussing their potential for success in an increasingly florid and complex DMT armamentarium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288049", "text": "Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background.\n", "type": "CHEMICAL", "entities": [ "BDE-49" ], "offsets": [ [ 32, 38 ] ] }, { "pmid": "23288049", "text": "Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years.", "type": "CHEMICAL", "entities": [ "Polybrominated diphenyl ethers", "PBDEs" ], "offsets": [ [ 0, 30 ], [ 32, 37 ] ] }, { "pmid": "23288049", "text": "PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms.", "type": "CHEMICAL", "entities": [ "PBDEs" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23288049", "text": "Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and", "type": "CHEMICAL", "entities": [ "PBDEs", "Br", "2,2',4,4'-tetrabromodiphenyl ether", "BDE-47" ], "offsets": [ [ 10, 15 ], [ 25, 27 ], [ 49, 83 ], [ 85, 91 ] ] }, { "pmid": "23288049", "text": "2,2',4,5'-tetrabromodiphenyl ether", "type": "CHEMICAL", "entities": [ "2,2',4,5'-tetrabromodiphenyl ether" ], "offsets": [ [ 0, 34 ] ] }, { "pmid": "23288049", "text": "[BDE-49]) have gained interest because of their high bioaccumulation.", "type": "CHEMICAL", "entities": [ "BDE-49" ], "offsets": [ [ 1, 7 ] ] }, { "pmid": "23288049", "text": "In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown.", "type": "CHEMICAL", "entities": [ "BDE-49", "BDE-47" ], "offsets": [ [ 33, 39 ], [ 146, 152 ] ] }, { "pmid": "23288049", "text": "To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC).", "type": "CHEMICAL", "entities": [ "BDE-49" ], "offsets": [ [ 27, 33 ] ] }, { "pmid": "23288049", "text": "BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50)", "type": "CHEMICAL", "entities": [ "BDE-49" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23288049", "text": "= 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288049", "text": "These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes.", "type": "CHEMICAL", "entities": [ "BDE-49", "PBDEs" ], "offsets": [ [ 83, 89 ], [ 123, 128 ] ] }, { "pmid": "23288049", "text": "Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23288049", "text": "PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.", "type": "CHEMICAL", "entities": [ "PBDE" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "3440035", "text": "Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists.\n", "type": "CHEMICAL", "entities": [ "lorglumide" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "3440035", "text": "Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists.", "type": "CHEMICAL", "entities": [ "5-(dipentylamino)-5-oxo-pentanoic acid" ], "offsets": [ [ 15, 53 ] ] }, { "pmid": "3440035", "text": "The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini.", "type": "CHEMICAL", "entities": [ "D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid", "lorglumide", "CR 1409" ], "offsets": [ [ 26, 98 ], [ 100, 110 ], [ 112, 119 ] ] }, { "pmid": "3440035", "text": "In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein).", "type": "CHEMICAL", "entities": [ "lorglumide", "ceruletide", "caerulein" ], "offsets": [ [ 8, 18 ], [ 126, 136 ], [ 138, 147 ] ] }, { "pmid": "3440035", "text": "It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis.", "type": "CHEMICAL", "entities": [ "ceruletide", "taurocholate" ], "offsets": [ [ 80, 90 ], [ 93, 105 ] ] }, { "pmid": "3440035", "text": "Lorglumide is therefore a useful pharmacological tool to study the functions of CCK.", "type": "CHEMICAL", "entities": [ "Lorglumide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "3440035", "text": "For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.", "type": "CHEMICAL", "entities": [ "lorglumide" ], "offsets": [ [ 121, 131 ] ] }, { "pmid": "23495205", "text": "Synthesis and Structure-Activity Relationship Studies of Derivatives of the Dual Aromatase-Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate.\n", "type": "CHEMICAL", "entities": [ "4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate" ], "offsets": [ [ 111, 182 ] ] }, { "pmid": "23495205", "text": "4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs).", "type": "CHEMICAL", "entities": [ "4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate", "Cl", "Br", "F" ], "offsets": [ [ 0, 71 ], [ 102, 104 ], [ 106, 108 ], [ 99, 100 ] ] }, { "pmid": "23495205", "text": "Structure-activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group.", "type": "CHEMICAL", "entities": [ "halogen", "halogen", "halogen", "methylene", "difluoromethylene", "para-cyanophenyl", "triazolyl", "imidazolyl" ], "offsets": [ [ 159, 166 ], [ 194, 201 ], [ 228, 235 ], [ 275, 284 ], [ 299, 316 ], [ 344, 360 ], [ 417, 426 ], [ 441, 451 ] ] }, { "pmid": "23495205", "text": "The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nM, respectively.", "type": "CHEMICAL", "entities": [ "imidazole", "steroid" ], "offsets": [ [ 47, 56 ], [ 107, 114 ] ] }, { "pmid": "23495205", "text": "The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay.", "type": "CHEMICAL", "entities": [ "phenol" ], "offsets": [ [ 7, 13 ] ] }, { "pmid": "23438471", "text": "The circadian clock circuitry and the AHR signaling pathway in physiology and pathology.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "Life forms populating the Earth must face environmental challenges to assure individual and species survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "The strategies predisposed to maintain organismal homeostasis and grant selective advantage rely on anticipatory phenomena facing periodic modifications, and compensatory phenomena facing unpredictable changes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "Biological processes bringing about these responses are respectively driven by the circadian timing system, a complex of biological oscillators entrained to the environmental light/dark cycle, and by regulatory and metabolic networks that precisely direct the body's adjustments to variations of external conditions and internal milieu.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "A critical role in organismal homeostatic functions is played by the aryl hydrocarbon receptor (AHR) complex, which senses environmental and endogenous compounds, influences metabolic responses controlling phase I/II gene expression, and modulates vital phenomena such as development, inflammation and adaptive immunity.", "type": "CHEMICAL", "entities": [ "aryl hydrocarbon" ], "offsets": [ [ 69, 85 ] ] }, { "pmid": "23438471", "text": "A physiological cross-talk between circadian and AHR signaling pathways has been evidenced.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "The alteration of AHR signaling pathway deriving from genetic damage with polymorphisms or mutations, or produced by exogenous or endogenous AHR activation, and chronodisruption caused by mismatch between the body's internal clock and geophysical time/social schedules, are capable of triggering pathological mechanisms involved in metabolic, immune-related and neoplastic diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23438471", "text": "On the other hand, the molecular components of the circadian clock circuitry and AHR signaling pathway may represent useful tools for preventive interventions and valuable targets of therapeutic approaches.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127600", "text": "Protective effect of cinnamon polyphenols against STZ-diabetic mice fed high-sugar, high-fat diet and its underlying mechanism.\n", "type": "CHEMICAL", "entities": [ "polyphenols", "STZ" ], "offsets": [ [ 30, 41 ], [ 50, 53 ] ] }, { "pmid": "23127600", "text": "This study was designed to investigate the potential effects of 14days' intragastrically given of cinnamon polyphenols (CPS) in treating diabetic mice induced by intraperitoneal injection of streptozotocin (150mgkg(-1)) and fed high-sugar, high-fat diet.", "type": "CHEMICAL", "entities": [ "polyphenols", "streptozotocin", "sugar" ], "offsets": [ [ 107, 118 ], [ 191, 205 ], [ 233, 238 ] ] }, { "pmid": "23127600", "text": "The diabetic mice model was successfully established through determining on fasting blood-glucose (FBG) test.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 90, 97 ] ] }, { "pmid": "23127600", "text": "As revealed by glucose oxidase (GOD) and radioimmunoassay (RIA), both dimethyldiguanide (DC, 0.6gkg(-1)d(-1)) and CPS (0.3, 0.6, 1.2gkg(-1)d(-1)) treatments significantly resulted in down-regulation of blood glucose and insulin levels in serum, while the levels of oxidative stress markers were markedly lowered through ELISA assay.", "type": "CHEMICAL", "entities": [ "glucose", "dimethyldiguanide", "glucose" ], "offsets": [ [ 15, 22 ], [ 70, 87 ], [ 208, 215 ] ] }, { "pmid": "23127600", "text": "Meanwhile, the pathological damage in islet with pancreatic beta cells was ameliorated by treatment of CPS at different doses, as shown in HE stain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127600", "text": "At the same time, the treatments also caused notable reduction of iNOS, NF-κB expressions showing in Western blot analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23127600", "text": "These findings demonstrate that cinnamon polyphenols can exert the hypoglycemic and hypolipidemic effects through the mechanisms that may be associated with repairing pancreatic beta cells in diabetic mice and improving its anti-oxidative capacity, as well as attenuating cytotoxicity via inhibition of iNOS, NF-κB activation.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 40, 51 ] ] }, { "pmid": "8263811", "text": "Nonadrenergic imidazoline binding sites on human platelets.\n", "type": "CHEMICAL", "entities": [ "imidazoline" ], "offsets": [ [ 14, 25 ] ] }, { "pmid": "8263811", "text": "Human platelets are shown to possess at least two high-affinity, imidazol(in)e-preferring binding sites that are pharmacologically distinct from alpha-2 adrenoceptors.", "type": "CHEMICAL", "entities": [ "imidazol(in)e" ], "offsets": [ [ 65, 78 ] ] }, { "pmid": "8263811", "text": "These nonadrenergic sites were radiolabeled even in the presence of a 10 microM norepinephrine mask of alpha-2 adrenoceptors.", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 80, 94 ] ] }, { "pmid": "8263811", "text": "Heterogeneity at the nonadrenergic sites was demonstrated by comparing [3H]idazoxan (IDX) binding vs. [125I]p-iodoclonidine (PIC) binding.", "type": "CHEMICAL", "entities": [ "[3H]idazoxan", "IDX", "[125I]p-iodoclonidine", "PIC" ], "offsets": [ [ 71, 83 ], [ 85, 88 ], [ 102, 123 ], [ 125, 128 ] ] }, { "pmid": "8263811", "text": "Nonadrenergic", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8263811", "text": "[125I]PIC-labeled sites were enriched in platelet plasma membranes, whereas the nonadrenergic sites labeled by [3H] IDX were codistributed between plasma and internal membranes (nonadrenergic [125I]PIC-labeled sites had Bmax = 62 fmol/mg in plasma membranes and 20 fmol/mg in internal membranes vs. the [3H]IDX-labeled sites had Bmax = 141 fmol/mg in plasma membranes and 192 fmol/mg in internal membranes).", "type": "CHEMICAL", "entities": [ "[125I]PIC", "[3H] IDX", "[125I]PIC", "[3H]IDX" ], "offsets": [ [ 0, 9 ], [ 111, 119 ], [ 192, 201 ], [ 303, 310 ] ] }, { "pmid": "8263811", "text": "Furthermore, competition binding studies in the presence of a 10 microM norepinephrine mask revealed major (approximately 75%) and minor (approximately 25%) binding components on plasma membranes for [125I]PIC.", "type": "CHEMICAL", "entities": [ "[125I]PIC", "norepinephrine" ], "offsets": [ [ 200, 209 ], [ 72, 86 ] ] }, { "pmid": "8263811", "text": "Affinities for the major nonadrenergic", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8263811", "text": "[125I]PIC binding site were highly comparable to human subtype-I1 imidazol(in)e receptor sites in the brain stem (rank order: moxonidine > clonidine > cirazoline >", "type": "CHEMICAL", "entities": [ "[125I]PIC", "imidazol(in)e", "moxonidine", "clonidine", "cirazoline" ], "offsets": [ [ 0, 9 ], [ 66, 79 ], [ 126, 136 ], [ 139, 148 ], [ 151, 161 ] ] }, { "pmid": "8263811", "text": "IDX > amiloride).", "type": "CHEMICAL", "entities": [ "IDX", "amiloride" ], "offsets": [ [ 0, 3 ], [ 6, 15 ] ] }, { "pmid": "8263811", "text": "However, the minor component of [125I]PIC binding was similar to a site reported in kidney, having low affinities for all compounds tested, except guanabenz.", "type": "CHEMICAL", "entities": [ "[125I]PIC", "guanabenz" ], "offsets": [ [ 32, 41 ], [ 147, 156 ] ] }, { "pmid": "8263811", "text": "Finally, a third nonadrenergic internal membrane site, labeled by [3H]IDX, was consistent with a subtype-I2 imidazol(in)e receptor site (rank order: cirazoline >", "type": "CHEMICAL", "entities": [ "[3H]IDX", "imidazol(in)e", "cirazoline" ], "offsets": [ [ 66, 73 ], [ 108, 121 ], [ 149, 159 ] ] }, { "pmid": "8263811", "text": "IDX >> amiloride > moxonidine > clonidine).", "type": "CHEMICAL", "entities": [ "amiloride", "moxonidine", "clonidine" ], "offsets": [ [ 7, 16 ], [ 19, 29 ], [ 32, 41 ] ] }, { "pmid": "8263811", "text": "Thus, based on differential subcellular distributions and affinity constants, human platelets appear to possess imidazoline receptors (subtype-I1 imidazol(in)e receptor and subtype-I2 imidazol(in)e receptor), plus a novel guanabenz-sensitive site, as well as an alpha-2A adrenoceptor.", "type": "CHEMICAL", "entities": [ "imidazoline", "imidazol(in)e", "imidazol(in)e", "guanabenz" ], "offsets": [ [ 112, 123 ], [ 146, 159 ], [ 184, 197 ], [ 222, 231 ] ] }, { "pmid": "8263811", "text": "These nonadrenoceptor binding sites may explain certain novel platelet aggregatory properties previously ascribed to clonidine and endogenous clonidine-displacing substance(s), and may serve as markers of imidazoline receptors in humans.", "type": "CHEMICAL", "entities": [ "clonidine", "clonidine", "imidazoline" ], "offsets": [ [ 117, 126 ], [ 142, 151 ], [ 205, 216 ] ] }, { "pmid": "23238103", "text": "Age dependent differences in the regulation of hippocampal steroid hormones and receptor genes: relations to motivation and cognition in male rats.\n", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 59, 66 ] ] }, { "pmid": "23238103", "text": "Estrogen and estrogenic functions are age-dependently involved in the modulation of learning, memory and mood in female humans and animals.", "type": "CHEMICAL", "entities": [ "Estrogen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23238103", "text": "However, the investigation of estrogenic effects in males has been largely neglected.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "Therefore, we investigated the hippocampal gene expression of estrogen receptors α and β (ERα, β) in 8-week-old, 12-week-old and 24-week-old male rats.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 62, 70 ] ] }, { "pmid": "23238103", "text": "To control for possible interactions between the expression of the estrogen receptor genes and other learning-related steroid receptors, androgen receptors (AR), corticosterone-binding glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) were also measured.", "type": "CHEMICAL", "entities": [ "estrogen", "steroid", "androgen", "corticosterone" ], "offsets": [ [ 63, 71 ], [ 114, 121 ], [ 133, 141 ], [ 158, 172 ] ] }, { "pmid": "23238103", "text": "Furthermore, the concentrations of the ligands 17β-estradiol, testosterone and corticosterone were measured.", "type": "CHEMICAL", "entities": [ "17β-estradiol", "testosterone", "corticosterone" ], "offsets": [ [ 43, 56 ], [ 58, 70 ], [ 75, 89 ] ] }, { "pmid": "23238103", "text": "The spatial training was conducted in a hole-board.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "The 8-week-old rats exhibited higher levels of general activity and exploration during the training and performed best with respect to spatial learning and memory, whereas no difference was found between the 12-week-old and 24-week-old rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "The trained 8-week-old rats exhibited increased gene expression of ERα compared with the untrained rats in this age group as well as the trained 12-week-old and 24-week-old rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "The concentrations of estradiol and testosterone, however, were generally higher in the 24-week-old rats than in the 8-week-old and 12-week-old rats.", "type": "CHEMICAL", "entities": [ "estradiol", "testosterone" ], "offsets": [ [ 16, 25 ], [ 30, 42 ] ] }, { "pmid": "23238103", "text": "The ERα mRNA concentrations correlated positively with behavior that indicate general learning motivation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "These results suggest a specific role of ERα in the age-related differences in motivation and subsequent success in the task.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23238103", "text": "Thus, estrogen and estrogenic functions may play a more prominent role in young male behavior and development than has been previously assumed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2886642", "text": "Effects of ORF 17583, other histamine H2-receptor antagonists and omeprazole on gastric acid secretory states in rats and dogs.\n", "type": "CHEMICAL", "entities": [ "ORF 17583", "histamine", "omeprazole" ], "offsets": [ [ 11, 20 ], [ 28, 37 ], [ 66, 76 ] ] }, { "pmid": "2886642", "text": "ORF 17583, a histamine H2-receptor antagonist, inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 4.9 mg/kg intraduodenal; 3.4 mg/kg p.o.; and 0.21 mg/kg i.p.)", "type": "CHEMICAL", "entities": [ "ORF 17583", "histamine" ], "offsets": [ [ 0, 9 ], [ 13, 22 ] ] }, { "pmid": "2886642", "text": "and in total gastric fistula or Heidenhain pouch dogs stimulated by betazole (ED50 = 0.12 mg/kg p.o. and 0.08 mg/kg i.v.), histamine, tetragastrin, bethanechol, 2-deoxy-D-glucose or a meal (ED50 values ranged from 0.11-0.26 mg/kg p.o.).", "type": "CHEMICAL", "entities": [ "betazole", "histamine", "tetragastrin", "bethanechol", "2-deoxy-D-glucose" ], "offsets": [ [ 68, 76 ], [ 123, 132 ], [ 134, 146 ], [ 148, 159 ], [ 161, 178 ] ] }, { "pmid": "2886642", "text": "The nonspecific inhibition of gastric acid by ORF 17583 supports the existence of interdependence between histamine and the gastrin and cholinergic receptors on the parietal cell surface.", "type": "CHEMICAL", "entities": [ "ORF 17583", "histamine" ], "offsets": [ [ 46, 55 ], [ 106, 115 ] ] }, { "pmid": "2886642", "text": "Antisecretory potency of ORF 17583 after intraduodenal administration in pylorus-ligated rats was 6.4 times greater than cimetidine, 1.8 times greater than ranitidine, equal to that of omeprazole and 8 times less than that of famotidine.", "type": "CHEMICAL", "entities": [ "ORF 17583", "cimetidine", "ranitidine", "omeprazole", "famotidine" ], "offsets": [ [ 25, 34 ], [ 121, 131 ], [ 156, 166 ], [ 185, 195 ], [ 226, 236 ] ] }, { "pmid": "2886642", "text": "Oral antisecretory potency of ORF 17583 in gastric fistula dogs was 31 times greater than cimetidine, 3.7 times greater than ranitidine and equal to that of omeprazole and famotidine.", "type": "CHEMICAL", "entities": [ "famotidine", "ORF 17583", "cimetidine", "ranitidine", "omeprazole" ], "offsets": [ [ 172, 182 ], [ 30, 39 ], [ 90, 100 ], [ 125, 135 ], [ 157, 167 ] ] }, { "pmid": "2886642", "text": "Studies using equieffective antisecretory doses of ORF 17583 and ranitidine in dogs suggested that ORF 17583 has a short duration of antisecretory activity similar to that of ranitidine.", "type": "CHEMICAL", "entities": [ "ORF 17583", "ranitidine", "ORF 17583", "ranitidine" ], "offsets": [ [ 51, 60 ], [ 65, 75 ], [ 99, 108 ], [ 175, 185 ] ] }, { "pmid": "23216335", "text": "Platelet-derived microparticles in overweight/obese women with the polycystic ovary syndrome.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "A substantial proportion of women with the polycystic ovary syndrome (PCOS) are obese and obesity is considered as a prothrombotic state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "Platelet-derived microparticles (PMPs) might be implicated in the activation of the coagulation cascade.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "We aimed to assess plasma PMPs in overweight/obese women with PCOS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "We measured plasma PMPs and determined anthropometric, metabolic, hormonal and ultrasonographic features of PCOS in 67 overweight/obese women with PCOS (with body mass index [BMI] >25.0 kg/m(2))", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "and in 21 BMI-matched healthy women.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "Circulating androgens and markers of insulin resistance (IR) were higher in women with PCOS than in controls.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23216335", "text": "Plasma PMPs were also higher in women with PCOS than in controls (p = 0.046).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "In women with PCOS, plasma PMPs correlated with the mean number of follicles in the ovaries (r = 0.343; p = 0.006).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "In controls, plasma PMPs did not correlate with any of the studied parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "In conclusion, plasma PMPs are elevated in overweight/obese women with PCOS compared with BMI-matched controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "The cause of this increase is unclear but both IR and hyperandrogenemia might be implicated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23216335", "text": "More studies are required to elucidate the pathogenesis of the elevation of PMPs in PCOS and to assess its implications on the cardiovascular risk of these patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17475673", "text": "Underexpression of the Na+-dependent neutral amino acid transporter ASCT2 in the spontaneously hypertensive rat kidney.\n", "type": "CHEMICAL", "entities": [ "Na+", "amino acid" ], "offsets": [ [ 23, 26 ], [ 45, 55 ] ] }, { "pmid": "17475673", "text": "This study examined the inward transport of l-[(14)C]alanine, an ASCT2 preferential substrate, in monolayers of immortalized renal proximal tubular epithelial (PTE) cells from Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats.", "type": "CHEMICAL", "entities": [ "l-[(14)C]alanine" ], "offsets": [ [ 44, 60 ] ] }, { "pmid": "17475673", "text": "The expression of ASCT2 in WKY and SHR PTE cells and kidney cortices from WKY and SHR was also evaluated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17475673", "text": "l-[(14)C]alanine uptake was highly dependent on extracellular Na(+).", "type": "CHEMICAL", "entities": [ "l-[(14)C]alanine", "Na(+)" ], "offsets": [ [ 0, 16 ], [ 62, 67 ] ] }, { "pmid": "17475673", "text": "Replacement of NaCl by LiCl or choline chloride abolished transport activity in SHR and WKY PTE cells.", "type": "CHEMICAL", "entities": [ "NaCl", "LiCl", "choline chloride" ], "offsets": [ [ 15, 19 ], [ 23, 27 ], [ 31, 47 ] ] }, { "pmid": "17475673", "text": "In the presence of the system L inhibitor BCH, Na(+)-dependent l-alanine uptake in WKY and SHR PTE cells was inhibited by alanine, serine, and cysteine, which is consistent with amino acid transport through ASCT2.", "type": "CHEMICAL", "entities": [ "Na(+)", "l-alanine", "alanine", "serine", "cysteine", "amino acid" ], "offsets": [ [ 47, 52 ], [ 63, 72 ], [ 122, 129 ], [ 131, 137 ], [ 143, 151 ], [ 178, 188 ] ] }, { "pmid": "17475673", "text": "The saturable component of Na(+)-dependent l-alanine transport under V(max) conditions in SHR PTE cells was one-half of that in WKY PTE cells, with similar K(m) values.", "type": "CHEMICAL", "entities": [ "Na(+)", "l-alanine" ], "offsets": [ [ 27, 32 ], [ 43, 52 ] ] }, { "pmid": "17475673", "text": "Differences in magnitude of Na(+)-dependent l-alanine uptake through ASCT2 between WKY and SHR PTE cells correlated positively with differences in ASCT2 protein expression, this being more abundant in WKY PTE cells.", "type": "CHEMICAL", "entities": [ "Na(+)", "l-alanine" ], "offsets": [ [ 28, 33 ], [ 44, 53 ] ] }, { "pmid": "17475673", "text": "Abundance of ASCT2 transcript and protein in kidney cortices of SHR rats was also lower than that in normotensive WKY rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17475673", "text": "In conclusion, immortalized SHR and WKY PTE cells take up l-alanine mainly through a high-affinity Na(+)-dependent amino acid transporter, with functional features of ASCT2 transport.", "type": "CHEMICAL", "entities": [ "l-alanine", "Na(+)", "amino acid" ], "offsets": [ [ 58, 67 ], [ 99, 104 ], [ 115, 125 ] ] }, { "pmid": "17475673", "text": "The activity and expression of the ASCT2 transporter were considerably lower in the SHR cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511086", "text": "The antipsychotic drugs sertindole and pimozide block erg3, a human brain K(+) channel.\n", "type": "CHEMICAL", "entities": [ "sertindole", "pimozide", "K(+)" ], "offsets": [ [ 24, 34 ], [ 39, 47 ], [ 74, 78 ] ] }, { "pmid": "11511086", "text": "The antipsychotic drugs sertindole and pimozide are known to prolong the QT interval on the electrocardiogram via a high affinity block of the cardiac K(+) channel known as HERG (human ether-a-go-go-related gene; erg1).", "type": "CHEMICAL", "entities": [ "K(+)", "sertindole", "pimozide" ], "offsets": [ [ 151, 155 ], [ 24, 34 ], [ 39, 47 ] ] }, { "pmid": "11511086", "text": "We wished to test whether these drugs also displayed high affinity for the related neuronal K(+) channel erg3.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 92, 96 ] ] }, { "pmid": "11511086", "text": "The cDNA encoding erg3 channel was cloned from a human brain library.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511086", "text": "Northern analysis confirmed that the channel was localized to brain relative to other tissues including heart, liver and lung.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511086", "text": "Within the brain, erg3 was expressed in higher amounts in the frontal lobe and cerebellum relative to the temporal, parietal and occipital lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11511086", "text": "Transient expression of erg3 in Chinese hamster ovary cells produced outwardly directed K(+) currents that activated at approximately -50 mV and produced a large transient component at positive membrane potentials.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 88, 92 ] ] }, { "pmid": "11511086", "text": "Inward tail currents measured at -100 mV were blocked in a dose-dependent fashion by sertindole resulting in an IC(50) value of 43 nM. Significant inhibition was observed at concentrations as low as 3 nM. Block of erg3 by sertindole also displayed a positive voltage-dependence.", "type": "CHEMICAL", "entities": [ "sertindole", "sertindole" ], "offsets": [ [ 222, 232 ], [ 85, 95 ] ] }, { "pmid": "11511086", "text": "Pimozide blocked erg3 channel currents with an IC(50) of 103 nM and significant inhibition was noted at concentrations of 10 nM and higher.", "type": "CHEMICAL", "entities": [ "Pimozide" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "11511086", "text": "We conclude that erg3 can be blocked by certain antipsychotic drugs like sertindole and pimozide.", "type": "CHEMICAL", "entities": [ "sertindole", "pimozide" ], "offsets": [ [ 73, 83 ], [ 88, 96 ] ] }, { "pmid": "11511086", "text": "Inhibition of erg3 or related K(+) channels in the brain may contribute to the efficacy/side effect profiles of some antipsychotic drugs.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 30, 34 ] ] }, { "pmid": "1352051", "text": "Different neuroleptics show common dose and time dependent effects in quantitative field potential analysis in freely moving rats.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1352051", "text": "Under the assumption that field potentials recorded from particular brain areas reflect the net balance of neurotransmitter activities, the dose- and time-dependent responses induced by intraperitoneal application of different neuroleptic drugs are quantified by spectral analysis of the electroencephalogram recorded from frontal cortex, hippocampus, striatum and reticular formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1352051", "text": "The actions of haloperidol, chlorpromazine, clozapine, prothipendyl and thioridazine in general were characterized by increases of the spectral power in the alpha 1 and beta range, at higher dosages also in the theta range.", "type": "CHEMICAL", "entities": [ "haloperidol", "chlorpromazine", "clozapine", "prothipendyl", "thioridazine" ], "offsets": [ [ 15, 26 ], [ 28, 42 ], [ 44, 53 ], [ 55, 67 ], [ 72, 84 ] ] }, { "pmid": "1352051", "text": "This observed pattern of changes is in line with the neuroleptic induced spectral changes reported in the literature for other animals and man.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1352051", "text": "In the light of the already known effects of other psychoactive drugs on the frequency content of field potentials in the rat, it should now be possible to classify different drugs in terms of their clinical indication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1352051", "text": "With respect to the type of neurotransmitter control underlying the changes produced by various neuroleptics, it is quite obvious from the comparisons with the respective drug effects that dopamine-D1-receptor controlled transmission is not responsible for this action.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 189, 197 ] ] }, { "pmid": "1352051", "text": "On the basis of earlier findings a possible interaction between dopamine-D2 receptor or glutamatergic transmitter control is discussed.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 64, 72 ] ] }, { "pmid": "23301860", "text": "Single-walled carbon nanotube surface control of complement recognition and activation.\n", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 14, 20 ] ] }, { "pmid": "23301860", "text": "Carbon nanotubes (CNTs) are receiving considerable attention in site-specific drug and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging.", "type": "CHEMICAL", "entities": [ "Carbon" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23301860", "text": "Despite these advances, nanotubes may activate the complement system (an integral part of innate immunity), which can induce clinically significant anaphylaxis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301860", "text": "We demonstrate that single-walled CNTs coated with human serum albumin activate the complement system through C1q-mediated classical and the alternative pathways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301860", "text": "Surface coating with methoxypoly(ethylene glycol)-based amphiphiles, which confers solubility and prolongs circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure.", "type": "CHEMICAL", "entities": [ "methoxypoly(ethylene glycol)" ], "offsets": [ [ 21, 49 ] ] }, { "pmid": "23301860", "text": "CNTs with linear poly(ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both L-ficolin and mannan-binding lectin recognition.", "type": "CHEMICAL", "entities": [ "poly(ethylene glycol)" ], "offsets": [ [ 17, 38 ] ] }, { "pmid": "23301860", "text": "The lectin pathway activation, however, did not trigger the amplification loop of the alternative pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301860", "text": "An amphiphile with branched poly(ethylene glycol) architecture also activated the lectin pathway but only through L-ficolin recognition.", "type": "CHEMICAL", "entities": [ "poly(ethylene glycol)" ], "offsets": [ [ 28, 49 ] ] }, { "pmid": "23301860", "text": "Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering of the effector arm of the complement system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301860", "text": "These observations provide a major step toward nanomaterial surface modification with polymers that have the properties to significantly improve innate immunocompatibility by limiting the formation of complement C3 and C5 convertases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17959709", "text": "Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil.\n", "type": "CHEMICAL", "entities": [ "vardenafil", "sildenafil" ], "offsets": [ [ 131, 141 ], [ 146, 156 ] ] }, { "pmid": "17959709", "text": "Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction.", "type": "CHEMICAL", "entities": [ "Vardenafil", "sildenafil" ], "offsets": [ [ 0, 10 ], [ 66, 76 ] ] }, { "pmid": "17959709", "text": "However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17959709", "text": "Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 112, 122 ] ] }, { "pmid": "17959709", "text": "The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "17959709", "text": "In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5.", "type": "CHEMICAL", "entities": [ "vardenafil", "sildenafil" ], "offsets": [ [ 44, 54 ], [ 76, 86 ] ] }, { "pmid": "17959709", "text": "It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "17959709", "text": "The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23478800", "text": "Cucurbitacin I inhibits rac1 activation in breast cancer cells by a reactive oxygen species-mediated mechanism and independently of janus tyrosine kinase 2 and p-rex1.\n", "type": "CHEMICAL", "entities": [ "Cucurbitacin I", "tyrosine", "oxygen" ], "offsets": [ [ 0, 14 ], [ 138, 146 ], [ 77, 83 ] ] }, { "pmid": "23478800", "text": "The small GTPase Rac1 has been widely implicated in mammary tumorigenesis and metastasis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23478800", "text": "Previous studies established that stimulation of ErbB receptors in breast cancer cells activates Rac1 and enhances motility via the Rac-guanine nucleotide exchange factor P-Rex1.", "type": "CHEMICAL", "entities": [ "guanine nucleotide" ], "offsets": [ [ 136, 154 ] ] }, { "pmid": "23478800", "text": "As the Janus tyrosine kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) pathway has been shown to be functionally associated with ErbB receptors, we asked if this pathway could mediate P-Rex1/Rac1 activation in response to ErbB ligands.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "23478800", "text": "Here we found that the anticancer agent cucurbitacin I, a Jak2 inhibitor, reduced the activation of Rac1 and motility in response to the ErbB3 ligand heregulin in breast cancer cells.", "type": "CHEMICAL", "entities": [ "cucurbitacin I" ], "offsets": [ [ 40, 54 ] ] }, { "pmid": "23478800", "text": "However, Rac1 activation was not affected by Jak2 or Stat3 RNA interference, suggesting that the effect of cucurbitacin I occurs through a Jak2-independent mechanism.", "type": "CHEMICAL", "entities": [ "cucurbitacin I" ], "offsets": [ [ 107, 121 ] ] }, { "pmid": "23478800", "text": "Cucurbitacin I also failed to affect the activation of P-Rex1 by heregulin.", "type": "CHEMICAL", "entities": [ "Cucurbitacin I" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "23478800", "text": "Subsequent analysis revealed that cucurbitacin I strongly activates RhoA and the Rho effector Rho kinase (ROCK) in breast cancer cells and induces the formation of stress fibers.", "type": "CHEMICAL", "entities": [ "cucurbitacin I" ], "offsets": [ [ 34, 48 ] ] }, { "pmid": "23478800", "text": "Interestingly, disruption of the RhoA-ROCK pathway prevented the inhibitory effect of cucurbitacin I on Rac1 activation by heregulin.", "type": "CHEMICAL", "entities": [ "cucurbitacin I" ], "offsets": [ [ 86, 100 ] ] }, { "pmid": "23478800", "text": "Lastly, we found that RhoA activation by cucurbitacin I is mediated by reactive oxygen species (ROS).", "type": "CHEMICAL", "entities": [ "cucurbitacin I", "oxygen" ], "offsets": [ [ 41, 55 ], [ 80, 86 ] ] }, { "pmid": "23478800", "text": "The ROS scavenger N-acetyl l-cysteine and the mitochondrial antioxidant Mito-TEMPO rescued the inhibitory effect of cucurbitacin I on Rac1 activation.", "type": "CHEMICAL", "entities": [ "N-acetyl l-cysteine", "cucurbitacin I" ], "offsets": [ [ 18, 37 ], [ 116, 130 ] ] }, { "pmid": "23478800", "text": "In conclusion, these results indicate that ErbB-driven Rac1 activation in breast cancer cells proceeds independently of the Jak2 pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23478800", "text": "Moreover, they established that the inhibitory effect of cucurbitacin I on Rac1 activity involves the alteration of the balance between Rho and Rac.", "type": "CHEMICAL", "entities": [ "cucurbitacin I" ], "offsets": [ [ 57, 71 ] ] }, { "pmid": "9890894", "text": "Common and specific determinants for fibroblast growth factors in the ectodomain of the receptor kinase complex.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9890894", "text": "The assembly and activation of oligomeric complexes of FGF, the transmembrane receptor kinase (FGFR), and heparan sulfate transmit intracellular signals regulating growth and function of cells.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 114, 121 ] ] }, { "pmid": "9890894", "text": "An understanding of the structural relationships between the three subunits and their redundancy and specificity is essential for understanding the ubiquitous FGF signaling system in health and disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9890894", "text": "Previously, we reported that a primary heparin or heparan sulfate binding site resides in a distinct sequence in immunoglobulin (Ig)-like module II of the three modules of FGFR.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 58, 65 ] ] }, { "pmid": "9890894", "text": "Here we report that in the absence of flanking sequences, isolated Ig module II of FGFR1 supports the binding of FGF-1, FGF-2, and FGF-7 in respective order of affinity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9890894", "text": "None of the three FGFs detectably bind Ig module I or the IIIb and IIIc splice variants of Ig module III in the absence of flanking sequences.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9890894", "text": "Ig module I and the C-terminus of Ig module III are dispensable for high-affinity binding of FGF-1, FGF-2, and FGF-7.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 20, 21 ] ] }, { "pmid": "9890894", "text": "Alterations in highly conserved Ig module II in the heparin binding domain and substitution of individual sequence domains spanning the entire sequence of Ig module II with those from Ig module I obliterated FGF binding.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9890894", "text": "Addition of a specific number of FGFR sequences to the C-terminus of Ig module II resulted in a gain in affinity for FGF-7.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 55, 56 ] ] }, { "pmid": "9890894", "text": "Several site-specific alterations in the C-terminus of full-length FGFR1IIIc, an isoform that otherwise absolutely rejects FGF-7, resulted in gain of FGF-7 binding.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 41, 42 ] ] }, { "pmid": "9890894", "text": "These results suggest that a complex of Ig module II and heparan sulfate is the base common active core of the FGFR ectodomain and that flanking structural domains modify FGF affinity and determine specificity.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 65, 72 ] ] }, { "pmid": "15452358", "text": "Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model.\n", "type": "CHEMICAL", "entities": [ "CP-101,606" ], "offsets": [ [ 120, 130 ] ] }, { "pmid": "15452358", "text": "In order to examine the site of action of an NR2B subtype-selective NMDA antagonist CP-101,606, we investigated its analgesic effect in a rat model of neuropathic pain at various routes of administration.", "type": "CHEMICAL", "entities": [ "NMDA", "CP-101,606" ], "offsets": [ [ 68, 72 ], [ 84, 94 ] ] }, { "pmid": "15452358", "text": "Mechanical allodynia was induced by chronic constriction injury (CCI) of the sciatic nerve in male Sprague-Dawley rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15452358", "text": "Subcutaneous treatment of the animals with CP-101,606 at 10 mg/kg significantly inhibited CCI-induced mechanical allodynia.", "type": "CHEMICAL", "entities": [ "CP-101,606" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "15452358", "text": "Intracerebroventricular injection of CP-101,606 at 10, 30 and 100 nmol also inhibited the mechanical allodynia in a dose-dependent manner, the statistically significant effect being achieved at the highest dose tested (100 nmol) without producing any behavioral abnormalities.", "type": "CHEMICAL", "entities": [ "CP-101,606" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "15452358", "text": "However, intrathecal injection of CP-101,606 at a dose of 300 nmol failed to inhibit CCI-induced allodynia.", "type": "CHEMICAL", "entities": [ "CP-101,606" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "15452358", "text": "A receptor binding assay using rat forebrain and spinal cord membrane preparations demonstrated that [3H]CP-101,606 bound to the brain NR2B receptor with a greater extent compared to the spinal cord one.", "type": "CHEMICAL", "entities": [ "[3H]CP-101,606" ], "offsets": [ [ 101, 115 ] ] }, { "pmid": "15452358", "text": "These findings suggest that the anti-allodynia effect of CP-101,606 is ascribable to blockade of NR2B receptors at the brain, but not at the spinal cord.", "type": "CHEMICAL", "entities": [ "CP-101,606" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "15452358", "text": "In contrast, intrathecal injection of a non-selective NMDA antagonist, memantine, significantly inhibited CCI-induced mechanical allodynia at a dose of 300 nmol, indicating the difference in the site of action between the non-selective NMDA antagonist and the NR2B-specific NMDA antagonist.", "type": "CHEMICAL", "entities": [ "NMDA", "memantine", "NMDA", "NMDA" ], "offsets": [ [ 54, 58 ], [ 71, 80 ], [ 236, 240 ], [ 274, 278 ] ] }, { "pmid": "16884688", "text": "Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16884688", "text": "Hereditary hyperekplexia is a neuromotor disorder characterized by exaggerated startle reflexes and muscle stiffness in the neonate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16884688", "text": "The disease has been associated with mutations in the glycine receptor subunit genes GLRA1 and GLRB.", "type": "CHEMICAL", "entities": [ "glycine" ], "offsets": [ [ 54, 61 ] ] }, { "pmid": "16884688", "text": "Here, we describe mutations within the neuronal glycine transporter 2 gene (GLYT2, or SLC6A5, ) of hyperekplexia patients, whose symptoms cannot be attributed to glycine receptor mutations.", "type": "CHEMICAL", "entities": [ "glycine", "glycine" ], "offsets": [ [ 48, 55 ], [ 162, 169 ] ] }, { "pmid": "16884688", "text": "One of the GLYT2 mutations identified causes truncation of the transporter protein and a complete loss of transport function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16884688", "text": "Our results are consistent with GLYT2 being a disease gene in human hyperekplexia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12504917", "text": "Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours.\n", "type": "CHEMICAL", "entities": [ "reserpine", "rasagiline", "amines" ], "offsets": [ [ 107, 116 ], [ 54, 64 ], [ 99, 105 ] ] }, { "pmid": "12504917", "text": "Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease.", "type": "CHEMICAL", "entities": [ "Rasagiline", "N-propargyl-1R(+)-aminoindan", "TVP1012", "monoamine" ], "offsets": [ [ 0, 10 ], [ 12, 40 ], [ 42, 49 ], [ 76, 85 ] ] }, { "pmid": "12504917", "text": "In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome.", "type": "CHEMICAL", "entities": [ "rasagiline", "monoamine", "L-tryptophan", "fluoxetine", "L-DOPA", "reserpine" ], "offsets": [ [ 37, 47 ], [ 55, 64 ], [ 113, 125 ], [ 127, 137 ], [ 142, 148 ], [ 166, 175 ] ] }, { "pmid": "12504917", "text": "Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses.", "type": "CHEMICAL", "entities": [ "Reserpine", "rasagiline" ], "offsets": [ [ 0, 9 ], [ 41, 51 ] ] }, { "pmid": "12504917", "text": "However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors.", "type": "CHEMICAL", "entities": [ "rasagiline", "L-DOPA", "L-tryptophan", "rasagiline", "fluoxetine", "tranylcypromine", "monoamine" ], "offsets": [ [ 24, 34 ], [ 62, 68 ], [ 72, 84 ], [ 111, 121 ], [ 149, 159 ], [ 299, 314 ], [ 333, 342 ] ] }, { "pmid": "12504917", "text": "Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1).", "type": "CHEMICAL", "entities": [ "dopamine", "DA", "rasagiline", "noradrenaline", "NA", "5-hydroxytryptamine", "5-HT" ], "offsets": [ [ 92, 100 ], [ 102, 104 ], [ 172, 182 ], [ 41, 54 ], [ 56, 58 ], [ 61, 80 ], [ 82, 86 ] ] }, { "pmid": "12504917", "text": "Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1).", "type": "CHEMICAL", "entities": [ "NA", "5-HT", "DA", "rasagiline" ], "offsets": [ [ 75, 77 ], [ 79, 83 ], [ 88, 90 ], [ 138, 148 ] ] }, { "pmid": "12504917", "text": "Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.", "type": "CHEMICAL", "entities": [ "Rasagiline", "monoamine", "monoamine" ], "offsets": [ [ 0, 10 ], [ 31, 40 ], [ 58, 67 ] ] }, { "pmid": "16399380", "text": "Characterization of the omega class of glutathione transferases.\n", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 39, 50 ] ] }, { "pmid": "16399380", "text": "The Omega class of cytosolic glutathione transferases was initially recognized by bioinformatic analysis of human sequence databases, and orthologous sequences were subsequently discovered in mouse, rat, pig, Caenorhabditis elegans, Schistosoma mansoni, and Drosophila melanogaster.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 29, 40 ] ] }, { "pmid": "16399380", "text": "In humans and mice, two GSTO genes have been recognized and their genetic structures and expression patterns identified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "In both species, GSTO1 mRNA is expressed in liver and heart as well as a range of other tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "GSTO2 is expressed predominantly in the testis, although moderate levels of expression are seen in other tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "Extensive immunohistochemistry of rat and human tissue sections has demonstrated cellular and subcellular specificity in the expression of GSTO1-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "The crystal structure of recombinant human GSTO1-1 has been determined, and it adopts the canonical GST fold.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "A cysteine residue in place of the catalytic tyrosine or serine residues found in other GSTs was shown to form a mixed disulfide with glutathione.", "type": "CHEMICAL", "entities": [ "glutathione", "cysteine", "tyrosine", "serine", "disulfide" ], "offsets": [ [ 134, 145 ], [ 2, 10 ], [ 45, 53 ], [ 57, 63 ], [ 119, 128 ] ] }, { "pmid": "16399380", "text": "Omega class GSTs have dehydroascorbate reductase and thioltransferase activities and also catalyze the reduction of monomethylarsonate, an intermediate in the pathway of arsenic biotransformation.", "type": "CHEMICAL", "entities": [ "monomethylarsonate", "arsenic" ], "offsets": [ [ 116, 134 ], [ 170, 177 ] ] }, { "pmid": "16399380", "text": "Other diverse actions of human GSTO1-1 include modulation of ryanodine receptors and interaction with cytokine release inhibitory drugs.", "type": "CHEMICAL", "entities": [ "ryanodine" ], "offsets": [ [ 61, 70 ] ] }, { "pmid": "16399380", "text": "In addition, GSTO1 has been linked to the age at onset of both Alzheimer's and Parkinson's diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "Several polymorphisms have been identified in the coding regions of the human GSTO1 and GSTO2 genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "Our laboratory has expressed recombinant human GSTO1-1 and GSTO2-2 proteins, as well as a number of polymorphic variants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16399380", "text": "The expression and purification of these proteins and determination of their enzymatic activity is described.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23395171", "text": "Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation.\n", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "23395171", "text": "Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca(2+)](i)) oscillation.", "type": "CHEMICAL", "entities": [ "calcium", "Ca(2+)" ], "offsets": [ [ 224, 231 ], [ 234, 240 ] ] }, { "pmid": "23395171", "text": "However, the coordination mechanism that mediates Ca(2+) oscillation during osteoclastogenesis remains ill defined.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 48, 54 ] ] }, { "pmid": "23395171", "text": "Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca(2+) oscillation during osteoclastogenesis.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 70, 76 ] ] }, { "pmid": "23395171", "text": "We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23395171", "text": "Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca(2+)", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 116, 122 ] ] }, { "pmid": "23395171", "text": "ATPase 2 (SERCA2) and modulates its activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23395171", "text": "Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca(2+)](i) oscillation, which results in reduced Ca(2+)/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 69, 75 ], [ 118, 124 ] ] }, { "pmid": "23395171", "text": "These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca(2+) signaling.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 107, 113 ] ] }, { "pmid": "17254025", "text": "Bimodal occurrence of aspartoacylase in myelin and cytosol of brain.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17254025", "text": "The growing use of N-acetylaspartate as an indicator of neuronal viability has fostered interest in the biological function(s) of this unusual amino acid derivative.", "type": "CHEMICAL", "entities": [ "amino acid", "N-acetylaspartate" ], "offsets": [ [ 143, 153 ], [ 19, 36 ] ] }, { "pmid": "17254025", "text": "In considering the various physiological roles that have been proposed for this relatively abundant molecule one is obliged to take into account its unusual metabolic compartmentalization, according to which synthesis and storage occur in the neuron and hydrolytic cleavage in the oligodendrocyte.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17254025", "text": "The latter reaction, catalyzed by aspartoacylase (ASPA), produces acetyl groups plus aspartate and has been proposed to occur in both soluble and membranous subfractions of white matter.", "type": "CHEMICAL", "entities": [ "acetyl", "aspartate" ], "offsets": [ [ 66, 72 ], [ 85, 94 ] ] }, { "pmid": "17254025", "text": "Our study supports such bimodal occurrence and we now present immunoblot, proteomic, and biochemical evidence that the membrane-bound form of ASPA is intrinsic to purified myelin membranes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17254025", "text": "This was supported by a novel TLC-based method for the assay of ASPA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17254025", "text": "That observation, together with previous demonstrations of numerous lipid-synthesizing enzymes in myelin, suggests utilization of acetyl groups liberated by myelin-localized ASPA for lipid synthesis within the myelin sheath.", "type": "CHEMICAL", "entities": [ "acetyl" ], "offsets": [ [ 130, 136 ] ] }, { "pmid": "17254025", "text": "Such synthesis might be selective and could explain the deficit of myelin lipids in animals lacking ASPA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Chemoprevention for high-risk women: tamoxifen and beyond.\n", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 37, 46 ] ] }, { "pmid": "11906441", "text": "The demonstration by the National Surgical Adjuvant Breast Project (NSABP) that 5 years of tamoxifen therapy is associated with an approximate 50% reduction in breast cancer incidence in high-risk women was a milestone in breast cancer prevention.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 91, 100 ] ] }, { "pmid": "11906441", "text": "Because tamoxifen is associated with increased risk of side-effects such as hot flashes, menstrual abnormalities, uterine cancer, and thromboembolic phenomena, its use will not be advisable or acceptable for all high-risk women.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "11906441", "text": "Women over 50 years of age appear to be at highest risk for serious adverse events, such as uterine cancer and thromboembolic phenomena.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Individuals in whom tamoxifen-associated breast cancer risk reduction appears to outweigh risk of serious side-effects include women with prior in situ or estrogen receptor (ER)-positive invasive cancer, atypical hyperplasia, and/or women ages 35-49 with a calculated Gail 5-year risk of > or =1.7%, hysterectomized women aged 50 and older with a 5-year Gail risk of > or =2.5%, and nonhysterectomized women aged 50 and older with a 5-year Gail risk of >5.0%.", "type": "CHEMICAL", "entities": [ "tamoxifen", "estrogen" ], "offsets": [ [ 20, 29 ], [ 155, 163 ] ] }, { "pmid": "11906441", "text": "It is not yet clear whether tamoxifen can reduce breast cancer incidence in women with BRCA1 and BRCA2 mutations, although preliminary evidence favors benefit for at least those with a BRCA2 mutation.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "11906441", "text": "Raloxifene is a selective ER modulator with less uterine estrogen agonist activity than tamoxifen, and it is hoped that it will result in fewer uterine cancers but will be equally efficacious in reducing the risk of breast cancer.", "type": "CHEMICAL", "entities": [ "Raloxifene", "estrogen", "tamoxifen" ], "offsets": [ [ 0, 10 ], [ 57, 65 ], [ 88, 97 ] ] }, { "pmid": "11906441", "text": "The NSABP is currently conducting a randomized study of tamoxifen versus raloxifene in high-risk postmenopausal women.", "type": "CHEMICAL", "entities": [ "tamoxifen", "raloxifene" ], "offsets": [ [ 56, 65 ], [ 73, 83 ] ] }, { "pmid": "11906441", "text": "Approximately one third of invasive cancers are ER negative.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Tamoxifen does not reduce the incidence of ER-negative cancers, nor does it appear to be effective in preventing the appearance of one third of ER-positive cancers.", "type": "CHEMICAL", "entities": [ "Tamoxifen" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11906441", "text": "Priorities in prevention research are to develop (a) biomarkers to refine short-term risk assessments based on epidemiologic models, (b) biomarkers predictive of response to specific classes of preventive agents, (c) drugs with fewer side-effects and/or effective in ER-negative or ER-positive tamoxifen-resistant precancerous disease, and (d) efficient clinical trial models to assess new agent efficacy.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 294, 303 ] ] }, { "pmid": "11906441", "text": "Breast intraepithelial neoplasia (IEN) may be sampled by minimally invasive techniques and is an attractive short-term risk biomarker.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Molecular abnormalities observed in IEN may be used to select potential agents for testing/therapy, and modulation of these abnormalities may be used in phase I trials to select appropriate doses and in phase II trials to assess response.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Breast density volume and certain serum markers such as insulin-like growth factor-1 are also being studied as potential risk and response biomarkers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "Reversal or prevention of advanced IEN as well as modulation of other risk biomarkers in randomized phase II and phase III trials is being evaluated as a means of more efficiently evaluating prevention drugs in the future.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11906441", "text": "A number of agents are being developed that target molecular abnormalities in IEN, have fewer or different side effects than tamoxifen, and may be effective in ER-negative or tamoxifen-resistant disease.", "type": "CHEMICAL", "entities": [ "tamoxifen", "tamoxifen" ], "offsets": [ [ 125, 134 ], [ 175, 184 ] ] }, { "pmid": "10694244", "text": "Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells.\n", "type": "CHEMICAL", "entities": [ "troglitazone", "leukotrienes" ], "offsets": [ [ 14, 26 ], [ 64, 76 ] ] }, { "pmid": "10694244", "text": "1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10694244", "text": "The effect of troglitazone, an anti-diabetic drug with insulin-sensitizing action, on antigen-induced production of leukotriene (LT) B(4), C(4) and E(4) and prostaglandin D(2) (PGD(2)) was examined in dinitrophenol (DNP)-specific immunoglobulin E (IgE)-sensitized RBL-2H3 mast cells following stimulation by the antigen, DNP-conjugated human serum albumin.", "type": "CHEMICAL", "entities": [ "leukotriene (LT) B(4), C(4) and E(4)", "prostaglandin D(2)", "troglitazone", "PGD(2)", "dinitrophenol", "DNP", "DNP" ], "offsets": [ [ 116, 152 ], [ 157, 175 ], [ 14, 26 ], [ 177, 183 ], [ 201, 214 ], [ 216, 219 ], [ 321, 324 ] ] }, { "pmid": "10694244", "text": "Levels of LTB(4), C(4) and E(4) and PGD(2) in the conditioned medium were enzyme-immunoassayed.", "type": "CHEMICAL", "entities": [ "LTB(4)", "PGD(2)" ], "offsets": [ [ 10, 16 ], [ 36, 42 ] ] }, { "pmid": "10694244", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10694244", "text": "Troglitazone inhibited the antigen-induced production of LTB(4), C(4) and E(4) and the potency of the inhibition was comparable to that of zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX) and a clinically used anti-asthmatic drug.", "type": "CHEMICAL", "entities": [ "Troglitazone", "LTB(4)", "zileuton" ], "offsets": [ [ 0, 12 ], [ 57, 63 ], [ 139, 147 ] ] }, { "pmid": "10694244", "text": "Neither troglitazone nor zileuton affected antigen-induced production of PGD(2), arachidonic acid release from membrane phospholipids and degranulation.", "type": "CHEMICAL", "entities": [ "troglitazone", "zileuton", "PGD(2)", "arachidonic acid" ], "offsets": [ [ 8, 20 ], [ 25, 33 ], [ 73, 79 ], [ 81, 97 ] ] }, { "pmid": "10694244", "text": "3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10694244", "text": "Troglitazone inhibited LTB(4) production by the supernatant fraction of RBL-2H3 cell lysate with similar potency to zileuton, suggesting that troglitazone inhibits LT production by direct inhibition of 5-LOX activity.", "type": "CHEMICAL", "entities": [ "Troglitazone", "LTB(4)", "zileuton", "troglitazone" ], "offsets": [ [ 0, 12 ], [ 23, 29 ], [ 116, 124 ], [ 142, 154 ] ] }, { "pmid": "10694244", "text": "4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10694244", "text": "Furthermore, it was shown that troglitazone as well as zileuton inhibited LTB(4) production in A23187-stimulated rat peritoneal neutrophils.", "type": "CHEMICAL", "entities": [ "troglitazone", "zileuton", "LTB(4)", "A23187" ], "offsets": [ [ 31, 43 ], [ 55, 63 ], [ 74, 80 ], [ 95, 101 ] ] }, { "pmid": "10694244", "text": "5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10694244", "text": "These findings suggest that troglitazone inhibits antigen-induced LT production in the IgE-sensitized RBL-2H3 cells and A23187-stimulated rat peritoneal neutrophils by direct inhibition of 5-LOX activity.", "type": "CHEMICAL", "entities": [ "troglitazone", "A23187" ], "offsets": [ [ 28, 40 ], [ 120, 126 ] ] }, { "pmid": "15951260", "text": "[Protein profile and vitamin A in children of school age in Ivory Coast].\n", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "15951260", "text": "The purpose of this transverse prospective study was to determine blood nutritional, immunity and inflammatory proteins change in vitamin A deficiency in children of school-age (262 children, aged 7 to 15 years).", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 130, 139 ] ] }, { "pmid": "15951260", "text": "Blood vitamin A has been determined by HPLC with UV detection.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 6, 15 ] ] }, { "pmid": "15951260", "text": "Proteins have been measured by radial immunodiffusion according to Mancini.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15951260", "text": "Results showed that 96 children (36.6%) presented a vitamin A deficiency (vitamin A < 200 microg/L with a retinol binding protein/transthyretin molar ratio = 0.29 +/- 0.06) while 166 (63.3%) children presented normal blood concentrations of vitamin A (vitamin A > or = 200 microg/L with a Retinol Binding Protein/Transthyretin molar ratio = 0.40 +/- 0.08).", "type": "CHEMICAL", "entities": [ "vitamin A", "vitamin A", "vitamin A", "vitamin A", "Retinol" ], "offsets": [ [ 52, 61 ], [ 74, 83 ], [ 241, 250 ], [ 252, 261 ], [ 289, 296 ] ] }, { "pmid": "15951260", "text": "This study showed that the retinol binding protein and the immunoglobulin A are lower in children with vitamin A deficiency.", "type": "CHEMICAL", "entities": [ "retinol", "vitamin A" ], "offsets": [ [ 27, 34 ], [ 103, 112 ] ] }, { "pmid": "15951260", "text": "On the other hand, an isolated increase of alpha-1 glycoprotein acid has been observed in boys with vitamin A deficiency.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 100, 109 ] ] }, { "pmid": "15951260", "text": "The vitamin A deficiency observed in this survey is due to a micronutrients deficiency in the diet which is essentially based on glucides.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "15951260", "text": "The positive correlation between vitamin A and immunoglobulin A concentrations might be the result of the vitamin A inductive effect during immunoglobulins A synthesis.", "type": "CHEMICAL", "entities": [ "vitamin A", "vitamin A" ], "offsets": [ [ 33, 42 ], [ 106, 115 ] ] }, { "pmid": "15951260", "text": "The isolated increasing of alpha-1 glycoprotein acid in boys with vitamin A deficiency has been assigned to the ecosensitiveness of the unfavourable environment.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 66, 75 ] ] }, { "pmid": "15951260", "text": "We therefore concluded that, in Ivorian primary-school-aged children with vitamin A deficiency, nutritional, immunity and inflammatory proteins which are modified are respectively retinol binding protein, immunoglobulin A and alpha-1 glycoprotein acid.", "type": "CHEMICAL", "entities": [ "vitamin A", "retinol" ], "offsets": [ [ 74, 83 ], [ 180, 187 ] ] }, { "pmid": "15944809", "text": "Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early afterdepolarizations in an intact heart model of LQT3.\nBACKGROUND: In long QT syndrome (LQTS), prolongation of the QT-interval is associated with sudden cardiac death resulting from potentially life-threatening polymorphic tachycardia of the torsade de pointes (TdP) type.", "type": "CHEMICAL", "entities": [ "Verapamil" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15944809", "text": "Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS.", "type": "CHEMICAL", "entities": [ "calcium", "verapamil" ], "offsets": [ [ 69, 76 ], [ 102, 111 ] ] }, { "pmid": "15944809", "text": "We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3. METHODS AND RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15944809", "text": "In 8 Langendorff-perfused rabbit hearts, veratridine (0.1 microM), an inhibitor of sodium channel inactivation, led to a marked increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p < 0.05) thereby mimicking LQT3.", "type": "CHEMICAL", "entities": [ "veratridine", "sodium" ], "offsets": [ [ 41, 52 ], [ 83, 89 ] ] }, { "pmid": "15944809", "text": "In bradycardic (AV-blocked) hearts, simultaneous recording of up to eight epi- and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p < 0.05) and reverse frequency-dependence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15944809", "text": "After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts.", "type": "CHEMICAL", "entities": [ "potassium", "veratridine" ], "offsets": [ [ 15, 24 ], [ 40, 51 ] ] }, { "pmid": "15944809", "text": "Additional infusion of verapamil (0.75 microM) suppressed EADs and consecutively TdP in all hearts.", "type": "CHEMICAL", "entities": [ "verapamil" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "15944809", "text": "Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization.", "type": "CHEMICAL", "entities": [ "Verapamil" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15944809", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15944809", "text": "Verapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3.", "type": "CHEMICAL", "entities": [ "Verapamil" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15944809", "text": "These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.", "type": "CHEMICAL", "entities": [ "verapamil" ], "offsets": [ [ 50, 59 ] ] }, { "pmid": "17253779", "text": "Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8- dihydroretinol.\n", "type": "CHEMICAL", "entities": [ "retinol", "all-trans-13,14-dihydroretinol", "all-trans-7,8- dihydroretinol" ], "offsets": [ [ 25, 32 ], [ 56, 86 ], [ 91, 120 ] ] }, { "pmid": "17253779", "text": "Metabolism of vitamin A, all-trans-retinol, leads to the formation of 11-cis-retinaldehyde, the visual chromophore, and all-trans-retinoic acid, which is involved in the regulation of gene expression through the retinoic acid receptor.", "type": "CHEMICAL", "entities": [ "all-trans-retinoic acid", "vitamin A", "retinoic acid", "all-trans-retinol", "11-cis-retinaldehyde" ], "offsets": [ [ 120, 143 ], [ 14, 23 ], [ 212, 225 ], [ 25, 42 ], [ 70, 90 ] ] }, { "pmid": "17253779", "text": "Enzymes and binding proteins involved in retinoid metabolism are highly conserved across species.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 41, 49 ] ] }, { "pmid": "17253779", "text": "We previously described a novel mammalian enzyme that saturates the 13-14 double bond of all-trans-retinol to produce all-trans-13,14-dihydroretinol, which then follows the same metabolic fate as that of all-trans-retinol.", "type": "CHEMICAL", "entities": [ "all-trans-retinol", "all-trans-13,14-dihydroretinol", "all-trans-retinol" ], "offsets": [ [ 89, 106 ], [ 118, 148 ], [ 204, 221 ] ] }, { "pmid": "17253779", "text": "Specifically, all-trans-13,14-dihydroretinol is transiently oxidized to all-trans-13,14-dihydroretinoic acid before being oxidized further by Cyp26 enzymes.", "type": "CHEMICAL", "entities": [ "all-trans-13,14-dihydroretinol", "all-trans-13,14-dihydroretinoic acid" ], "offsets": [ [ 14, 44 ], [ 72, 108 ] ] }, { "pmid": "17253779", "text": "Here, we report the identification of two putative RetSat homologues in zebrafish, one of which, zebrafish RetSat A (zRetSat A), also had retinol saturase activity, whereas zebrafish RetSat B (zRetSat B) was inactive under similar conditions.", "type": "CHEMICAL", "entities": [ "retinol" ], "offsets": [ [ 138, 145 ] ] }, { "pmid": "17253779", "text": "Unlike mouse RetSat (mRetSat), zRetSat A had an altered bond specificity saturating either the 13-14 or 7-8 double bonds of all-trans-retinol to produce either all-trans-13,14-dihydroretinol or all-trans-7,8-dihydroretinol, respectively.", "type": "CHEMICAL", "entities": [ "all-trans-retinol", "all-trans-13,14-dihydroretinol", "all-trans-7,8-dihydroretinol" ], "offsets": [ [ 124, 141 ], [ 160, 190 ], [ 194, 222 ] ] }, { "pmid": "17253779", "text": "zRetSat A also saturated the 13-14 or 7-8 double bonds of all-trans-3,4-didehydroretinol (vitamin A2), a second endogenous form of vitamin A in zebrafish.", "type": "CHEMICAL", "entities": [ "all-trans-3,4-didehydroretinol", "vitamin A2", "vitamin A" ], "offsets": [ [ 58, 88 ], [ 90, 100 ], [ 131, 140 ] ] }, { "pmid": "17253779", "text": "The dual enzymatic activity of zRetSat A displays a newly acquired specificity for the 13-14 double bond retained in higher vertebrates and also the evolutionarily preserved activity of bacterial phytoene desaturases and plant carotenoid isomerases.", "type": "CHEMICAL", "entities": [ "phytoene" ], "offsets": [ [ 196, 204 ] ] }, { "pmid": "17253779", "text": "Expression of zRetSat A was restricted to the liver and intestine of hatchlings and adult zebrafish, whereas zRetSat B was expressed in the same tissues but at earlier developmental stages.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17253779", "text": "Exogenous all-trans-retinol, all-trans-13,14-dihydroretinol, or all-trans-7,8-dihydroretinol led to the strong induction of the expression of the retinoic acid-metabolizing enzyme, Cyp26A1, arguing for an active signaling function of dihydroretinoid metabolites in zebrafish.", "type": "CHEMICAL", "entities": [ "all-trans-retinol", "all-trans-13,14-dihydroretinol", "all-trans-7,8-dihydroretinol", "retinoic acid", "dihydroretinoid" ], "offsets": [ [ 10, 27 ], [ 29, 59 ], [ 64, 92 ], [ 146, 159 ], [ 234, 249 ] ] }, { "pmid": "17253779", "text": "These findings point to a conserved function but altered specificity of RetSat in vertebrates, leading to the generation of various dihydroretinoid compounds, some of which could have signaling functions.", "type": "CHEMICAL", "entities": [ "dihydroretinoid" ], "offsets": [ [ 132, 147 ] ] }, { "pmid": "17510308", "text": "Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes.\n", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "17510308", "text": "BACKGROUND: CYP2C9 polymorphisms are associated with decreased S-warfarin clearance and lower maintenance dosage.", "type": "CHEMICAL", "entities": [ "S-warfarin" ], "offsets": [ [ 63, 73 ] ] }, { "pmid": "17510308", "text": "Decreased expression of VKORC1 resulting from the -1639G>", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "A substitution has also been implicated in lower warfarin dose requirements.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "17510308", "text": "We investigated the additional contribution of this polymorphism to the variance in warfarin dose.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 84, 92 ] ] }, { "pmid": "17510308", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "Sixty-five patients with stable anticoagulation were genotyped for CYP2C9 and VKORC1 with Tag-It allele-specific primer extension technology.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "Plasma S-warfarin concentrations and warfarin maintenance dose were compared among patients on the basis of the VKORC1 -1639G>", "type": "CHEMICAL", "entities": [ "S-warfarin", "warfarin" ], "offsets": [ [ 7, 17 ], [ 37, 45 ] ] }, { "pmid": "17510308", "text": "A genotype.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "Eighty percent of CYP2C9*1/*1 patients stabilized on <4.0 mg/day warfarin had at least 1 VKORC1 -1639A allele.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 65, 73 ] ] }, { "pmid": "17510308", "text": "Mean warfarin doses (SD) were 6.7 (3.3), 4.3 (2.2), and 2.7 (1.2) mg/day for patients with the VKORC1 -1639GG, GA, and AA genotypes, respectively.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 5, 13 ] ] }, { "pmid": "17510308", "text": "Steady-state plasma concentrations of S-warfarin were lowest in patients with the VKORC1 -1639AA genotype and demonstrated a positive association with the VKORC1 -1639G allele copy number (trend P = 0.012).", "type": "CHEMICAL", "entities": [ "S-warfarin" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "17510308", "text": "A model including VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 110, 118 ] ] }, { "pmid": "17510308", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "The VKORC1 -1639A allele accounts for low dosage requirements of most patients without a CYP2C9 variant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17510308", "text": "Higher plasma S-warfarin concentrations corresponding to increased warfarin maintenance dosages support a hypothesis for increased expression of the VKORC1 -1639G allele.", "type": "CHEMICAL", "entities": [ "S-warfarin", "warfarin" ], "offsets": [ [ 14, 24 ], [ 67, 75 ] ] }, { "pmid": "17510308", "text": "VKORC1 and CYP2C9 genotypes, age, sex, and body weight account for the majority of variance in warfarin dose among our study population.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "20517484", "text": "The role of rasagiline in the treatment of Parkinson's disease.\n", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "20517484", "text": "Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% to 2% of people older than 60 years.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20517484", "text": "Treatment of PD consists of symptomatic therapies while neuroprotective strategies have remained elusive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20517484", "text": "Rasagiline is a novel, potent, and irreversible monoamine oxidase type B (MAO-B) inhibitor which has been approved for treatment of PD.", "type": "CHEMICAL", "entities": [ "Rasagiline", "monoamine" ], "offsets": [ [ 0, 10 ], [ 48, 57 ] ] }, { "pmid": "20517484", "text": "Rasagiline inhibits MAO-B more potently than selegiline and has the advantage of once-daily dosing.", "type": "CHEMICAL", "entities": [ "Rasagiline" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "20517484", "text": "In several large, randomized, placebo-controlled trials, rasagiline has demonstrated efficacy as monotherapy in early PD and as adjunctive therapy in advanced PD.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "20517484", "text": "In addition, rasagiline has been shown to have neuroprotective effects in in vitro and in vivo studies.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "20517484", "text": "The recently completed delayed-start ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) trial suggests a potential disease-modifying effect for rasagiline 1 mg/day, though the clinical import of this finding has yet to be established.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 167, 177 ] ] }, { "pmid": "10626836", "text": "Lithium modulates desensitization of the glutamate receptor subtype gluR3 in Xenopus oocytes.\n", "type": "CHEMICAL", "entities": [ "Lithium", "glutamate" ], "offsets": [ [ 0, 7 ], [ 41, 50 ] ] }, { "pmid": "10626836", "text": "Analysis of splice variants and site-directed mutants of the AMPA receptor GluR3 expressed in Xenopus oocytes has shown that lithium produces a large potentiation of the GluR3 flop splice variant and suggested that lithium might inhibit rapid desensitization, which is characteristic of this receptor (Karkanias, N. and Papke, R., Subtype-specific effects of lithium on glutamate receptor function.", "type": "CHEMICAL", "entities": [ "lithium", "lithium", "lithium", "glutamate", "AMPA" ], "offsets": [ [ 125, 132 ], [ 215, 222 ], [ 359, 366 ], [ 370, 379 ], [ 61, 65 ] ] }, { "pmid": "10626836", "text": "J. Neurophysiol., 81 (1999) 1506-1512).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626836", "text": "We now show that mutation of the 769R/ G desensitization site (Lomeli, H.M.J., Melcher, T., Hoger, T., Geiger, J.R., Kuner, T., Monyer, H., Higuchi, M.B.A. and Seeburg, P.H, Control of kinetic properties of AMPA receptor channels by nuclear RNA editing.", "type": "CHEMICAL", "entities": [ "AMPA" ], "offsets": [ [ 207, 211 ] ] }, { "pmid": "10626836", "text": "Science, 9(266) (1994) 1709-1713) greatly attenuates the lithium-induced potentiation of GluR3.", "type": "CHEMICAL", "entities": [ "lithium" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "10626836", "text": "Additionally, experiments with the non-desensitizing site-directed mutant GluR3(L507Y) (Stern-Bach, Y., Russo, S., Neuman, M. and Rosenmund, C., A point mutation in the glutamate binding site blocks desensitization of AMPA receptors.", "type": "CHEMICAL", "entities": [ "AMPA", "glutamate" ], "offsets": [ [ 218, 222 ], [ 169, 178 ] ] }, { "pmid": "10626836", "text": "Neuron, 21 (1998) 907-918) further confirms that lithium enhances GluR3 responses by reducing desensitization, since lithium's effects are reversed in this mutant.", "type": "CHEMICAL", "entities": [ "lithium" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "10626836", "text": "Lithium's effects on GluR3 desensitization are distinct from the effects of aniracetam on desensitization.", "type": "CHEMICAL", "entities": [ "aniracetam" ], "offsets": [ [ 76, 86 ] ] }, { "pmid": "10626836", "text": "Specifically, aniracetam, which potentiates wild-type AMPA receptors, is ineffective on the non-desensitizing GluR3(L507Y) mutant, but has synergistic effects with lithium on wild-type receptors.", "type": "CHEMICAL", "entities": [ "aniracetam", "AMPA", "lithium" ], "offsets": [ [ 14, 24 ], [ 54, 58 ], [ 164, 171 ] ] }, { "pmid": "11009561", "text": "Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats.\n", "type": "CHEMICAL", "entities": [ "tetrahydrobiopterin" ], "offsets": [ [ 23, 42 ] ] }, { "pmid": "11009561", "text": "We have reported that a deficiency of tetrahydrobiopterin (BH(4)), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O(2)(-))", "type": "CHEMICAL", "entities": [ "NO", "superoxide anion", "O(2)(-)", "tetrahydrobiopterin", "BH(4)" ], "offsets": [ [ 101, 103 ], [ 208, 224 ], [ 226, 233 ], [ 38, 57 ], [ 59, 64 ] ] }, { "pmid": "11009561", "text": "generation in the insulin-resistant state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11009561", "text": "To further confirm this hypothesis, we investigated the effects of dietary treatment with BH(4) on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats.", "type": "CHEMICAL", "entities": [ "BH(4)" ], "offsets": [ [ 90, 95 ] ] }, { "pmid": "11009561", "text": "Oral supplementation of BH(4) (10 mg. kg(-1).", "type": "CHEMICAL", "entities": [ "BH(4)" ], "offsets": [ [ 24, 29 ] ] }, { "pmid": "11009561", "text": "d(-1)) for 8 weeks significantly increased the BH(4) content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats).", "type": "CHEMICAL", "entities": [ "BH(4)", "fructose", "fructose" ], "offsets": [ [ 47, 52 ], [ 114, 122 ], [ 124, 132 ] ] }, { "pmid": "11009561", "text": "Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH(4) treatment.", "type": "CHEMICAL", "entities": [ "fructose", "BH(4)" ], "offsets": [ [ 84, 92 ], [ 120, 125 ] ] }, { "pmid": "11009561", "text": "The BH(4) treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O(2)(-) production compared with those in fructose-fed rats.", "type": "CHEMICAL", "entities": [ "BH(4)", "O(2)(-)", "fructose" ], "offsets": [ [ 4, 9 ], [ 117, 124 ], [ 159, 167 ] ] }, { "pmid": "11009561", "text": "The BH(4) treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats.", "type": "CHEMICAL", "entities": [ "triglyceride", "fructose", "BH(4)" ], "offsets": [ [ 109, 121 ], [ 144, 152 ], [ 4, 9 ] ] }, { "pmid": "11009561", "text": "Moreover, BH(4) treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-kappaB and activating protein-1, which were increased in fructose-fed rats.", "type": "CHEMICAL", "entities": [ "BH(4)", "fructose", "peroxide", "fructose" ], "offsets": [ [ 10, 15 ], [ 33, 41 ], [ 78, 86 ], [ 275, 283 ] ] }, { "pmid": "11009561", "text": "The BH(4) treatment of control rats did not have any significant effects on these parameters.", "type": "CHEMICAL", "entities": [ "BH(4)" ], "offsets": [ [ 4, 9 ] ] }, { "pmid": "11009561", "text": "These results indicate that BH(4) augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.", "type": "CHEMICAL", "entities": [ "BH(4)" ], "offsets": [ [ 28, 33 ] ] }, { "pmid": "23543413", "text": "A Re-evaluation of the Role of hCTR1, the Human High Affinity Cu Transporter in Pt-Drug Entry into Human Cells.\n", "type": "CHEMICAL", "entities": [ "Cu", "Pt" ], "offsets": [ [ 62, 64 ], [ 80, 82 ] ] }, { "pmid": "23543413", "text": "Cisplatin (cDDP) is an anti-cancer drug used in a number of malignancies including testicular, ovarian, cervical, bladder, lung, head, and neck cancers.", "type": "CHEMICAL", "entities": [ "Cisplatin", "cDDP" ], "offsets": [ [ 0, 9 ], [ 11, 15 ] ] }, { "pmid": "23543413", "text": "Its use is limited by the development of resistance, often rationalized via effects on cellular uptake.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23543413", "text": "It has been claimed that hCTR1, the human high affinity copper transporter, is the major entry pathway for cDDP and related drugs via a mechanism that mimics copper.", "type": "CHEMICAL", "entities": [ "copper", "cDDP" ], "offsets": [ [ 56, 62 ], [ 107, 111 ] ] }, { "pmid": "23543413", "text": "This is an unexpected property of hCTR1, a highly selective copper (I) transporter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23543413", "text": "We compared the uptake rates of copper with cDDP (and several analogs) into HEK293 cells over-expressing wild-type or mutant hCTR1, mouse embryonic fibroblasts (mefs) that do or do not express CTR1, and human ovarian tumor cells, sensitive or resistant to cDDP.", "type": "CHEMICAL", "entities": [ "cDDP" ], "offsets": [ [ 256, 260 ] ] }, { "pmid": "23543413", "text": "We have also compared the effects of extracellular copper, which causes regulatory endocytosis of hCTR1, to those of cDDP.", "type": "CHEMICAL", "entities": [ "copper", "cDDP" ], "offsets": [ [ 51, 57 ], [ 117, 121 ] ] }, { "pmid": "23543413", "text": "We confirm the correlation between higher hCTR1 levels and higher Pt-drug uptake in tumor cells sensitive to the drug.", "type": "CHEMICAL", "entities": [ "Pt" ], "offsets": [ [ 66, 68 ] ] }, { "pmid": "23543413", "text": "However, we show that hCTR1 is not the major entry route of platinum-drugs and that the copper transporter is not internalized in response to extracellular drug.", "type": "CHEMICAL", "entities": [ "platinum", "copper" ], "offsets": [ [ 60, 68 ], [ 88, 94 ] ] }, { "pmid": "23543413", "text": "Our data suggest the major entry pathway for platinum-drugs is not saturable at relevant concentrations and not protein-mediated.", "type": "CHEMICAL", "entities": [ "platinum" ], "offsets": [ [ 45, 53 ] ] }, { "pmid": "23543413", "text": "Clinical trials have been initiated that depend upon regulating membrane levels of hCTR1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23543413", "text": "If reduced drug uptake is a major factor in resistance, hCTR1 is unlikely to be a productive target in attempts to enhance efficacy, although the proteins involved in copper homeostasis may play a role.", "type": "CHEMICAL", "entities": [ "copper" ], "offsets": [ [ 167, 173 ] ] }, { "pmid": "25225185", "text": "Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization.\n", "type": "CHEMICAL", "entities": [ "brexpiprazole", "serotonin", "dopamine", "norepinephrine" ], "offsets": [ [ 17, 30 ], [ 34, 43 ], [ 45, 53 ], [ 59, 73 ] ] }, { "pmid": "25225185", "text": "Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression.", "type": "CHEMICAL", "entities": [ "Brexpiprazole", "aripiprazole" ], "offsets": [ [ 0, 13 ], [ 76, 88 ] ] }, { "pmid": "25225185", "text": "Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D2 autoreceptors, and alpha1- and alpha2-adrenergic receptors.", "type": "CHEMICAL", "entities": [ "brexpiprazole", "serotonin", "5-HT", "dopamine", "DA" ], "offsets": [ [ 86, 99 ], [ 103, 112 ], [ 114, 118 ], [ 166, 174 ], [ 176, 178 ] ] }, { "pmid": "25225185", "text": "In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use.", "type": "CHEMICAL", "entities": [ "aripiprazole" ], "offsets": [ [ 168, 180 ] ] }, { "pmid": "25225185", "text": "In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole (ED50 = 230 and 700 mug/kg, respectively).", "type": "CHEMICAL", "entities": [ "brexpiprazole", "5-HT", "aripiprazole" ], "offsets": [ [ 12, 25 ], [ 61, 65 ], [ 118, 130 ] ] }, { "pmid": "25225185", "text": "In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 = 110 mug/kg), demonstrating 5-HT2A antagonistic action.", "type": "CHEMICAL", "entities": [ "brexpiprazole", "DOI", "2,5-dimethoxy-4-iodoamphetamine", "norepinephrine" ], "offsets": [ [ 24, 37 ], [ 113, 116 ], [ 118, 149 ], [ 154, 168 ] ] }, { "pmid": "25225185", "text": "Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 = 61 mug/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors.", "type": "CHEMICAL", "entities": [ "Brexpiprazole", "DA", "apomorphine" ], "offsets": [ [ 0, 13 ], [ 52, 54 ], [ 63, 74 ] ] }, { "pmid": "25225185", "text": "Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors.", "type": "CHEMICAL", "entities": [ "aripiprazole", "DA", "brexpiprazole" ], "offsets": [ [ 14, 26 ], [ 85, 87 ], [ 97, 110 ] ] }, { "pmid": "25225185", "text": "In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons.", "type": "CHEMICAL", "entities": [ "brexpiprazole" ], "offsets": [ [ 20, 33 ] ] }, { "pmid": "25225185", "text": "Furthermore, it increased 5-HT release by terminal alpha2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 26, 30 ] ] }, { "pmid": "25225185", "text": "In the lateral geniculate nucleus, brexpiprazole displayed alpha1B-adrenoceptor antagonistic action.", "type": "CHEMICAL", "entities": [ "brexpiprazole" ], "offsets": [ [ 35, 48 ] ] }, { "pmid": "25225185", "text": "Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.", "type": "CHEMICAL", "entities": [ "brexpiprazole", "monoamine" ], "offsets": [ [ 73, 86 ], [ 90, 99 ] ] }, { "pmid": "23580257", "text": "Anti-asthmatic Effects of Baicalin in a Mouse Model of Allergic Asthma.\n", "type": "CHEMICAL", "entities": [ "Baicalin" ], "offsets": [ [ 26, 34 ] ] }, { "pmid": "23580257", "text": "The aim of the study was to investigate the anti-asthmatic effects of baicalin (BA) and the possible mechanisms.", "type": "CHEMICAL", "entities": [ "baicalin" ], "offsets": [ [ 70, 78 ] ] }, { "pmid": "23580257", "text": "Asthma model was established by ovalbumin (OVA) intraperitoneal injection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": "A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg), and BA (10 mg/kg, 20 mg/kg, 40 mg/kg).", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "23580257", "text": "Airway resistance (RI) and lung compliance (Cdyn) were measured, histological studies were evaluated by the hematoxylin and eosin staining, Th1/Th2, OVA-specific serum, and BALF IgE levels and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay, and Th17 cells was evaluated by flow cytometry (FCM).", "type": "CHEMICAL", "entities": [ "hematoxylin", "eosin" ], "offsets": [ [ 100, 111 ], [ 116, 121 ] ] }, { "pmid": "23580257", "text": "Our study demonstrated that BA inhibited OVA-induced increases in RI and eosinophil count; interleukin (IL)-4, IL-17A levels, and Cdyn were recovered and increased IFN-γ level in bronchoalveolar lavage fluid.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": "Histological studies demonstrated that BA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": "FCM studies demonstrated that BA substantially inhibited Th17 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": "These findings suggest that BA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": "Copyright ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23580257", "text": " 2013 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22859660", "text": "Effects of fenofibrate, a PPAR-α ligand, on the haemodynamics of glycerol-induced renal failure in rats.\n", "type": "CHEMICAL", "entities": [ "fenofibrate", "glycerol" ], "offsets": [ [ 11, 22 ], [ 65, 73 ] ] }, { "pmid": "22859660", "text": "The modulating effect of peroxisome proliferator-activated receptor α ligand on haemodynamic effects of phenylepherine (PE), angiotensin II (AII), endothelin 1 (ET1), acetylcholine (Ach), sodium nitroprusside (SNP) and isoproterenol (ISO) were evaluated in glycerol-induced acute kidney injury in rats.", "type": "CHEMICAL", "entities": [ "phenylepherine", "acetylcholine", "Ach", "sodium nitroprusside", "SNP", "isoproterenol", "ISO", "glycerol" ], "offsets": [ [ 103, 117 ], [ 166, 179 ], [ 181, 184 ], [ 187, 207 ], [ 209, 212 ], [ 218, 231 ], [ 233, 236 ], [ 256, 264 ] ] }, { "pmid": "22859660", "text": "The effect of PE on fenofibrate-treated animals was a dose-dependent increase in mean arterial blood pressure (MAP).", "type": "CHEMICAL", "entities": [ "fenofibrate" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "22859660", "text": "For AII and ET1, MAP was also increased for the fenofibrate group but not in a dose-dependent fashion.", "type": "CHEMICAL", "entities": [ "fenofibrate" ], "offsets": [ [ 46, 57 ] ] }, { "pmid": "22859660", "text": "On the medullary blood flow (MBF), while the lower doses of PE and AII increased the perfusion unit on the fenofibrate-treated group, the higher doses decreased the perfusion unit.", "type": "CHEMICAL", "entities": [ "fenofibrate" ], "offsets": [ [ 105, 116 ] ] }, { "pmid": "22859660", "text": "The ET1 increased the perfusion unit on this group but not in dose-dependent fashion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22859660", "text": "The effects of PE and AII on the cortical blood flow (CBF) of fenofibrate-treated group is similar to that of MBF for the same group but not for ET1.", "type": "CHEMICAL", "entities": [ "fenofibrate" ], "offsets": [ [ 60, 71 ] ] }, { "pmid": "22859660", "text": "The effect of Ach, SNP and ISO in all the groups was the decrease in MAP.", "type": "CHEMICAL", "entities": [ "Ach", "SNP", "ISO" ], "offsets": [ [ 12, 15 ], [ 17, 20 ], [ 25, 28 ] ] }, { "pmid": "22859660", "text": "ISO caused dose-dependent increase in MBF of fenofibrate-treated group.", "type": "CHEMICAL", "entities": [ "fenofibrate" ], "offsets": [ [ 43, 54 ] ] }, { "pmid": "22859660", "text": "The effect of Ach, SNP and ISO on the CBF perfusion unit was that of the increase for the fenofibrate-treated group.", "type": "CHEMICAL", "entities": [ "Ach", "SNP", "ISO", "fenofibrate" ], "offsets": [ [ 12, 15 ], [ 17, 20 ], [ 25, 28 ], [ 88, 99 ] ] }, { "pmid": "22859660", "text": "The study showed that fenofibrate did not attenuate increased blood pressure induced by PE, AII and ET1 but caused enhanced vasodilation by Ach, SNP and ISO.", "type": "CHEMICAL", "entities": [ "fenofibrate", "Ach", "SNP", "ISO" ], "offsets": [ [ 20, 31 ], [ 138, 141 ], [ 143, 146 ], [ 151, 154 ] ] }, { "pmid": "23159529", "text": "Nanobody-albumin nanoparticles (NANAPs) for the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells.\n", "type": "CHEMICAL", "entities": [ "17864" ], "offsets": [ [ 84, 89 ] ] }, { "pmid": "23159529", "text": "A novel, EGFR-targeted nanomedicine has been developed in the current study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159529", "text": "Glutaraldehyde crosslinked albumin nanoparticles with a size of approximately 100nm were loaded with the multikinase inhibitor 17864-L(x)-a platinum-bound sunitinib analogue-which couples the drug to methionine residues of albumin and is released in a reductive environment.", "type": "CHEMICAL", "entities": [ "17864", "platinum", "sunitinib", "methionine", "Glutaraldehyde" ], "offsets": [ [ 127, 132 ], [ 140, 148 ], [ 155, 164 ], [ 200, 210 ], [ 0, 14 ] ] }, { "pmid": "23159529", "text": "Albumin nanoparticles were surface-coated with bifunctional polyethylene glycol 3500 (PEG) and a nanobody-the single variable domain of an antibody-(Ega1) against the epidermal growth factor receptor (EGFR).", "type": "CHEMICAL", "entities": [ "polyethylene glycol", "PEG" ], "offsets": [ [ 60, 79 ], [ 86, 89 ] ] }, { "pmid": "23159529", "text": "EGa1-PEG functionalized nanoparticles showed a 40-fold higher binding to EGFR-positive 14C squamous head and neck cancer cells in comparison to PEGylated nanoparticles.", "type": "CHEMICAL", "entities": [ "PEG", "14C" ], "offsets": [ [ 5, 8 ], [ 87, 90 ] ] }, { "pmid": "23159529", "text": "17864-L(x) loaded EGa1-PEG nanoparticles were internalized by clathrin-mediated endocytosis and ultimately digested in lysosomes.", "type": "CHEMICAL", "entities": [ "17864", "PEG" ], "offsets": [ [ 0, 5 ], [ 23, 26 ] ] }, { "pmid": "23159529", "text": "The intracellular routing of EGa1 targeted nanoparticles leads to a successful release of the kinase inhibitor in the cell and inhibition of proliferation whereas the non-targeted formulations had no antiproliferative effects on 14C cells.", "type": "CHEMICAL", "entities": [ "14C" ], "offsets": [ [ 229, 232 ] ] }, { "pmid": "23159529", "text": "The drug loaded targeted nanoparticles were as effective as the free drug in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159529", "text": "These results demonstrate that multikinase inhibitor loaded nanoparticles are interesting nanomedicines for the treatment of EGFR-positive cancers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Endogenously produced asymmetrically methylated arginine residues are competitive inhibitors of all three isoforms of nitric oxide synthase (NOS).", "type": "CHEMICAL", "entities": [ "nitric oxide", "arginine" ], "offsets": [ [ 118, 130 ], [ 48, 56 ] ] }, { "pmid": "10950934", "text": "The enzyme dimethylarginine dimethylaminohydrolase (DDAH) specifically hydrolyzes these asymmetrically methylated arginine residues to citrulline and methylamines.", "type": "CHEMICAL", "entities": [ "dimethylarginine", "arginine" ], "offsets": [ [ 11, 27 ], [ 114, 122 ] ] }, { "pmid": "10950934", "text": "Previously we have proposed that regulation of asymmetric methylarginine concentration by DDAH may provide a novel mechanism for the regulation of NOS activity in vivo.", "type": "CHEMICAL", "entities": [ "methylarginine" ], "offsets": [ [ 58, 72 ] ] }, { "pmid": "10950934", "text": "Recently we reported the cloning of human DDAH and identified a novel human DDAH isoform (DDAH I and DDAH II, respectively).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Here we report that the DDAH1 gene maps to chromosome 1p22 and confirm that DDAH2 maps to the MHC III region of chromosome 6p21.3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Extensive analysis of the distribution of DDAH1 and DDAH2 mRNA in 50 human tissues indicates differential expression of DDAH isoforms in brain regions, in immune cells, and during development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "DDAH2 expression predominates in highly vascularized tissues that express the endothelial NOS isoform and in immune tissues that can express iNOS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Whereas DDAH2 is expressed at relatively high levels in all fetal tissues examined, DDAH1 expression varies little between fetal and adult tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "The chromosomal localization of the DDAHs is consistent with gene duplication, and consistent with this, comparison of the gene structures indicates that the intron/exon organization is highly conserved.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Phylogenetic analysis of DDAH sequences from diverse species suggests that DDAH gene duplication occurred prior to the emergence of bony fish some 400 million years ago.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10950934", "text": "Overall the data suggest that DDAH2 may be the more ancient of the two genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23465612", "text": "Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.\n", "type": "CHEMICAL", "entities": [ "aspartates", "dihydroisoquinoline" ], "offsets": [ [ 103, 113 ], [ 32, 51 ] ] }, { "pmid": "23465612", "text": "The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described.", "type": "CHEMICAL", "entities": [ "dihydroisoquinoline" ], "offsets": [ [ 51, 70 ] ] }, { "pmid": "23465612", "text": "Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23465612", "text": "Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond.", "type": "CHEMICAL", "entities": [ "carboxylic acid", "hydrogen" ], "offsets": [ [ 19, 34 ], [ 131, 139 ] ] }, { "pmid": "23465612", "text": "This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "Antidepressant use and glycemic control.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "Past research on the association of antidepressant medication use with glycemic control abnormalities has produced mixed results.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "To examine the association of antidepressant use with glycemic control abnormalities and screen-positive diabetes in a representative population sample of US adults without a diagnosis of diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "METHODS: Using data from adult participants of the National Health and Nutrition Examination Survey (NHANES, 2005-2010), the association of antidepressant use with continuous measures of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, insulin sensitivity and screen-positive diabetes according to HbA1c, fasting blood sugar and 2-h oral glucose tolerance test were assessed.", "type": "CHEMICAL", "entities": [ "sugar", "glucose", "glucose" ], "offsets": [ [ 208, 213 ], [ 224, 231 ], [ 350, 357 ] ] }, { "pmid": "23334176", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "Antidepressant use was not associated with increased levels of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, reduced insulin sensitivity or increased prevalence of screen-positive diabetes.", "type": "CHEMICAL", "entities": [ "sugar", "glucose" ], "offsets": [ [ 84, 89 ], [ 100, 107 ] ] }, { "pmid": "23334176", "text": "Results were mostly consistent across sociodemographic groups and across different lengths of exposure, different classes of antidepressants and levels of body mass index.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "In this representative population sample, antidepressant use was not associated with an increased risk of abnormalities in glycemic control or undetected diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23334176", "text": "Positive findings from past research may be attributable to detection bias, in that individuals prescribed antidepressants may be more likely to be tested and diagnosed with diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Tissue-type plasminogen activator (tPA), a serine protease well known for generating plasmin, has been demonstrated to induce matrix metalloproteinase-9 (MMP-9) gene expression and protein secretion in renal interstitial fibroblasts.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 43, 49 ] ] }, { "pmid": "16303771", "text": "However, exactly how tPA transduces its signal into the nucleus to control gene expression is unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "This study investigated the mechanism by which tPA induces MMP-9 gene expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Both wild-type and non-enzymatic mutant tPA were found to induce MMP-9 expression in rat kidney interstitial fibroblasts (NRK-49F), indicating that the actions of tPA are independent of its proteolytic activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "tPA bound to the low density lipoprotein receptor-related protein-1 (LRP-1) in NRK-49F cells, and this binding was competitively abrogated by the LRP-1 antagonist, the receptor-associated protein.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "In mouse embryonic fibroblasts (PEA-13) lacking LRP-1, tPA failed to induce MMP-9 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Furthermore, tPA induced rapid tyrosine phosphorylation on the beta subunit of LRP-1, which was followed by the activation of Mek1 and its downstream Erk-1 and -2.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 31, 39 ] ] }, { "pmid": "16303771", "text": "Blockade of Erk-1/2 activation by the Mek1 inhibitor abolished MMP-9 induction by tPA in NRK-49F cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Conversely, overexpression of constitutively activated Mek1 induced Erk-1/2 phosphorylation and MMP-9 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "In mouse obstructed kidney, tPA, LRP-1, and MMP-9 were concomitantly induced in the renal interstitium.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16303771", "text": "Collectively, these results suggest that besides its classical proteolytic activity, tPA acts as a cytokine that binds to the cell membrane receptor LRP-1, induces its tyrosine phosphorylation, and triggers intracellular signal transduction, thereby inducing specific gene expression in renal interstitial fibroblasts.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 168, 176 ] ] }, { "pmid": "23628509", "text": "Cyclopenta[c]phenanthrenes - Chemistry and biological activity.\n", "type": "CHEMICAL", "entities": [ "Cyclopenta[c]phenanthrenes" ], "offsets": [ [ 0, 26 ] ] }, { "pmid": "23628509", "text": "Despite cyclopenta-fused polycyclic aromatic hydrocarbons (CP-PAHs) having been detected in the environment, the ability of these compounds to induce cellular and tissue responses remains poorly characterized.", "type": "CHEMICAL", "entities": [ "CP-PAHs", "cyclopenta-fused polycyclic aromatic hydrocarbons" ], "offsets": [ [ 59, 66 ], [ 8, 57 ] ] }, { "pmid": "23628509", "text": "In this review, we look at the chemistry and biological activity of the cyclopenta[c]phenanthrenes (CP[c]Ph) as potential chemicals of concern in the process of risk assessment.", "type": "CHEMICAL", "entities": [ "cyclopenta[c]phenanthrenes", "CP[c]Ph" ], "offsets": [ [ 72, 98 ], [ 100, 107 ] ] }, { "pmid": "23628509", "text": "The first part of the review deals with the environmental occurrence and chemistry of CP-PAHs, focusing on available methods of CP[c]Ph chemical synthesis.", "type": "CHEMICAL", "entities": [ "CP-PAHs", "CP[c]Ph" ], "offsets": [ [ 86, 93 ], [ 128, 135 ] ] }, { "pmid": "23628509", "text": "The most interesting structural feature of the CP[c]Ph is the presence of a pseudo fjord-region constructed by the cyclopentane ring.", "type": "CHEMICAL", "entities": [ "CP[c]Ph", "cyclopentane" ], "offsets": [ [ 47, 54 ], [ 115, 127 ] ] }, { "pmid": "23628509", "text": "This compound can be treated either as a structurally similar one to B[c]Ph, or as a phenanthrene skeleton with an electrodonating alkyl substituent in the bay-region of the molecule.", "type": "CHEMICAL", "entities": [ "B[c]Ph", "phenanthrene", "alkyl" ], "offsets": [ [ 69, 75 ], [ 85, 97 ], [ 131, 136 ] ] }, { "pmid": "23628509", "text": "The second thread, providing available data on the adverse effects of CP[c]Ph compounds on cells and tissues of living organisms, mainly fish, improves our understanding of these possible environmental hazards.", "type": "CHEMICAL", "entities": [ "CP[c]Ph" ], "offsets": [ [ 70, 77 ] ] }, { "pmid": "23628509", "text": "The data show that CP[c]Ph is less potent at inducing CYP1A gene expression in rainbow trout than benzo[a]pyrene (B[a]P), a well-known Ah-receptor agonist.", "type": "CHEMICAL", "entities": [ "CP[c]Ph", "benzo[a]pyrene", "B[a]P" ], "offsets": [ [ 19, 26 ], [ 98, 112 ], [ 114, 119 ] ] }, { "pmid": "23628509", "text": "Interestingly, the CP[c]Ph dependent up-regulation of CYP1A mRNA is positively correlated with the incidences of clastogenic changes in rainbow trout erythrocytes.", "type": "CHEMICAL", "entities": [ "CP[c]Ph" ], "offsets": [ [ 19, 26 ] ] }, { "pmid": "23628509", "text": "CP[c]Ph has, comparably to B[a]P, a potential to repress expression of tumor suppressor p53, in the head kidney of rainbow trout.", "type": "CHEMICAL", "entities": [ "CP[c]Ph", "B[a]P" ], "offsets": [ [ 0, 7 ], [ 27, 32 ] ] }, { "pmid": "23628509", "text": "Furthermore, estrogen responsive genes in fish liver, ERα and VTG, are not induced by CP[c]Ph, suggesting that the compound has no endocrine disrupting potential.", "type": "CHEMICAL", "entities": [ "estrogen", "CP[c]Ph" ], "offsets": [ [ 13, 21 ], [ 86, 93 ] ] }, { "pmid": "23628509", "text": "However, some CP[c]Phs show mutagenic activity when investigated in the Ames test, and exhibit genotoxic properties in in vitro micronucleus assay.", "type": "CHEMICAL", "entities": [ "CP[c]Phs" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "23628509", "text": "The above characteristics suggest that CP-PAHs are chemicals of concern for which potential pathways of exposure should be further identified.", "type": "CHEMICAL", "entities": [ "CP-PAHs" ], "offsets": [ [ 38, 45 ] ] }, { "pmid": "10933803", "text": "Zymogen factor IX potentiates factor IXa-catalyzed factor X activation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10933803", "text": "Intrinsic factor X activation is accelerated >10(7)-fold by assembly of the entire complex on the activated platelet surface.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10933803", "text": "We have now observed that increasing the concentration of zymogen factor IX to physiologic levels ( approximately 100 nM) potentiates factor IXa-catalyzed activation of factor X on both activated platelets and on negatively charged phospholipid vesicles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10933803", "text": "In the presence and absence of factor VIIIa, factor IX (100 nM) lowered the K(d,appFIXa) approximately 4-fold on platelets and 2-10-fold on lipid vesicles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10933803", "text": "Treatment of two factor IX preparations with active-site inhibitors did not affect these observations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10933803", "text": "Autoradiographs of PAGE-separated reactions containing either (125)I-labeled factor IX or (125)I-labeled factor X showed that the increased factor X activation was not due to factor Xa-mediated feedback activation of factor IX and that there was increased cleavage of factor X heavy chain in the presence of factor IX in comparison with control reactions but only in the presence of both the enzyme and the surface.", "type": "CHEMICAL", "entities": [ "(125)I", "(125)I" ], "offsets": [ [ 62, 68 ], [ 90, 96 ] ] }, { "pmid": "10933803", "text": "Since plasma concentrations of prothrombin, factor VII, protein C, or protein S did not by themselves potentiate factor Xa generation and did not interfere with the potentiation of the reaction of factor IX, the effect is specific for factor IX and is not attributable to the Gla domain of all vitamin K-dependent proteins.", "type": "CHEMICAL", "entities": [ "vitamin K" ], "offsets": [ [ 294, 303 ] ] }, { "pmid": "10933803", "text": "These observations indicate that under physiologic conditions, plasma levels of the zymogen factor IX specifically increase the affinity of factor IXa for the intrinsic factor X activation complex.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Biosynthesis, assembly and secretion of coagulation factor VIII.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Factor VIII is a large complex glycoprotein that is deficient in hemophilia A. It has a domain organization consisting of A1-A2-B-A3-C1-C2 where the B domain is a heavily glycosylated region that is dispensable for procoagulant activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Factor VIII expression is 10-to 20-fold lower than the homologous coagulation factor V. Factor VIII expression is limited due to a low level of steady-state messenger RNA in the cytoplasm and inefficient transport of the primary translation product from the endoplasmic reticulum to the Golgi apparatus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Within the secretory pathway, factor VIII is processed to a heterodimer of the heavy chain (domains A1-A2-B) in a metal ion association with the light chain (domains A3-C1-C2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Upon secretion from the cell, von Willebrand factor binds the light chain of factor VIII and stabilizes the factor, preventing degradation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Protein folding within the mammalian secretory pathway is facilitated by molecular chaperones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Within the endoplasmic reticulum, factor VIII exhibits stable interaction with protein chaperones identified as the immunoglobulin-binding protein (BiP), calnexin and calreticulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "BiP is a peptide-dependent ATPase that interacts with exposed hydrophobic surfaces on unfolded proteins or unassembled protein subunits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "A potential BiP binding site within factor VIII has been identified.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Mutation of a single amino acid residue in the potential BiP binding site increased the secretion efficiency of factor VIII by threefold.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 21, 31 ] ] }, { "pmid": "9607108", "text": "Interestingly, the proposed BiP binding site is adjacent to a type-1 copper binding site within the A1 domain that is required for interaction between the factor VIII A1 domain and the A3 domain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "We propose that Cu(I) binds the type-1 copper ion-binding site in the A1 domain and provides the essential requirement for a stable interaction between the heavy and light chains.", "type": "CHEMICAL", "entities": [ "Cu(I)", "copper" ], "offsets": [ [ 16, 21 ], [ 39, 45 ] ] }, { "pmid": "9607108", "text": "Calnexin and calreticulin are transmembrane and lumenal proteins, respectively, localized to the endoplasmic reticulum, which associate transiently with many soluble and membrane glycoproteins during folding and subunit assembly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "The calnexin and calreticulin interaction with factor VIII occurs primarily through amino-terminal linked oligosaccharides within the heavily glycosylated factor VIII B domain and this interaction appears to be required for factor VIII secretion.", "type": "CHEMICAL", "entities": [ "amino" ], "offsets": [ [ 84, 89 ] ] }, { "pmid": "9607108", "text": "The findings suggest that factor VIII cycles through interactions with BiP, calnexin and calreticulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "Although the interaction with BiP does not appear to be required for factor VIII secretion, data suggest that the calnexin and/or calreticulin interaction is required for secretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9607108", "text": "The observations suggest a unique requirement for carbohydrate processing and calnexin/calreticulin interaction that may limit the productive secretion of factor VIII and have implications for approaches towards somatic cell gene therapy for hemophilia A.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 50, 62 ] ] }, { "pmid": "23260350", "text": "Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.\n", "type": "CHEMICAL", "entities": [ "benzofuran", "leukotriene A(4)" ], "offsets": [ [ 18, 28 ], [ 65, 81 ] ] }, { "pmid": "23260350", "text": "Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response.", "type": "CHEMICAL", "entities": [ "Leukotrienes" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23260350", "text": "Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4).", "type": "CHEMICAL", "entities": [ "LTA(4)", "LTB(4)", "Leukotriene A(4)" ], "offsets": [ [ 114, 120 ], [ 124, 130 ], [ 0, 16 ] ] }, { "pmid": "23260350", "text": "LTB(4) is a known pro-inflammatory mediator.", "type": "CHEMICAL", "entities": [ "LTB(4)" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23260350", "text": "This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors.", "type": "CHEMICAL", "entities": [ "benzofurans" ], "offsets": [ [ 69, 80 ] ] }, { "pmid": "23260350", "text": "The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling.", "type": "CHEMICAL", "entities": [ "benzofuran", "LTB(4)" ], "offsets": [ [ 4, 14 ], [ 71, 77 ] ] }, { "pmid": "23260350", "text": "Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).", "type": "CHEMICAL", "entities": [ "Benzofuran" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12112047", "text": "Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury.\n", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12112047", "text": "Hypoxic-ischemic brain injury in the perinatal period is a major cause of morbidity and mortality.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12112047", "text": "Presently, there are no proven effective therapies with which to safeguard the human neonatal brain against this type of injury.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12112047", "text": "Minocycline, a semisynthetic tetracycline, has been shown to be neuroprotective in certain adult ischemic injury/stroke and neurodegenerative disease models.", "type": "CHEMICAL", "entities": [ "Minocycline", "tetracycline" ], "offsets": [ [ 0, 11 ], [ 29, 41 ] ] }, { "pmid": "12112047", "text": "However, minocycline's neuroprotective effects have not been assessed after insults to the neonatal brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12112047", "text": "We now report that minocycline administered either immediately before or immediately after a hypoxic-ischemic insult substantially blocks tissue damage in a rodent model of neonatal hypoxic-ischemic brain injury.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "12112047", "text": "Minocycline treatment prevents the formation of activated caspase-3, a known effector of apoptosis, as well as the appearance of a calpain cleaved substrate, a marker of excitotoxic/necrotic cell death.", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12112047", "text": "To our knowledge, this is the first report of a systemic treatment that can be administered after a hypoxic-ischemic insult, which provides robust, nearly complete neuroprotection to the developing brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12112047", "text": "Our data suggest that minocycline or a related neuroprotective tetracycline may be a candidate to consider in human clinical trials to protect the developing brain against hypoxic-ischemic-induced damage.", "type": "CHEMICAL", "entities": [ "minocycline", "tetracycline" ], "offsets": [ [ 22, 33 ], [ 63, 75 ] ] }, { "pmid": "16206183", "text": "In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 42, 50 ] ] }, { "pmid": "16206183", "text": "Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 89, 96 ] ] }, { "pmid": "16206183", "text": "Similar to cocaine, other local anesthetics bind to the dopamine transporter (DAT) and inhibit DA uptake in rodent and monkey brain.", "type": "CHEMICAL", "entities": [ "cocaine", "dopamine", "DA" ], "offsets": [ [ 11, 18 ], [ 56, 64 ], [ 95, 97 ] ] }, { "pmid": "16206183", "text": "Additionally, local anesthetics are self-administered in rhesus monkeys, indicative of abuse liability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16206183", "text": "The present study examined the reinforcing and DAT effects of the local anesthetics dimethocaine, procaine and cocaine using in vivo techniques.", "type": "CHEMICAL", "entities": [ "dimethocaine", "procaine", "cocaine" ], "offsets": [ [ 84, 96 ], [ 98, 106 ], [ 111, 118 ] ] }, { "pmid": "16206183", "text": "Monkeys were trained to respond under a second-order schedule for i.v. cocaine administration (0.10 or 0.30 mg/kg/infusion).", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 71, 78 ] ] }, { "pmid": "16206183", "text": "When responding was stable, dimethocaine (0.030-1.7 mg/kg/ infusion) or procaine (0.10-10 mg/kg/ infusion) was substituted for the cocaine training dose.", "type": "CHEMICAL", "entities": [ "dimethocaine", "procaine", "cocaine" ], "offsets": [ [ 28, 40 ], [ 72, 80 ], [ 131, 138 ] ] }, { "pmid": "16206183", "text": "Dimethocaine administration produced higher response rates compared with that of procaine, and was a more potent reinforcer.", "type": "CHEMICAL", "entities": [ "Dimethocaine", "procaine" ], "offsets": [ [ 0, 12 ], [ 81, 89 ] ] }, { "pmid": "16206183", "text": "Drug effects on behavior were related to DAT occupancy in monkey striatum during neuroimaging with positron emission tomography (PET).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16206183", "text": "DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT).", "type": "CHEMICAL", "entities": [ "8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane", "FECNT" ], "offsets": [ [ 48, 122 ], [ 124, 129 ] ] }, { "pmid": "16206183", "text": "DAT occupancy was between 66 and 82% and <10-41% for doses of dimethocaine and procaine that maintained maximum response rates, respectively.", "type": "CHEMICAL", "entities": [ "dimethocaine", "procaine" ], "offsets": [ [ 62, 74 ], [ 79, 87 ] ] }, { "pmid": "16206183", "text": "Finally, in vivo microdialysis in awake subjects determined drug-induced changes in extracellular DA in the caudate nucleus.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 98, 100 ] ] }, { "pmid": "16206183", "text": "There was close correspondence between peak increases in DA and DAT occupancy.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 57, 59 ] ] }, { "pmid": "16206183", "text": "Overall, reinforcing effects were consistent with DAT effects determined with in vivo techniques.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16206183", "text": "The results further support a role for the DAT in the abuse liability of local anesthetics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "Bone growth retardation in mouse embryos expressing human collagenase 1.\nCellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "The extracellular matrix through the activation of cellular receptors transmits these signals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively.", "type": "CHEMICAL", "entities": [ "BrdU", "bromodeoxyuridine" ], "offsets": [ [ 126, 130 ], [ 107, 124 ] ] }, { "pmid": "17652426", "text": "Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17652426", "text": "These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19203467", "text": "Neurochemical effects of the monoamine oxidase inhibitor phenelzine on brain GABA and alanine: A comparison with vigabatrin.\n", "type": "CHEMICAL", "entities": [ "vigabatrin", "monoamine", "phenelzine", "GABA", "alanine" ], "offsets": [ [ 113, 123 ], [ 29, 38 ], [ 57, 67 ], [ 77, 81 ], [ 86, 93 ] ] }, { "pmid": "19203467", "text": "PURPOSE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19203467", "text": "To compare phenelzine (PLZ), an antidepressant drug with anxiolytic properties which inhibits monoamine oxidase (MAO) but also elevates rat brain levels of the amino acids ?", "type": "CHEMICAL", "entities": [ "monoamine", "amino acids", "phenelzine", "PLZ" ], "offsets": [ [ 94, 103 ], [ 160, 171 ], [ 11, 21 ], [ 23, 26 ] ] }, { "pmid": "19203467", "text": "-aminobutyric acid (GABA) and alanine (ALA), with vigabatrin (VIG), an anticonvulsant which elevates brain GABA by inhibition of GABA transaminase (GABA-T), with regard to their actions on brain levels of GABA and ALA and on activities of MAO, GABA-T and ALA transaminase (ALA-T).", "type": "CHEMICAL", "entities": [ "aminobutyric acid", "GABA", "alanine", "ALA", "vigabatrin", "VIG", "GABA", "GABA", "GABA", "GABA", "ALA", "GABA", "ALA", "ALA" ], "offsets": [ [ 1, 18 ], [ 20, 24 ], [ 30, 37 ], [ 39, 42 ], [ 50, 60 ], [ 62, 65 ], [ 107, 111 ], [ 129, 133 ], [ 148, 152 ], [ 205, 209 ], [ 214, 217 ], [ 244, 248 ], [ 255, 258 ], [ 273, 276 ] ] }, { "pmid": "19203467", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19203467", "text": "Male rats were administered PLZ (10 mg/kg) or VIG (1,000 mg/kg) i.p., and the rats were euthanized 4 hours later and the brains removed for analysis of levels of GABA and ALA (by electron capture gas chromatography after derivatization) and activities of MAO, GABA-T and ALA-T (radiochemical assays).", "type": "CHEMICAL", "entities": [ "PLZ", "VIG", "GABA", "ALA", "GABA", "ALA" ], "offsets": [ [ 28, 31 ], [ 46, 49 ], [ 162, 166 ], [ 171, 174 ], [ 260, 264 ], [ 271, 274 ] ] }, { "pmid": "19203467", "text": "RESULTS: Both PLZ and VIG inhibited GABA-T and elevated GABA levels.", "type": "CHEMICAL", "entities": [ "PLZ", "VIG", "GABA", "GABA" ], "offsets": [ [ 14, 17 ], [ 22, 25 ], [ 36, 40 ], [ 56, 60 ] ] }, { "pmid": "19203467", "text": "Only PLZ inhibited MAO and ALA-T and elevated ALA levels.", "type": "CHEMICAL", "entities": [ "PLZ", "ALA", "ALA" ], "offsets": [ [ 5, 8 ], [ 27, 30 ], [ 46, 49 ] ] }, { "pmid": "19203467", "text": "The effects of PLZ on both amino acids and their transaminases were blocked by pre-treatment with the MAO inhibitor tranylcypromine.", "type": "CHEMICAL", "entities": [ "tranylcypromine", "PLZ", "amino acids" ], "offsets": [ [ 116, 131 ], [ 15, 18 ], [ 27, 38 ] ] }, { "pmid": "19203467", "text": "This pretreament had no effect on the inhibition of GABA-T or the elevation of brain GABA levels produced by VIG.", "type": "CHEMICAL", "entities": [ "GABA", "GABA", "VIG" ], "offsets": [ [ 52, 56 ], [ 85, 89 ], [ 109, 112 ] ] }, { "pmid": "19203467", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19203467", "text": "At the doses studied, PLZ was as effective as VIG at elevating brain GABA levels, but, unlike VIG, also inhibited MAO and ALA-T (and increased brain ALA levels).", "type": "CHEMICAL", "entities": [ "PLZ", "VIG", "GABA", "VIG", "ALA", "ALA" ], "offsets": [ [ 22, 25 ], [ 46, 49 ], [ 69, 73 ], [ 94, 97 ], [ 122, 125 ], [ 149, 152 ] ] }, { "pmid": "19203467", "text": "Pretreatment of rats with the MAO inhibitor tranylcypromine prevented the increase in brain GABA and ALA levels with PLZ, but did not block the effect of VIG on GABA.", "type": "CHEMICAL", "entities": [ "tranylcypromine", "GABA", "ALA", "PLZ", "VIG", "GABA" ], "offsets": [ [ 44, 59 ], [ 92, 96 ], [ 101, 104 ], [ 117, 120 ], [ 154, 157 ], [ 161, 165 ] ] }, { "pmid": "19203467", "text": "These observations with tranylcypromine and PLZ support the hypothesis that an active metabolite of PLZ produced by the actions of MAO on this drug plays a major role in its GABA- and ALA-elevating actions.", "type": "CHEMICAL", "entities": [ "tranylcypromine", "PLZ", "PLZ", "GABA", "ALA" ], "offsets": [ [ 24, 39 ], [ 44, 47 ], [ 100, 103 ], [ 174, 178 ], [ 184, 187 ] ] }, { "pmid": "1705633", "text": "Clinical pharmacology of enalkiren, a novel, dipeptide renin inhibitor.\n", "type": "CHEMICAL", "entities": [ "enalkiren", "dipeptide" ], "offsets": [ [ 25, 34 ], [ 45, 54 ] ] }, { "pmid": "1705633", "text": "Enalkiren (A-64662), a potent, dipeptide renin inhibitor, mimics the transition state of the human renin substrate, angiotensinogen.", "type": "CHEMICAL", "entities": [ "Enalkiren", "A-64662", "dipeptide" ], "offsets": [ [ 0, 9 ], [ 11, 18 ], [ 31, 40 ] ] }, { "pmid": "1705633", "text": "Enalkiren has been shown to produce dose-related suppression of plasma renin activity (PRA) and angiotensin II when administered intravenously.", "type": "CHEMICAL", "entities": [ "Enalkiren", "angiotensin II" ], "offsets": [ [ 0, 9 ], [ 96, 110 ] ] }, { "pmid": "1705633", "text": "Doses of enalkiren of less than 0.1 mg/kg induced little hemodynamic response in normotensive and hypertensive volunteers despite marked suppression of PRA.", "type": "CHEMICAL", "entities": [ "enalkiren" ], "offsets": [ [ 9, 18 ] ] }, { "pmid": "1705633", "text": "However, at doses of 0.3 and 1.2 mg/kg, enalkiren produced significant, dose-related decreases in systolic and diastolic blood pressure (BP) in hypertensive patients, and the BP response was enhanced by pretreatment with hydrochlorothiazide.", "type": "CHEMICAL", "entities": [ "enalkiren", "hydrochlorothiazide" ], "offsets": [ [ 40, 49 ], [ 221, 240 ] ] }, { "pmid": "1705633", "text": "The effects of enalkiren on PRA and BP are prolonged despite its relatively short elimination phase plasma half-life (1.6 h).", "type": "CHEMICAL", "entities": [ "enalkiren" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "1705633", "text": "Persistent pharmacologic activity without evidence of tachyphylaxis was demonstrated during 1 week of treatment in hypertensive patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705633", "text": "The observed dissociation between suppression of PRA and BP response and the recruitment of dose-related BP decrements, despite complete suppression of PRA, are unexplained phenomena.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1705633", "text": "The results of clinical trials with enalkiren are encouraging, and suggest that renin inhibitors may be safe, useful therapeutic agents in the management of hypertension.", "type": "CHEMICAL", "entities": [ "enalkiren" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "11861820", "text": "Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.\nAdministration of a high-dose regimen of methamphetamine (METH) rapidly and profoundly decreases plasmalemmal and vesicular dopamine (DA) transport in the striatum, as assessed in synaptosomes and purified vesicles, respectively.", "type": "CHEMICAL", "entities": [ "dopamine", "DA", "methamphetamine", "METH", "Methylenedioxymethamphetamine", "dopamine" ], "offsets": [ [ 258, 266 ], [ 268, 270 ], [ 175, 190 ], [ 192, 196 ], [ 0, 29 ], [ 67, 75 ] ] }, { "pmid": "11861820", "text": "To determine whether these responses were common to other amphetamines of abuse, effects of methylenedioxymethamphetamine (MDMA) on the plasmalemmal DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) were assessed.", "type": "CHEMICAL", "entities": [ "amphetamines", "methylenedioxymethamphetamine", "MDMA", "DA", "monoamine" ], "offsets": [ [ 58, 70 ], [ 92, 121 ], [ 123, 127 ], [ 149, 151 ], [ 184, 193 ] ] }, { "pmid": "11861820", "text": "Similar to effects of METH reported previously, multiple high-dose MDMA administrations rapidly (within 1 h) decreased plasmalemmal DA uptake, as assessed ex vivo in synaptosomes prepared from treated rats.", "type": "CHEMICAL", "entities": [ "METH", "MDMA", "DA" ], "offsets": [ [ 22, 26 ], [ 67, 71 ], [ 132, 134 ] ] }, { "pmid": "11861820", "text": "Unlike effects of multiple METH injections, this deficit was reversed completely 24 h after drug treatment.", "type": "CHEMICAL", "entities": [ "METH" ], "offsets": [ [ 27, 31 ] ] }, { "pmid": "11861820", "text": "Also in contrast to effects of multiple METH injections, 1) MDMA caused little or no decrease in binding of the DAT ligand WIN35428, and 2) neither prevention of hyperthermia nor prior depletion of DA prevented the MDMA-induced reduction in plasmalemmal DA transport.", "type": "CHEMICAL", "entities": [ "DA", "METH", "MDMA", "WIN35428", "DA", "MDMA" ], "offsets": [ [ 254, 256 ], [ 40, 44 ], [ 60, 64 ], [ 123, 131 ], [ 198, 200 ], [ 215, 219 ] ] }, { "pmid": "11861820", "text": "However, a role for phosphorylation was suggested because pretreatment with protein kinase C inhibitors attenuated the deficit caused by MDMA in an in vitro model system.", "type": "CHEMICAL", "entities": [ "MDMA" ], "offsets": [ [ 137, 141 ] ] }, { "pmid": "11861820", "text": "In addition to affecting DAT function, MDMA rapidly decreased vesicular DA transport as assessed in striatal vesicles prepared from treated rats.", "type": "CHEMICAL", "entities": [ "MDMA", "DA" ], "offsets": [ [ 39, 43 ], [ 72, 74 ] ] }, { "pmid": "11861820", "text": "Unlike effects of multiple METH injections reported previously, this decrease partially recovered by 24 h after drug treatment.", "type": "CHEMICAL", "entities": [ "METH" ], "offsets": [ [ 27, 31 ] ] }, { "pmid": "11861820", "text": "Taken together, these results reveal several differences between effects of MDMA and previously reported METH on DAT and VMAT-2; differences that may underlie the dissimilar neurotoxic profile of these agents.", "type": "CHEMICAL", "entities": [ "MDMA", "METH" ], "offsets": [ [ 76, 80 ], [ 105, 109 ] ] }, { "pmid": "23458730", "text": "Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats.\n", "type": "CHEMICAL", "entities": [ "baicalin", "dextromethorphan" ], "offsets": [ [ 46, 54 ], [ 76, 92 ] ] }, { "pmid": "23458730", "text": "Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties.", "type": "CHEMICAL", "entities": [ "Baicalin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23458730", "text": "In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats.", "type": "CHEMICAL", "entities": [ "baicalin", "dextromethorphan", "DXM" ], "offsets": [ [ 58, 66 ], [ 88, 104 ], [ 106, 109 ] ] }, { "pmid": "23458730", "text": "Lineweaver-Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs).", "type": "CHEMICAL", "entities": [ "baicalin" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "23458730", "text": "Concomitant administration of baicalin (0.90g/kg, i.v.) and DXM (10mg/kg, i.v.) increased the maximum drug concentration (Cmax) (37%) and the area under concentration-time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P<0.01).", "type": "CHEMICAL", "entities": [ "baicalin", "DXM", "DXM" ], "offsets": [ [ 30, 38 ], [ 60, 63 ], [ 232, 235 ] ] }, { "pmid": "23458730", "text": "The change in the AUC of DXM was significantly correlated with the Cmax and AUC of baicalin (P<0.05).", "type": "CHEMICAL", "entities": [ "DXM", "baicalin" ], "offsets": [ [ 25, 28 ], [ 83, 91 ] ] }, { "pmid": "23458730", "text": "The inhibitory effects of multiple doses of baicalin (0.90g/kg, i.v., 12days) on the metabolism of DXM were similar to those observed following a single dose in rats.", "type": "CHEMICAL", "entities": [ "baicalin", "DXM" ], "offsets": [ [ 44, 52 ], [ 99, 102 ] ] }, { "pmid": "23458730", "text": "The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P<0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities.", "type": "CHEMICAL", "entities": [ "baicalin", "baicalin", "baicalin", "DXM" ], "offsets": [ [ 76, 84 ], [ 197, 205 ], [ 298, 306 ], [ 334, 337 ] ] }, { "pmid": "23206862", "text": "Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile.\n", "type": "CHEMICAL", "entities": [ "benzimidazole" ], "offsets": [ [ 26, 39 ] ] }, { "pmid": "23206862", "text": "Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 169, 175 ] ] }, { "pmid": "23206862", "text": "Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1975995", "text": "Esmolol reduces autonomic hypersensitivity and length of seizures induced by electroconvulsive therapy.\n", "type": "CHEMICAL", "entities": [ "Esmolol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "1975995", "text": "We evaluated the clinical effectiveness of esmolol, an ultra-short-acting beta 1-adrenergic receptor blocking drug, to control the sinus tachycardia and increase in arterial blood pressures induced by electroconvulsive therapy (ECT).", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "1975995", "text": "Each of 20 patients, ASA physical status I-III, participated in a double-blind, randomized study, involving four match-pair trials (placebo versus esmolol) during ECT.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 147, 154 ] ] }, { "pmid": "1975995", "text": "Each patient acted as his or her own control (total number of ECT procedures, 160).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1975995", "text": "We administered a 4-min infusion of either placebo or esmolol at the rate of 500 micrograms.kg-1.min-1.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 54, 61 ] ] }, { "pmid": "1975995", "text": "We then induced anesthesia with methohexital and succinylcholine.", "type": "CHEMICAL", "entities": [ "methohexital", "succinylcholine" ], "offsets": [ [ 32, 44 ], [ 49, 64 ] ] }, { "pmid": "1975995", "text": "After administration of electrical stimulation for ECT, the rate of infusion decreased to 300 micrograms.kg-1.min-1 for three additional minutes and was then discontinued.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1975995", "text": "Statistically significant reductions in mean heart rate from minute 2 until minute 15 and in maximum heart rate (the mean of each patient's maximum heart rate after seizure changed from 152 +/- 23 to 115 +/- 24 beats/min) occurred in patients given esmolol.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 249, 256 ] ] }, { "pmid": "1975995", "text": "During and immediately after infusion, arterial blood pressure also decreased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1975995", "text": "Finally, the length of seizures decreased, as manifested clinically from 48 +/- 18 to 39 +/- 14 s and on electroencephalogram from 86 +/- 41 to 67 +/- 28 s.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1975995", "text": "We conclude that esmolol effectively controls the hyperdynamic response to ECT and reduces the length of seizures.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 17, 24 ] ] }, { "pmid": "1975995", "text": "The significance of the latter to the overall effectiveness of ECT is not known.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23406315", "text": "A genetically encoded and gate for cell-targeted metabolic labeling of proteins.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23406315", "text": "We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23406315", "text": "The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNA(Met).", "type": "CHEMICAL", "entities": [ "methionyl", "Met", "azidonorleucine", "Anl", "Met" ], "offsets": [ [ 46, 55 ], [ 97, 100 ], [ 111, 126 ], [ 128, 131 ], [ 141, 144 ] ] }, { "pmid": "23406315", "text": "Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 110, 111 ], [ 117, 118 ] ] }, { "pmid": "23406315", "text": "Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide-alkyne cycloaddition.", "type": "CHEMICAL", "entities": [ "Anl", "copper" ], "offsets": [ [ 0, 3 ], [ 89, 95 ] ] }, { "pmid": "23406315", "text": "Protein labeling is apparent within 5 min after addition of Anl to bacterial cells in which the AND gate has been activated.", "type": "CHEMICAL", "entities": [ "Anl" ], "offsets": [ [ 60, 63 ] ] }, { "pmid": "23406315", "text": "This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23406315", "text": "The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 224, 225 ], [ 231, 232 ] ] }, { "pmid": "23406315", "text": "The observed labeling profile is predicted accurately from the strengths of the individual input signals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16973691", "text": "Relative myotoxic and haemodynamic effects of the beta-agonists fenoterol and clenbuterol measured in conscious unrestrained rats.\n", "type": "CHEMICAL", "entities": [ "fenoterol", "clenbuterol" ], "offsets": [ [ 64, 73 ], [ 78, 89 ] ] }, { "pmid": "16973691", "text": "The beta(2)-adrenoceptor (beta(2)-AR) agonists clenbuterol and fenoterol have similar beneficial effects in animal models of heart failure.", "type": "CHEMICAL", "entities": [ "clenbuterol", "fenoterol" ], "offsets": [ [ 47, 58 ], [ 63, 72 ] ] }, { "pmid": "16973691", "text": "However, large doses of clenbuterol can induce cardiomyocyte death, and it is not known which of these agents has the most favourable therapeutic profile.", "type": "CHEMICAL", "entities": [ "clenbuterol" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "16973691", "text": "We have investigated the cardiotoxicity of clenbuterol and fenoterol alongside that of isoprenaline, and compared their haemodynamic effects.", "type": "CHEMICAL", "entities": [ "clenbuterol", "fenoterol", "isoprenaline" ], "offsets": [ [ 43, 54 ], [ 59, 68 ], [ 87, 99 ] ] }, { "pmid": "16973691", "text": "Wistar rats (n = 6 per group) were subcutaneously injected with each beta-agonist (0.003-3 mmol kg(-1)) or saline, and cardiomyocyte apoptosis was detected by caspase 3 immunohistochemistry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16973691", "text": "In a separate experiment, rats (n = 4) were given equivalent doses to those used in the myotoxicity studies, in a randomized cross-over design, and their blood pressure recorded via radiotelemetry.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16973691", "text": "Injection of 0.3 mmol kg(-1) fenoterol or isoprenaline, but not clenbuterol, induced significant cardiomyocyte apoptosis (0.4 +/- 0.05%; P < 0.05).", "type": "CHEMICAL", "entities": [ "fenoterol", "isoprenaline", "clenbuterol" ], "offsets": [ [ 29, 38 ], [ 42, 54 ], [ 64, 75 ] ] }, { "pmid": "16973691", "text": "At 3 mmol kg(-1), all agonists induced apoptosis (fenoterol, 1.1 +/- 0.1%; isoprenaline, 0.9 +/- 0.8%; and clenbuterol, 0.4 +/- 0.07%; P < 0.05).", "type": "CHEMICAL", "entities": [ "fenoterol", "isoprenaline", "clenbuterol" ], "offsets": [ [ 50, 59 ], [ 75, 87 ], [ 107, 118 ] ] }, { "pmid": "16973691", "text": "beta(1)-Adrenoceptor antagonism (10 mg kg(-1) bisoprolol) prevented 92% (P < 0.05) of apoptosis induced by all three agonists, but clenbuterol-induced apoptosis could also be prevented by 96% (P < 0.05) by beta(2)-AR antagonism (10 mg kg(-1) ICI 118 551).", "type": "CHEMICAL", "entities": [ "bisoprolol", "clenbuterol" ], "offsets": [ [ 46, 56 ], [ 131, 142 ] ] }, { "pmid": "16973691", "text": "Clenbuterol decreased diastolic (1.3- to 1.6-fold; P < 0.05) and systolic blood pressure (1.3-fold; P < 0.05), and doses > 0.3 mmol kg(-1) increased heart rate (1.4-fold; P < 0.05).", "type": "CHEMICAL", "entities": [ "Clenbuterol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16973691", "text": "Fenoterol increased heart rate (1.2- to 1.4-fold; P < 0.05), and doses > 0.3 mmol kg(-1) decreased diastolic blood pressure (1.3-fold; P < 0.05).", "type": "CHEMICAL", "entities": [ "Fenoterol" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16973691", "text": "In conclusion, the cardiotoxicity of fenoterol was similar to isoprenaline and greater than clenbuterol, and fenoterol had less desirable haemodynamic effects.", "type": "CHEMICAL", "entities": [ "fenoterol", "isoprenaline", "clenbuterol", "fenoterol" ], "offsets": [ [ 37, 46 ], [ 62, 74 ], [ 92, 103 ], [ 109, 118 ] ] }, { "pmid": "23315644", "text": "Characterization of four new mouse cytochrome P450 enzymes of the CYP2J subfamily.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "linoleic acid" ], "offsets": [ [ 114, 130 ], [ 137, 150 ] ] }, { "pmid": "23315644", "text": "The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "All four new CYP2J proteins were expressed in Sf21 insect cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives.", "type": "CHEMICAL", "entities": [ "epoxides", "hydroxy" ], "offsets": [ [ 50, 58 ], [ 63, 70 ] ] }, { "pmid": "23315644", "text": "Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23315644", "text": "We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313730", "text": "The effect of manganese on dopamine toxicity and dopamine transporter (DAT) in control and DAT transfected HEK cells.\n", "type": "CHEMICAL", "entities": [ "manganese", "dopamine", "dopamine" ], "offsets": [ [ 14, 23 ], [ 27, 35 ], [ 49, 57 ] ] }, { "pmid": "23313730", "text": "Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 20, 22 ] ] }, { "pmid": "23313730", "text": "Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT).", "type": "CHEMICAL", "entities": [ "Mn", "amphetamine", "dopamine" ], "offsets": [ [ 78, 80 ], [ 162, 173 ], [ 209, 217 ] ] }, { "pmid": "23313730", "text": "Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT.", "type": "CHEMICAL", "entities": [ "Mn", "Mn" ], "offsets": [ [ 45, 47 ], [ 126, 128 ] ] }, { "pmid": "23313730", "text": "DA toxicity was saturable suggesting that transport may be rate limiting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313730", "text": "When Mn and DA were added simultaneously to the media, cell toxicity was similar to that produced by Mn alone suggesting that Mn may suppress DA uptake in the DAT containing cells.", "type": "CHEMICAL", "entities": [ "Mn", "Mn", "Mn" ], "offsets": [ [ 5, 7 ], [ 101, 103 ], [ 126, 128 ] ] }, { "pmid": "23313730", "text": "Preincubation of DA prior to the addition of Mn resulted in cell death which was essentially additive with that produced independently by the two agents.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 45, 47 ] ] }, { "pmid": "23313730", "text": "Mn was also shown to decrease DA uptake and amphetamine-induced DA efflux in DAT containing cells.", "type": "CHEMICAL", "entities": [ "Mn", "amphetamine" ], "offsets": [ [ 0, 2 ], [ 44, 55 ] ] }, { "pmid": "23313730", "text": "Time-lapsed confocal microscopy indicates that Mn can promote trafficking of cell surface DAT into intracellular compartments which may account for the decrease in DA uptake and DA efflux in these cells.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 47, 49 ] ] }, { "pmid": "23313730", "text": "Mn-induced internalization of DAT may provide an explanation for disruption in DA transmission previously reported in the striatum.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 0, 2 ] ] }, { "pmid": "14711372", "text": "Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal.\n", "type": "CHEMICAL", "entities": [ "carnitine", "carnitine" ], "offsets": [ [ 20, 29 ], [ 66, 75 ] ] }, { "pmid": "14711372", "text": "CPT I (carnitine palmitoyltransferase I) catalyses the conversion of palmitoyl-CoA into palmitoylcarnitine in the presence of L-carnitine, facilitating the entry of fatty acids into mitochondria.", "type": "CHEMICAL", "entities": [ "L-carnitine", "fatty acids", "palmitoyl-CoA", "carnitine", "palmitoylcarnitine" ], "offsets": [ [ 126, 137 ], [ 165, 176 ], [ 69, 82 ], [ 7, 16 ], [ 88, 106 ] ] }, { "pmid": "14711372", "text": "We propose a 3-D (three-dimensional) structural model for L-CPT I (liver CPT I), based on the similarity of this enzyme to the recently crystallized mouse carnitine acetyltransferase.", "type": "CHEMICAL", "entities": [ "carnitine" ], "offsets": [ [ 155, 164 ] ] }, { "pmid": "14711372", "text": "The model includes 607 of the 773 amino acids of L-CPT I, and the positions of carnitine, CoA and the palmitoyl group were assigned by superposition and docking analysis.", "type": "CHEMICAL", "entities": [ "amino acids", "carnitine", "CoA", "palmitoyl" ], "offsets": [ [ 34, 45 ], [ 79, 88 ], [ 90, 93 ], [ 102, 111 ] ] }, { "pmid": "14711372", "text": "Functional analysis of this 3-D model included the mutagenesis of several amino acids in order to identify putative catalytic residues.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 74, 85 ] ] }, { "pmid": "14711372", "text": "Mutants D477A, D567A and E590D showed reduced L-CPT", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14711372", "text": "I activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14711372", "text": "In addition, individual mutation of amino acids forming the conserved Ser685-Thr686-Ser687 motif abolished enzyme activity in mutants T686A and S687A and altered K(m) and the catalytic efficiency for carnitine in mutant S685A.", "type": "CHEMICAL", "entities": [ "amino acids", "carnitine" ], "offsets": [ [ 36, 47 ], [ 200, 209 ] ] }, { "pmid": "14711372", "text": "We conclude that the catalytic residues are His473 and Asp477, while Ser687 probably stabilizes the transition state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14711372", "text": "Several conserved lysines, i.e. Lys455, Lys505, Lys560 and Lys561, were also mutated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14711372", "text": "Only mutants K455A and K560A showed decreases in activity of 50%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14711372", "text": "The model rationalizes the finding of nine natural mutations in patients with hereditary L-CPT I deficiencies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500545", "text": "Oxysterols in cancer cell proliferation and death.\n", "type": "CHEMICAL", "entities": [ "Oxysterols" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23500545", "text": "Oxysterols have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells, while they have little or no effect on senescent cells.", "type": "CHEMICAL", "entities": [ "Oxysterols" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23500545", "text": "The mechanisms by which oxysterols may influence proliferation are manifold: they control the transcription and the turnover of the key enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, by binding to Insig-1, Insig-2 and liver X receptors.", "type": "CHEMICAL", "entities": [ "oxysterols", "cholesterol", "3-hydroxy-3-methylglutaryl CoA" ], "offsets": [ [ 24, 34 ], [ 146, 157 ], [ 169, 199 ] ] }, { "pmid": "23500545", "text": "Oxysterols are thought to be generated in proportion to the rate of cholesterol synthesis.", "type": "CHEMICAL", "entities": [ "Oxysterols", "cholesterol" ], "offsets": [ [ 0, 10 ], [ 68, 79 ] ] }, { "pmid": "23500545", "text": "Although there is no consensus about the mechanism by which these oxysterols are generated in vivo, it clearly has to be ubiquitous.", "type": "CHEMICAL", "entities": [ "oxysterols" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "23500545", "text": "The 25- and the 27-cholesterol hydroxylases, present in almost all tissues, are possible candidates.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23500545", "text": "Cholesterol uptake from lipoproteins, intracellular vesicle transport and lipid transfer are also modified by oxysterols.", "type": "CHEMICAL", "entities": [ "Cholesterol", "oxysterols" ], "offsets": [ [ 0, 11 ], [ 110, 120 ] ] }, { "pmid": "23500545", "text": "Oxysterols interfere with ERK, hedgehog and wnt pathways of proliferation and differentiation.", "type": "CHEMICAL", "entities": [ "Oxysterols" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23500545", "text": "When administered in vitro to cancer cell lines, oxysterols invariably both slow down proliferation and provoke cell death.", "type": "CHEMICAL", "entities": [ "oxysterols" ], "offsets": [ [ 49, 59 ] ] }, { "pmid": "23500545", "text": "Perhaps is it sufficient to stop proliferation of a cancer to provoke its eradication.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23500545", "text": "Therefore, the two facets of oxysterol action that seem important for cancer treatment, cytostaticity and cytotoxicity, will be discussed.", "type": "CHEMICAL", "entities": [ "oxysterol" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "23473032", "text": "In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation.\n", "type": "CHEMICAL", "entities": [ "glutamine", "citrate" ], "offsets": [ [ 114, 123 ], [ 61, 68 ] ] }, { "pmid": "23473032", "text": "Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate.", "type": "CHEMICAL", "entities": [ "α-ketoglutarate", "glutamine", "citrate" ], "offsets": [ [ 117, 132 ], [ 36, 45 ], [ 58, 65 ] ] }, { "pmid": "23473032", "text": "To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23473032", "text": "HIF expression drastically reduced intracellular citrate levels.", "type": "CHEMICAL", "entities": [ "citrate" ], "offsets": [ [ 48, 55 ] ] }, { "pmid": "23473032", "text": "Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC.", "type": "CHEMICAL", "entities": [ "acetate", "citrate", "citrate" ], "offsets": [ [ 36, 43 ], [ 47, 54 ], [ 96, 103 ] ] }, { "pmid": "23473032", "text": "These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis.", "type": "CHEMICAL", "entities": [ "citrate" ], "offsets": [ [ 53, 60 ] ] }, { "pmid": "23473032", "text": "Using [(1-13)C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice.", "type": "CHEMICAL", "entities": [ "[(1-13)C]glutamine" ], "offsets": [ [ 5, 23 ] ] }, { "pmid": "23473032", "text": "Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts.", "type": "CHEMICAL", "entities": [ "glutamine" ], "offsets": [ [ 53, 62 ] ] }, { "pmid": "23301897", "text": "Bioactive flavaglines and other constituents isolated from Aglaia perviridis.\n", "type": "CHEMICAL", "entities": [ "flavaglines" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "23301897", "text": "Eight new compounds, including two cyclopenta[b]benzopyran derivatives (1, 2), two cyclopenta[b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits, leaves, and twigs and of the roots of Aglaia perviridis collected in Vietnam.", "type": "CHEMICAL", "entities": [ "cycloartane triterpenoids", "chloroform", "methanol", "cyclopenta[b]benzopyran", "cyclopenta[b]benzofuran" ], "offsets": [ [ 133, 158 ], [ 249, 259 ], [ 291, 299 ], [ 35, 58 ], [ 83, 106 ] ] }, { "pmid": "23301897", "text": "Isolation work was monitored using human colon cancer cells (HT-29) and facilitated with an LC/MS dereplication procedure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301897", "text": "The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301897", "text": "The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configuration of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate", "type": "CHEMICAL", "entities": [ "diol", "dimolybdenum tetraacetate" ], "offsets": [ [ 129, 133 ], [ 174, 199 ] ] }, { "pmid": "23301897", "text": "[Mo2(AcO)4] induced circular dichroism procedure.", "type": "CHEMICAL", "entities": [ "Mo2(AcO)4" ], "offsets": [ [ 1, 10 ] ] }, { "pmid": "23301897", "text": "Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED50 0.0007 μM).", "type": "CHEMICAL", "entities": [ "rocaglaol", "rocaglate" ], "offsets": [ [ 110, 119 ], [ 12, 21 ] ] }, { "pmid": "23301897", "text": "The new compounds 2-4 were also active against this cell line, with ED50 values ranging from 0.46 to 4.7 μM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301897", "text": "The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23301897", "text": "In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), and a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay.", "type": "CHEMICAL", "entities": [ "perviridicin B", "rocaglate", "sesquiterpene", "2-oxaisodauc-5-en-12-al" ], "offsets": [ [ 28, 42 ], [ 60, 69 ], [ 107, 120 ], [ 122, 145 ] ] }, { "pmid": "23567950", "text": "Synthesis and biological evaluation of novel aliphatic amido-quaternary ammonium salts for anticancer chemotherapy: Part II.\n", "type": "CHEMICAL", "entities": [ "aliphatic amido-quaternary ammonium salts" ], "offsets": [ [ 45, 86 ] ] }, { "pmid": "23567950", "text": "A series of novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated for their anticancer effects involving induction of RhoB. Most of these compounds, featuring open-ring forms of aliphatic amido-quaternary ammonium salts, exhibited potent anti-proliferative activities in human cancer cell lines, including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23.", "type": "CHEMICAL", "entities": [ "aliphatic amido-quaternary ammonium salts", "aliphatic amido-quaternary ammonium salts" ], "offsets": [ [ 18, 59 ], [ 203, 244 ] ] }, { "pmid": "23567950", "text": "In further evaluation, the representative compound N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide (3b) exhibited potent pro-apoptotic activity, through RhoB activation, in HeLa cells.", "type": "CHEMICAL", "entities": [ "N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide" ], "offsets": [ [ 51, 126 ] ] }, { "pmid": "16876126", "text": "RNA interference-triggered reversal of ABCC2-dependent cisplatin resistance in human cancer cells.\n", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 55, 64 ] ] }, { "pmid": "16876126", "text": "The adenosine triphosphate binding cassette (ABC)-transporter ABCC2 (MRP2/cMOAT) can mediate resistance against the commonly used anticancer drugs cisplatin and paclitaxel.", "type": "CHEMICAL", "entities": [ "cisplatin", "paclitaxel", "adenosine triphosphate" ], "offsets": [ [ 147, 156 ], [ 161, 171 ], [ 4, 26 ] ] }, { "pmid": "16876126", "text": "To overcome the ABCC2-depending drug resistance, two specific anti-ABCC2 small interfering RNAs (siRNAs) were designed for transient triggering of the gene-silencing RNA interference (RNAi) pathway in the cisplatin-resistant human ovarian carcinoma cell line A2780RCIS.", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 205, 214 ] ] }, { "pmid": "16876126", "text": "Since both siRNAs showed biological activity, for stable inhibition of ABCC2 a corresponding short hairpin RNA (shRNA)-encoding expression vector was designed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16876126", "text": "By treatment of A2780RCIS cells with this construct, the expressions of the targeted ABCC2 encoding mRNA and transport protein were inhibited.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16876126", "text": "These effects were accompanied by reversal of resistance against cisplatin and paclitaxel.", "type": "CHEMICAL", "entities": [ "cisplatin", "paclitaxel" ], "offsets": [ [ 65, 74 ], [ 79, 89 ] ] }, { "pmid": "16876126", "text": "Thus, the data demonstrate the utility of the analyzed RNAs as powerful laboratory tools and indicate that siRNA- and shRNA-mediated RNAi-based gene therapeutic approaches may be applicable in preventing and reversing ABCC2-depending drug resistance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8836655", "text": "Epinastine (WAL 801CL) modulates the noncholinergic contraction in guinea-pig airways in vitro by a prejunctional 5-HT1-like receptor.\n", "type": "CHEMICAL", "entities": [ "Epinastine", "WAL 801CL" ], "offsets": [ [ 0, 10 ], [ 12, 21 ] ] }, { "pmid": "8836655", "text": "Electrical field stimulation (EFS) of guinea-pig airways, in vitro, evokes an excitatory nonadrenergic noncholinergic (eNANC) contraction mediated by release of tachykinins from sensory nerve endings.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8836655", "text": "Epinastine (WAL 801CL) is an antihistaminic drug with binding affinity at certain other receptors, including alpha-adrenergic receptors and various serotonin (5-HT) receptor subtypes.", "type": "CHEMICAL", "entities": [ "Epinastine", "WAL 801CL", "serotonin", "5-HT" ], "offsets": [ [ 0, 10 ], [ 12, 21 ], [ 148, 157 ], [ 159, 163 ] ] }, { "pmid": "8836655", "text": "It is used in asthma treatment; however, its mechanism of action remains to be fully defined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8836655", "text": "We have investigated whether epinastine could modulate the eNANC contraction in guinea-pig airways in vitro, and have tried to elucidate its receptor mechanism.", "type": "CHEMICAL", "entities": [ "epinastine" ], "offsets": [ [ 29, 39 ] ] }, { "pmid": "8836655", "text": "Epinastine (0.1-100 microM) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 91 +/- 7% at 100 microM. Pretreatment of the tissues with combined 5-HT1/5-HT2 antagonists, methysergide (1 microM) or methiothepin (0.1 microM), significantly attenuated the inhibitory effect of epinastine on the noncholinergic contraction.", "type": "CHEMICAL", "entities": [ "Epinastine", "methysergide", "methiothepin", "epinastine" ], "offsets": [ [ 0, 10 ], [ 230, 242 ], [ 257, 269 ], [ 334, 344 ] ] }, { "pmid": "8836655", "text": "Pretreatment with tropisetron (1 microM), a 5-HT3 antagonist, ketanserin (10 microM), a 5-HT2 antagonist, thioperamide (10 microM), a histamine H3 antagonist, or phentolamine (10 microM), an alpha-adrenergic antagonist, however, had no effect.", "type": "CHEMICAL", "entities": [ "tropisetron", "ketanserin", "thioperamide", "histamine", "phentolamine" ], "offsets": [ [ 18, 29 ], [ 62, 72 ], [ 106, 118 ], [ 134, 143 ], [ 162, 174 ] ] }, { "pmid": "8836655", "text": "Chlorpheniramine (10 microM), another histamine H1 receptor antagonist without significant 5-HT receptor binding affinity, did not produce any inhibition of the eNANC contraction.", "type": "CHEMICAL", "entities": [ "Chlorpheniramine", "histamine", "5-HT" ], "offsets": [ [ 0, 16 ], [ 38, 47 ], [ 91, 95 ] ] }, { "pmid": "8836655", "text": "Epinastine (100 microM) did not displace the dose-response curve to exogenously applied substance P (0.01-10 microM).", "type": "CHEMICAL", "entities": [ "Epinastine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "8836655", "text": "These results suggest that epinastine, although identified as a 5-HT antagonist, acts as a 5-HT1 agonist and that it inhibits the noncholinergic contraction in guinea-pig airways through stimulation of a prejunctional 5-HT1-like receptor, located to sensory nerves.", "type": "CHEMICAL", "entities": [ "epinastine", "5-HT" ], "offsets": [ [ 27, 37 ], [ 64, 68 ] ] }, { "pmid": "23615073", "text": "Vitamin C forestalls cigarette smoke induced NF-κB activation in alveolar epithelial cells.\n", "type": "CHEMICAL", "entities": [ "Vitamin C" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23615073", "text": "Cigarette smoking causes cellular oxidative stress resulting in inflammatory diseases of lung wherein transcription factor NF-κB plays an important role.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23615073", "text": "It is possible that vitamin C, an antioxidant, may prevent cigarette smoke (CS)-induced NF-κB activation that involves degradation of I-κBε and nuclear translocation of c-Rel/p50 in alveolar epithelial cells.", "type": "CHEMICAL", "entities": [ "vitamin C" ], "offsets": [ [ 18, 27 ] ] }, { "pmid": "23615073", "text": "Therefore, to examine the hypothesis, we verified the effect of vitamin C on CS-induced expression of NF-κB driven luciferase reporter and NF-κB binding at its target DNA by EMSA in alveolar epithelial A549 cells.", "type": "CHEMICAL", "entities": [ "vitamin C" ], "offsets": [ [ 59, 68 ] ] }, { "pmid": "23615073", "text": "We also examined the level of I-κBε and sub-cellular distribution of c-Rel by western blotting and immunofluorescence respectively in CSE-treated A549 cells with or without vitamin C pretreatment.", "type": "CHEMICAL", "entities": [ "vitamin C" ], "offsets": [ [ 166, 175 ] ] }, { "pmid": "23615073", "text": "We observed a significant reduction in CSE induced luciferase expression, NF-κB DNA binding, I-κBε degradation and c-Rel nuclear translocation in cells pretreated with vitamin C. To further validate the result, we examined sub-cellular distribution of c-Rel in lungs of CS-exposed guinea pigs treated or untreated with vitamin C. Result showed that vitamin C treatment resulted in markedly reduced c-Rel nuclear translocation.", "type": "CHEMICAL", "entities": [ "vitamin C", "vitamin C", "vitamin C" ], "offsets": [ [ 310, 319 ], [ 340, 349 ], [ 159, 168 ] ] }, { "pmid": "23615073", "text": "All these results demonstrate that vitamin C prevents CS(E)-induced NF-κB activation and thus it could be used for the prevention of CS-induced inflammatory diseases.", "type": "CHEMICAL", "entities": [ "vitamin C" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "23376161", "text": "Catalpol suppresses advanced glycation end-products-induced inflammatory responses through inhibition of reactive oxygen species in human monocytic THP-1 cells.\n", "type": "CHEMICAL", "entities": [ "Catalpol", "oxygen" ], "offsets": [ [ 0, 8 ], [ 114, 120 ] ] }, { "pmid": "23376161", "text": "Advanced glycation end-products (AGEs) play a pivotal role in the development of diabetic complications by inducing inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23376161", "text": "We previously reported that the fresh roots of Rehmannia glutinosa Libosch., which have been used for the treatment of diabetes in traditional Korean medicine, also have the potential to suppress AGE-mediated inflammatory response in THP-1 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23376161", "text": "In the present study, we isolated catalpol from R. glutinosa, and examined whether it has anti-inflammatory effects on AGE-stimulated THP-1 cells.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "23376161", "text": "Catalpol reduced the expression of pro-inflammatory mediates, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), inducible NO synthase (iNOS), and receptor for AGE (RAGE).", "type": "CHEMICAL", "entities": [ "Catalpol", "NO" ], "offsets": [ [ 0, 8 ], [ 153, 155 ] ] }, { "pmid": "23376161", "text": "Promoter and electromobility shift assays showed that transcriptional activation of NF-κB was significantly reduced by catalpol treatment, while AP-1 was not.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 117, 125 ] ] }, { "pmid": "23376161", "text": "Catalpol also suppressed AGE-induced phosphorylation of mitogen activated protein (MAP) kinases, degradation of IκBα and the nuclear localization of NF-κB.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23376161", "text": "Moreover, the production of intracellular reactive oxygen species (ROS) elicited by AGE was also suppressed by catalpol treatment, through dual action of reducing ROS itself and inhibiting NADPH oxidase activity.", "type": "CHEMICAL", "entities": [ "oxygen", "catalpol", "NADPH" ], "offsets": [ [ 45, 51 ], [ 105, 113 ], [ 183, 188 ] ] }, { "pmid": "23376161", "text": "Our findings indicate that catalpol suppresses AGE-mediated inflammation by inhibiting ROS production and NF-κB activity.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 21, 29 ] ] }, { "pmid": "23376161", "text": "We suggest that catalpol, a major constituent of the fresh roots of R. glutinosa, contributes to the prevention of AGE-mediated diabetic complications.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "20596674", "text": "Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line.\n", "type": "CHEMICAL", "entities": [ "Moxifloxacin", "etoposide" ], "offsets": [ [ 0, 12 ], [ 22, 31 ] ] }, { "pmid": "20596674", "text": "Etoposide (VP-16) is a topoisomerase-II (topo II) inhibitor chemotherapeutic agent.", "type": "CHEMICAL", "entities": [ "Etoposide", "VP-16" ], "offsets": [ [ 0, 9 ], [ 11, 16 ] ] }, { "pmid": "20596674", "text": "Studies have shown that a combination of VP-16 with other drugs demonstrates better clinical responses.", "type": "CHEMICAL", "entities": [ "VP-16" ], "offsets": [ [ 41, 46 ] ] }, { "pmid": "20596674", "text": "The aim of this study was to investigate the effects of moxifloxacin (MXF) and VP-16 on cellular topo II activity in drug-treated cells and evaluate the influence of MXF on the mode of action of VP-16, on proliferation and apoptosis of HT-29 cells.", "type": "CHEMICAL", "entities": [ "moxifloxacin", "MXF", "VP-16", "MXF", "VP-16" ], "offsets": [ [ 56, 68 ], [ 70, 73 ], [ 79, 84 ], [ 166, 169 ], [ 195, 200 ] ] }, { "pmid": "20596674", "text": "Decatenation assay, band depletion and Western blot analysis, cytotoxic assay (MTT), flow cytometric studies (cell cycle and survivin expression), apoptosis (DAPI-sulforhodamine staining and caspase 3 activity) and IL-8 and VEGF secretion were determined.", "type": "CHEMICAL", "entities": [ "MTT", "DAPI", "sulforhodamine" ], "offsets": [ [ 79, 82 ], [ 158, 162 ], [ 163, 177 ] ] }, { "pmid": "20596674", "text": "MXF or VP-16 slightly affected cellular topo II activity in nuclear extracts derived from drug-treated cells while the combination enhanced inhibitory activity and the reduction in band depletion of topo II.", "type": "CHEMICAL", "entities": [ "MXF", "VP-16" ], "offsets": [ [ 0, 3 ], [ 7, 12 ] ] }, { "pmid": "20596674", "text": "VP-16 induced cell cycle arrest at G2/M and the appearance of the subG1 peak which was increased by the addition of MXF.", "type": "CHEMICAL", "entities": [ "MXF", "VP-16" ], "offsets": [ [ 116, 119 ], [ 0, 5 ] ] }, { "pmid": "20596674", "text": "Apoptosis studies (DAPI staining and caspase 3 activity) showed a marked increase in the presence of MXF and VP-16 compared to VP-16 alone.", "type": "CHEMICAL", "entities": [ "DAPI", "MXF", "VP-16", "VP-16" ], "offsets": [ [ 19, 23 ], [ 101, 104 ], [ 109, 114 ], [ 127, 132 ] ] }, { "pmid": "20596674", "text": "VP-16 induced the release of IL-8, and addition of MXF reduced enhanced release and the spontaneous release of VEGF from the cells.", "type": "CHEMICAL", "entities": [ "VP-16", "MXF" ], "offsets": [ [ 0, 5 ], [ 51, 54 ] ] }, { "pmid": "20596674", "text": "In conclusion, the results suggest that the enhancement in the reduction of topo II activity by the combined MXF/VP-16 treatments was probably due to the increase in the level of the DNA-enzyme cleavable complexes formed by both drugs.", "type": "CHEMICAL", "entities": [ "MXF", "VP-16" ], "offsets": [ [ 109, 112 ], [ 113, 118 ] ] }, { "pmid": "20596674", "text": "The unique combination of MXF/VP-16 may have clinical benefits and a cytotoxic drug 'sparing effect' and should be further studied in vivo.", "type": "CHEMICAL", "entities": [ "MXF", "VP-16" ], "offsets": [ [ 26, 29 ], [ 30, 35 ] ] }, { "pmid": "14719072", "text": "Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model.\n", "type": "CHEMICAL", "entities": [ "Thymidine", "TAS-102", "thymidine" ], "offsets": [ [ 0, 9 ], [ 103, 110 ], [ 21, 30 ] ] }, { "pmid": "14719072", "text": "TAS-102 is a new oral anti-cancer drug preparation, composed of a 1:0.5 mixture (on a molar basis) of alpha,alpha,alpha-trifluorothymidine (FTD) and 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI).", "type": "CHEMICAL", "entities": [ "TAS-102", "alpha,alpha,alpha-trifluorothymidine", "FTD", "5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione hydrochloride", "TPI" ], "offsets": [ [ 0, 7 ], [ 102, 138 ], [ 140, 143 ], [ 149, 232 ], [ 234, 237 ] ] }, { "pmid": "14719072", "text": "TAS-102 currently undergoing clinical trials, has been demonstrated to have at least two mechanisms, inhibition of TS and incorporation into DNA.", "type": "CHEMICAL", "entities": [ "TAS-102" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "14719072", "text": "We hypothesized that the thymidine metabolism enzyme may be a crucial factor that affects the antitumor activity of TAS-102.", "type": "CHEMICAL", "entities": [ "thymidine", "TAS-102" ], "offsets": [ [ 25, 34 ], [ 116, 123 ] ] }, { "pmid": "14719072", "text": "In the present study, we measured the enzyme activity of thymidine kinase (TK), thymidine phosphorylase (TP) and thymidilate synthase (TS) in human cancer xenografts to investigate the contribution of these enzymes to the sensitivity of TAS-102.", "type": "CHEMICAL", "entities": [ "thymidine", "thymidine", "thymidilate", "TAS-102" ], "offsets": [ [ 57, 66 ], [ 80, 89 ], [ 113, 124 ], [ 237, 244 ] ] }, { "pmid": "14719072", "text": "Antitumor activity of TAS-102 appears to be associated with TK, tumor growth and TS.", "type": "CHEMICAL", "entities": [ "TAS-102" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "14719072", "text": "However, the most related factors in this study were the TK and TP ratio.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14719072", "text": "There was a significant correlation (p=0.04) between tumor growth inhibition and this ratio.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14719072", "text": "These results suggested that the activation and degradation pattern of FTD plays an important role in the efficacy of TAS-102 and that it is possible to use the TK/TP ratio to predict response to TAS-102 therapy.", "type": "CHEMICAL", "entities": [ "FTD", "TAS-102", "TAS-102" ], "offsets": [ [ 71, 74 ], [ 118, 125 ], [ 196, 203 ] ] }, { "pmid": "14719072", "text": "We also studied the influence of TPI on the capacity of exogenous dThd to reverse FTD-dependent growth inhibition.", "type": "CHEMICAL", "entities": [ "TPI", "FTD" ], "offsets": [ [ 33, 36 ], [ 82, 85 ] ] }, { "pmid": "14719072", "text": "Thymidine (dThd) levels rescued the effect of FTD in vitro and significantly increased in serum after administration of TAS-102 or TPI alone but not FTD alone.", "type": "CHEMICAL", "entities": [ "Thymidine", "FTD", "TAS-102", "TPI", "FTD" ], "offsets": [ [ 0, 9 ], [ 46, 49 ], [ 120, 127 ], [ 131, 134 ], [ 149, 152 ] ] }, { "pmid": "14719072", "text": "This may suggest the possibility of a decrease in antitumor effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14719072", "text": "However, our study indicated that the therapeutic index was clearly increased by FTD combined with TPI, compared with FTD alone, suggesting FTD-induced toxicity to sensitive host tissue can be selectively reversed with dThd.", "type": "CHEMICAL", "entities": [ "FTD", "TPI", "FTD", "FTD" ], "offsets": [ [ 81, 84 ], [ 99, 102 ], [ 118, 121 ], [ 140, 143 ] ] }, { "pmid": "14719072", "text": "In conclusion, TK and TPI effects on TP play important roles in the cytotoxic action of TAS-102, and it is possible to use the TK/TP ratio to predict more precisely individual resistance or sensitivity.", "type": "CHEMICAL", "entities": [ "TPI", "TAS-102" ], "offsets": [ [ 22, 25 ], [ 88, 95 ] ] }, { "pmid": "23554049", "text": "Furanodiene Presents Synergistic Anti-proliferative Activity With Paclitaxel Via", "type": "CHEMICAL", "entities": [ "Furanodiene", "Paclitaxel" ], "offsets": [ [ 0, 11 ], [ 66, 76 ] ] }, { "pmid": "23554049", "text": "Altering Cell Cycle and Integrin Signaling in 95-D Lung Cancer Cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23554049", "text": "Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines.", "type": "CHEMICAL", "entities": [ "Furanodiene", "FUR", "terpenoid" ], "offsets": [ [ 0, 11 ], [ 13, 16 ], [ 31, 40 ] ] }, { "pmid": "23554049", "text": "Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells.", "type": "CHEMICAL", "entities": [ "FUR", "paclitaxel", "TAX" ], "offsets": [ [ 50, 53 ], [ 59, 69 ], [ 71, 74 ] ] }, { "pmid": "23554049", "text": "Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase.", "type": "CHEMICAL", "entities": [ "FUR", "TAX" ], "offsets": [ [ 23, 26 ], [ 92, 95 ] ] }, { "pmid": "23554049", "text": "The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23554049", "text": "The dramatically down-regulated expression of integrin β4, focal adhesion kinase and paxillin might partially contribute to the synergic effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23554049", "text": "Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.", "type": "CHEMICAL", "entities": [ "FUR", "FUR" ], "offsets": [ [ 6, 9 ], [ 207, 210 ] ] }, { "pmid": "23554049", "text": "Copyright ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23554049", "text": " 2013 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "The mechanisms responsible for garlic - drug interactions and their in vivo relevance.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "Garlic phytochemicals and garlic supplements influence the pharmacokinetic and pharmacodynamic behavior of concomitantly ingested drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "In this paper we have summarized the mechanisms responsible for first-pass intestinal pharmacokinetic interactions by investigating the intestinal permeability of some cardiovascular, antiviral drugs, their transport with hepatic transporters and CYP3A4 metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "Transporter-enzyme interplay was studied with several in vitro models of varying complexity: rat small intestine and Caco-2 cell monolayers were used in studies of intestinal processes, and hepatic pharmacokinetics was monitored in HepG2 cells, isolated rat hepatocytes and rat liver slices.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "Garlic phytochemicals from aged garlic extract modified the activities of secretory and absorptive transporters in both intestine and liver and competitively inhibited CYP3A4 enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21838705", "text": "The increased activities of the most important intestinal efflux (P-glycoprotein - Pgp, Multidrug Resistance Associated Protein 2 - MRP-2, Breast Cancer Resistance Protein - BCRP) and uptake (MonoCarboxylate Transporter 1 - MCT1, Organic Anion Transporting Polypeptide - OATP, Peptide transporter 1 - PepT1) transporters were caused by changes in electrophysiological membrane properties and by allosteric modifications.", "type": "CHEMICAL", "entities": [ "MonoCarboxylate" ], "offsets": [ [ 192, 207 ] ] }, { "pmid": "21838705", "text": "Because clinical studies investigating interactions between garlic and human immunodeficiency virus protease inhibitors saquinavir and ritonavir have already been performed, we used these in vivo data to evaluate the in vitro results and the reliability of the models employed as screening tools for forecasting the potential of first-pass intestinal metabolism changes.", "type": "CHEMICAL", "entities": [ "saquinavir", "ritonavir" ], "offsets": [ [ 120, 130 ], [ 135, 144 ] ] }, { "pmid": "21838705", "text": "We also assessed the probability of pharmacokinetic interactions with garlic of the novel drug darunavir and other cardiovascular drugs.", "type": "CHEMICAL", "entities": [ "darunavir" ], "offsets": [ [ 95, 104 ] ] }, { "pmid": "21838705", "text": "Finally, selected garlic phytochemicals were tested for their ability to influence P-glycoprotein and CYP3A4 activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1361547", "text": "The effects of labetalol and dilevalol on isolated cardiovascular preparations of the guinea-pig and rat.\n", "type": "CHEMICAL", "entities": [ "labetalol", "dilevalol" ], "offsets": [ [ 15, 24 ], [ 29, 38 ] ] }, { "pmid": "1361547", "text": "Differing effects of labetalol and dilevalol on cardiovascular preparations have been reported.", "type": "CHEMICAL", "entities": [ "labetalol", "dilevalol" ], "offsets": [ [ 21, 30 ], [ 35, 44 ] ] }, { "pmid": "1361547", "text": "I have studied the effects of labetalol and dilevalol on the contractile responses of the rat and guinea-pig left atria and rat portal vein.", "type": "CHEMICAL", "entities": [ "labetalol", "dilevalol" ], "offsets": [ [ 30, 39 ], [ 44, 53 ] ] }, { "pmid": "1361547", "text": "On the guinea-pig left atria low concentrations of labetalol (> or = 10(-8) M) and of dilevalol (> or = 10(-7) M) inhibited to a small extent the responses to electrical cardiac stimulation, which is indicative of membrane stabilizing activity.", "type": "CHEMICAL", "entities": [ "labetalol", "dilevalol" ], "offsets": [ [ 51, 60 ], [ 86, 95 ] ] }, { "pmid": "1361547", "text": "Labetalol (> or = 3 x 10(-8) M) and dilevalol (> or = 10(-8) M) caused surmountable antagonism of the isoprenaline responses of the atria and the pA2 values were 8.60 and 8.98 at the beta 1-adrenoceptors of the rat left atria and 7.90 and 8.31, respectively, on the guinea-pig left atria which has functional beta", "type": "CHEMICAL", "entities": [ "Labetalol", "dilevalol", "isoprenaline" ], "offsets": [ [ 0, 9 ], [ 36, 45 ], [ 102, 114 ] ] }, { "pmid": "1361547", "text": "1- and beta 2-adrenoceptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1361547", "text": "Labetalol and dilevalol (both at > or = 10(-7) M) attenuated the spontaneous contractile activity of the rat portal vein and the attenuation to labetalol at 10(-6)", "type": "CHEMICAL", "entities": [ "Labetalol", "dilevalol", "labetalol" ], "offsets": [ [ 0, 9 ], [ 14, 23 ], [ 144, 153 ] ] }, { "pmid": "1361547", "text": "M was abolished by ICI 118,551 which illustrates that the labetalol-induced attenuation is beta 2-adrenoceptor mediated.", "type": "CHEMICAL", "entities": [ "ICI 118,551", "labetalol" ], "offsets": [ [ 19, 30 ], [ 58, 67 ] ] }, { "pmid": "1361547", "text": "The isoprenaline attenuation responses of the portal vein were inhibited by labetalol and dilevalol (both at > or = 10(-7) M) and the pA2 value for the labetalol at beta 2-adrenoceptors was 7.59.", "type": "CHEMICAL", "entities": [ "isoprenaline", "labetalol", "dilevalol", "labetalol" ], "offsets": [ [ 4, 16 ], [ 76, 85 ], [ 90, 99 ], [ 152, 161 ] ] }, { "pmid": "1361547", "text": "It is concluded that labetalol and dilevalol are beta 1-adrenoceptor selective antagonists.", "type": "CHEMICAL", "entities": [ "labetalol", "dilevalol" ], "offsets": [ [ 21, 30 ], [ 35, 44 ] ] }, { "pmid": "10682471", "text": "[Effect of mifepristone on the expression of progesterone receptor messenger RNA and protein in uterine leiomyomata].\n", "type": "CHEMICAL", "entities": [ "mifepristone", "progesterone" ], "offsets": [ [ 11, 23 ], [ 45, 57 ] ] }, { "pmid": "10682471", "text": "OBJECTIVE: To determine the expression of progesterone receptor (PR) mRNA and PR protein levels in the myometrium and leiomyomata from untreated and mifepristone pretreated women with leiomyoma and to examine the mechanism of mifepristone treatment on uterine leiomyomata.", "type": "CHEMICAL", "entities": [ "mifepristone", "mifepristone", "progesterone" ], "offsets": [ [ 149, 161 ], [ 226, 238 ], [ 42, 54 ] ] }, { "pmid": "10682471", "text": "METHODS: Expression of PR mRNA and PR protein were determined by Northern blot and HAP of single-dose saturated analysis in myometrium and leiomyomata (center and marginal area) from 27 untreated and 6 mifepristone pretreated women with leiomyomata.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 202, 214 ] ] }, { "pmid": "10682471", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10682471", "text": "PR mRNA abundance and PR protein levels in both myomatous center and marginal area were significantly greater than those in corporal myometrium (P < 0.01) in both follicular and luteal phases, but similar between myomatous center and marginal area (P > 0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10682471", "text": "6 cases pretreated with mifepristone 25 mg/day for 3 months were operated, all but one patient displayed a decrease in leiomyomata volume.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 24, 36 ] ] }, { "pmid": "10682471", "text": "PR mRNA abundance in both myometruim and leiomyomata (center and marginal area) was significantly decreased in 4 patients continuing mifepristone treatment before the operation but not in the other 2 patients stopping RU486 1 month before operation.", "type": "CHEMICAL", "entities": [ "mifepristone", "RU486" ], "offsets": [ [ 133, 145 ], [ 218, 223 ] ] }, { "pmid": "10682471", "text": "PR protein levels in these tissues showed significant decrease in all 6 cases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10682471", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10682471", "text": "There are overexpression of PRmRNA and PR protein in leiomyomata.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10682471", "text": "One of the mechanism of mifepristone action on decreasing leiomyomata volume may be related to suppression on expression of PR gene.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 24, 36 ] ] }, { "pmid": "10682471", "text": "It seems that suppression on transcription of PR gene is reversible, but on translation of PR gene may maintain in a relatively longer period.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10954021", "text": "Accumulation of cystathionine, cystathionine ketimine, and perhydro-1,4-thiazepine-3,5-dicarboxylic acid in whole brain and various regions of the brain of D, L-propargylglycine-treated rats.\n", "type": "CHEMICAL", "entities": [ "D, L-propargylglycine", "cystathionine", "cystathionine ketimine", "perhydro-1,4-thiazepine-3,5-dicarboxylic acid" ], "offsets": [ [ 156, 177 ], [ 16, 29 ], [ 31, 53 ], [ 59, 104 ] ] }, { "pmid": "10954021", "text": "Experimental cystathioninuria was induced in rats by administration of the cystathionine gamma-lyase inhibitor, D,L-propargylglycine.", "type": "CHEMICAL", "entities": [ "D,L-propargylglycine", "cystathionine" ], "offsets": [ [ 112, 132 ], [ 75, 88 ] ] }, { "pmid": "10954021", "text": "The cystathionine metabolites, cystathionine ketimine (CK) and perhydro-1,4-thiazepine-3,5-dicarboxylic acid (PHTZDC), were identified in whole brain and various regions of the brain in D,L-propargylglycine-treated rats.", "type": "CHEMICAL", "entities": [ "cystathionine", "cystathionine ketimine", "CK", "perhydro-1,4-thiazepine-3,5-dicarboxylic acid", "PHTZDC", "D,L-propargylglycine" ], "offsets": [ [ 4, 17 ], [ 31, 53 ], [ 55, 57 ], [ 63, 108 ], [ 110, 116 ], [ 186, 206 ] ] }, { "pmid": "10954021", "text": "The concentration of CK and PHTZDC in whole brain and various regions of the brain increased gradually after administration of D,L-propargylglycine, and reached the highest value at about 20 hours.", "type": "CHEMICAL", "entities": [ "CK", "PHTZDC", "D,L-propargylglycine" ], "offsets": [ [ 21, 23 ], [ 28, 34 ], [ 127, 147 ] ] }, { "pmid": "10954021", "text": "CK and PHTZDC accumulated in whole brain and various regions of the brain in proportion to the amount of accumulated cystathionine after D,L-propargylglycine administration.", "type": "CHEMICAL", "entities": [ "CK", "PHTZDC", "D,L-propargylglycine" ], "offsets": [ [ 0, 2 ], [ 7, 13 ], [ 137, 157 ] ] }, { "pmid": "10954021", "text": "The concentration of these compounds in the cerebellum was higher versus the other regions of the rat brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "Changes in A1C Levels Are Significantly Associated With Changes in Levels of the Cardiovascular Risk Biomarker hs-CRP: Results from SteP Study.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "OBJECTIVEThe effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high-sensitivity C-reactive protein (hs-CRP) in insulin-naïve patients with type 2 diabetes.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 76, 83 ] ] }, { "pmid": "23435160", "text": "RESEARCH DESIGN AND METHODSThe Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naïve patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "RESULTSReductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: -3.64 mg/dL (95% CI -4.21 to -3.06) versus -2.18 mg/dL (-2.93 to -1.43), respectively (P = 0.002).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (β) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02).CONCLUSIONSReductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435160", "text": "Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17085856", "text": "Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice.\n", "type": "CHEMICAL", "entities": [ "Adenosine", "benzodiazepine" ], "offsets": [ [ 0, 9 ], [ 45, 59 ] ] }, { "pmid": "17085856", "text": "The aim of the present experiment was to assess the involvement of adenosine receptor antagonists in benzodiazepine (BDZ) withdrawal signs, observed as the seizure susceptibility in mice.", "type": "CHEMICAL", "entities": [ "benzodiazepine", "BDZ", "adenosine" ], "offsets": [ [ 101, 115 ], [ 117, 120 ], [ 67, 76 ] ] }, { "pmid": "17085856", "text": "The discontinuation of chronic treatment with temazepam or diazepam decreased seizure threshold (one of BDZ withdrawal signs).", "type": "CHEMICAL", "entities": [ "temazepam", "diazepam", "BDZ" ], "offsets": [ [ 46, 55 ], [ 59, 67 ], [ 104, 107 ] ] }, { "pmid": "17085856", "text": "The concomitant application of subconvulsive dose of pentetrazole (55.0 mg/kg) with low dose of flumazenil (5.0 mg/kg) - a BDZ receptor antagonist, immediately induced BDZ withdrawal signs in these animals.", "type": "CHEMICAL", "entities": [ "pentetrazole", "flumazenil", "BDZ", "BDZ" ], "offsets": [ [ 53, 65 ], [ 96, 106 ], [ 123, 126 ], [ 168, 171 ] ] }, { "pmid": "17085856", "text": "The non-selective adenosine receptor antagonist (caffeine), and the selective adenosine A1 receptor antagonist (DPCPX), injected 15 min before the application of pentetrazole and flumazenil, were able to intensify BDZ withdrawal signs in mice.", "type": "CHEMICAL", "entities": [ "adenosine", "caffeine", "adenosine", "DPCPX", "pentetrazole", "flumazenil", "BDZ" ], "offsets": [ [ 18, 27 ], [ 49, 57 ], [ 78, 87 ], [ 112, 117 ], [ 162, 174 ], [ 179, 189 ], [ 214, 217 ] ] }, { "pmid": "17085856", "text": "The most apparent effects were observed after administration of DPCPX, indicating that the adenosine A1 receptor may play a more important role in these effects.", "type": "CHEMICAL", "entities": [ "DPCPX", "adenosine" ], "offsets": [ [ 64, 69 ], [ 91, 100 ] ] }, { "pmid": "17085856", "text": "The obtained data demonstrate that the adenosinergic system is involved in BDZ withdrawal signs in mice, and adenosine A1 receptor plays an important role in this process.", "type": "CHEMICAL", "entities": [ "BDZ", "adenosine" ], "offsets": [ [ 75, 78 ], [ 109, 118 ] ] }, { "pmid": "15102890", "text": "Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide.\n", "type": "CHEMICAL", "entities": [ "glyburide", "cholesterol" ], "offsets": [ [ 101, 110 ], [ 46, 57 ] ] }, { "pmid": "15102890", "text": "Scavenger receptor class B type I (SR-BI) and ABCA1 are structurally dissimilar cell surface proteins that play key roles in HDL metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15102890", "text": "SR-BI is a receptor that binds HDL with high affinity and mediates both the selective lipid uptake of cholesteryl esters from lipid-rich HDL to cells and the efflux of unesterified cholesterol from cells to HDL.", "type": "CHEMICAL", "entities": [ "cholesteryl esters", "cholesterol" ], "offsets": [ [ 102, 120 ], [ 181, 192 ] ] }, { "pmid": "15102890", "text": "ABCA1 mediates the efflux of unesterified cholesterol and phospholipids from cells to lipid-poor apolipoprotein A-I (apoA-I).", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "15102890", "text": "The activities of ABCA1 and other ATP binding cassette superfamily members are inhibited by the drug glyburide, and SR-BI-mediated lipid transport is blocked by small molecule inhibitors called BLTs.", "type": "CHEMICAL", "entities": [ "ATP", "glyburide" ], "offsets": [ [ 34, 37 ], [ 101, 110 ] ] }, { "pmid": "15102890", "text": "Here, we show that one BLT, [1-(2-methoxy-phenyl)-3-naphthalen-2-yl-urea] (BLT-4), blocked ABCA1-mediated cholesterol efflux to lipid-poor apoA-I at a potency similar to that for its inhibition of SR-BI (IC(50) approximately 55-60 microM).", "type": "CHEMICAL", "entities": [ "BLT", "1-(2-methoxy-phenyl)-3-naphthalen-2-yl-urea", "BLT-4", "cholesterol" ], "offsets": [ [ 23, 26 ], [ 29, 72 ], [ 75, 80 ], [ 106, 117 ] ] }, { "pmid": "15102890", "text": "Reciprocally, glyburide blocked SR-BI-mediated selective lipid uptake and efflux at a potency similar to that for its inhibition of ABCA1 (IC(50) approximately 275-300 microM).", "type": "CHEMICAL", "entities": [ "glyburide" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "15102890", "text": "As is the case with BLTs, glyburide increased the apparent affinity of HDL binding to SR-BI.", "type": "CHEMICAL", "entities": [ "glyburide" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "15102890", "text": "The reciprocal inhibition of SR-BI and ABCA1 by BLT-4 and glyburide raises the possibility that these proteins may share similar or common steps in their mechanisms of lipid transport.", "type": "CHEMICAL", "entities": [ "glyburide" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "23444334", "text": "Protective effect of butylated hydroxytoluene on ferric nitrilotriacetate induced hepatotoxicity and oxidative stress in mice.\n", "type": "CHEMICAL", "entities": [ "butylated hydroxytoluene", "ferric nitrilotriacetate" ], "offsets": [ [ 21, 45 ], [ 49, 73 ] ] }, { "pmid": "23444334", "text": "The present study was undertaken to evaluate the possible ameliorating effect of butylated hydroxyl toluene (BHT), associated with ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress and liver injury in mice.", "type": "CHEMICAL", "entities": [ "BHT", "ferric nitrilotriacetate", "Fe-NTA", "butylated hydroxyl toluene" ], "offsets": [ [ 109, 112 ], [ 131, 155 ], [ 157, 163 ], [ 81, 107 ] ] }, { "pmid": "23444334", "text": "The treatment of mice with Fe-NTA alone enhances ornithine decarboxylase activity to 4.6 folds, protein carbonyl formation increased up to 2.9 folds and DNA synthesis expressed in terms of [(3)H] thymidine incorporation increased to 3.2 folds, and antioxidants and antioxidant enzymes decreased to 1.8-2.5 folds, compared with the corresponding saline-treated controls.", "type": "CHEMICAL", "entities": [ "Fe-NTA", "ornithine", "carbonyl", "[(3)H] thymidine" ], "offsets": [ [ 27, 33 ], [ 49, 58 ], [ 104, 112 ], [ 189, 205 ] ] }, { "pmid": "23444334", "text": "These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of BHT.", "type": "CHEMICAL", "entities": [ "BHT" ], "offsets": [ [ 93, 96 ] ] }, { "pmid": "23444334", "text": "Our data show that BHT can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent.", "type": "CHEMICAL", "entities": [ "BHT", "Fe-NTA" ], "offsets": [ [ 17, 20 ], [ 58, 64 ] ] }, { "pmid": "22872607", "text": "AKRs expression in peripheral blood lymphocytes from smokers: The role of body mass index.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22872607", "text": "Aldo-keto reductases (AKRs) metabolize a wide range of substrates, including polycyclic aromatic hydrocarbons (PAHs), generating metabolites (o-quinones) and reactive oxygen species (ROS), which are capable of initiating and promoting carcinogenesis.", "type": "CHEMICAL", "entities": [ "Aldo-keto", "PAHs", "o-quinones", "oxygen", "polycyclic aromatic hydrocarbons" ], "offsets": [ [ 0, 9 ], [ 111, 115 ], [ 142, 152 ], [ 167, 173 ], [ 77, 109 ] ] }, { "pmid": "22872607", "text": "Exposure to PAHs, their metabolites, and ROS further increase AKRs isoform expression that may amplify oxidative damage.", "type": "CHEMICAL", "entities": [ "PAHs" ], "offsets": [ [ 12, 16 ] ] }, { "pmid": "22872607", "text": "Human AKR enzymes are highly polymorphic, and allelic variants may contribute to different AKRs expression in individuals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22872607", "text": "Despite the importance of AKRs in PAHs metabolism, there are no studies that evaluate, in general human populations, the effect of PAHs on AKRs expression in peripheral blood lymphocytes (PBLs).", "type": "CHEMICAL", "entities": [ "PAHs", "PAHs" ], "offsets": [ [ 34, 38 ], [ 131, 135 ] ] }, { "pmid": "22872607", "text": "The aim of this study was to determine the effect of tobacco smoke exposure, and AKR1A1*2 and AKR1C3*2 polymorphisms, on AKR1A1 and AKR1C1-AKR1C3 messenger RNA (mRNA) levels in PBLs from smokers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22872607", "text": "In the smoker group, there is a statistically significant positive association between AKR1A1, AKR1C1, and AKR1C3 mRNA induction and urine cotinine levels in individuals with a body mass index (BMI) less than 25.", "type": "CHEMICAL", "entities": [ "cotinine" ], "offsets": [ [ 139, 147 ] ] }, { "pmid": "22872607", "text": "However, AKR1A1*2 and AKR1C3*2 alleles did not influence AKR1A1 and AKR1C1-AKR1C3 mRNA levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22872607", "text": "These results suggest that AKRs induction by PAHs in smokers' PBLs is associated with BMI; therefore, the role of adipose tissue accumulation in PAHs' effects needs further investigation.", "type": "CHEMICAL", "entities": [ "PAHs", "PAHs" ], "offsets": [ [ 45, 49 ], [ 145, 149 ] ] }, { "pmid": "23333901", "text": "Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model.\n", "type": "CHEMICAL", "entities": [ "β-Lapachone", "poloxamer" ], "offsets": [ [ 32, 43 ], [ 44, 53 ] ] }, { "pmid": "23333901", "text": "β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1).", "type": "CHEMICAL", "entities": [ "NAD(P)H", "quinone", "β-Lap", "1,2-orthonaphthoquinone" ], "offsets": [ [ 114, 121 ], [ 122, 129 ], [ 12, 17 ], [ 24, 47 ] ] }, { "pmid": "23333901", "text": "NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333901", "text": "However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays.", "type": "CHEMICAL", "entities": [ "β-Lap" ], "offsets": [ [ 58, 63 ] ] }, { "pmid": "23333901", "text": "We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth.", "type": "CHEMICAL", "entities": [ "β-Lap", "methylated-β-cyclodextrin", "poloxamer 407", "β-Lap" ], "offsets": [ [ 10, 15 ], [ 37, 62 ], [ 63, 76 ], [ 92, 97 ] ] }, { "pmid": "23333901", "text": "This ternary system is fluid at room temperature, gels over 29°C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333901", "text": "Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle.", "type": "CHEMICAL", "entities": [ "β-Lap" ], "offsets": [ [ 10, 15 ] ] }, { "pmid": "23333901", "text": "Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333901", "text": "These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23090712", "text": "Lanthanum (III) regulates the nitrogen assimilation in soybean seedlings under ultraviolet-B radiation.\n", "type": "CHEMICAL", "entities": [ "Lanthanum (III)", "nitrogen" ], "offsets": [ [ 0, 15 ], [ 30, 38 ] ] }, { "pmid": "23090712", "text": "Ultraviolet-B (UV-B, 280-320 nm) radiation has seriously affected the growth of plants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23090712", "text": "Finding the technology/method to alleviate the damage of UV-B radiation has become a frontal topic in the field of environmental science.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23090712", "text": "The pretreatment with rare earth elements (REEs) is an effective method, but the regulation mechanism of REEs is unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23090712", "text": "Here, the regulation effects of lanthanum (La(III)) on nitrogen assimilation in soybean seedlings (Glycine max L.) under ultraviolet-B radiation were investigated to elucidate the regulation mechanism of REEs on plants under UV-B radiation.", "type": "CHEMICAL", "entities": [ "lanthanum", "La(III)", "nitrogen" ], "offsets": [ [ 31, 40 ], [ 42, 49 ], [ 54, 62 ] ] }, { "pmid": "23090712", "text": "UV-B radiation led to the inhibition in the activities of the key enzymes (nitrate reductase, glutamine synthetase, glutamate synthase) in the nitrogen assimilation, the decrease in the contents of nitrate and soluble proteins, as well as the increase in the content of amino acid in soybean seedlings.", "type": "CHEMICAL", "entities": [ "nitrate", "glutamine", "glutamate", "nitrogen", "nitrate", "amino acid" ], "offsets": [ [ 74, 81 ], [ 93, 102 ], [ 115, 124 ], [ 142, 150 ], [ 197, 204 ], [ 269, 279 ] ] }, { "pmid": "23090712", "text": "The change degree of UV-B radiation at the high level (0.45 W m(-2)) was higher than that of UV-B radiation at the low level (0.15 W m(-2)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23090712", "text": "The pretreatment with 20 mg L(-1) La(III) could alleviate the effects of UV-B radiation on the activities of nitrate reductase, glutamine synthetase, glutamate synthase, and glutamate dehydrogenase, promoting amino acid conversion and protein synthesis in soybean seedlings.", "type": "CHEMICAL", "entities": [ "La(III)", "nitrate", "glutamine", "glutamate", "glutamate", "amino acid" ], "offsets": [ [ 27, 34 ], [ 102, 109 ], [ 121, 130 ], [ 143, 152 ], [ 167, 176 ], [ 202, 212 ] ] }, { "pmid": "23090712", "text": "The regulation effect of La(III) under UV-B radiation at the low level was better than that of UV-B radiation at the high level.", "type": "CHEMICAL", "entities": [ "La(III)" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "23090712", "text": "The results indicated that the pretreatment with 20 mg L(-1) La(III) could alleviate the inhibition of UV-B radiation on nitrogen assimilation in soybean seedlings.", "type": "CHEMICAL", "entities": [ "La(III)", "nitrogen" ], "offsets": [ [ 51, 58 ], [ 111, 119 ] ] }, { "pmid": "15285788", "text": "Significant receptor affinities of metabolites and a degradation product of mometasone furoate.\n", "type": "CHEMICAL", "entities": [ "mometasone furoate" ], "offsets": [ [ 76, 94 ] ] }, { "pmid": "15285788", "text": "Mometasone furoate (MF) is a highly potent glucocorticoid used topically to treat inflammation in the lung, nose and on the skin.", "type": "CHEMICAL", "entities": [ "Mometasone furoate", "MF" ], "offsets": [ [ 0, 18 ], [ 20, 22 ] ] }, { "pmid": "15285788", "text": "However, so far no information has been published on the human glucocorticoid receptor activity of the metabolites or degradation products of MF.", "type": "CHEMICAL", "entities": [ "MF" ], "offsets": [ [ 142, 144 ] ] }, { "pmid": "15285788", "text": "We have now determined the relative receptor binding affinities of the known metabolite 6beta-OH MF and the degradation product 9,11-epoxy MF to understand their possible contribution to undesirable systemic side effects.", "type": "CHEMICAL", "entities": [ "6beta-OH MF", "9,11-epoxy MF" ], "offsets": [ [ 88, 99 ], [ 128, 141 ] ] }, { "pmid": "15285788", "text": "In competition experiments with human lung glucocorticoid receptors we have determined the relative receptor affinities (RRA) of these substances with reference to dexamethasone (RRA = 100).", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 164, 177 ] ] }, { "pmid": "15285788", "text": "We have discovered that 6beta-OH MF and 9,11-epoxy MF display RRAs of 206 +/- 15 and 220 +/- 22, respectively.", "type": "CHEMICAL", "entities": [ "6beta-OH MF", "9,11-epoxy MF" ], "offsets": [ [ 24, 35 ], [ 40, 53 ] ] }, { "pmid": "15285788", "text": "This level of activity is similar to that of the clinically used inhaled corticosteroid flunisolide (RRA 180 +/- 11).", "type": "CHEMICAL", "entities": [ "corticosteroid", "flunisolide" ], "offsets": [ [ 73, 87 ], [ 88, 99 ] ] }, { "pmid": "15285788", "text": "Furthermore we observed that 9,11-epoxy MF is a chemically reactive metabolite.", "type": "CHEMICAL", "entities": [ "9,11-epoxy MF" ], "offsets": [ [ 29, 42 ] ] }, { "pmid": "15285788", "text": "In recovery experiments with human plasma and lung tissue we found a time dependent decrease in extractability of the compound.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15285788", "text": "Hence, we provide data that might contribute to the understanding of the pharmacokinetics as well as the clinical effects of MF.", "type": "CHEMICAL", "entities": [ "MF" ], "offsets": [ [ 125, 127 ] ] }, { "pmid": "23374869", "text": "Inhibition of monoamine oxidase by phthalide analogues.\n", "type": "CHEMICAL", "entities": [ "monoamine", "phthalide" ], "offsets": [ [ 14, 23 ], [ 35, 44 ] ] }, { "pmid": "23374869", "text": "Based on recent reports that the small molecules, isatin and phthalimide, are suitable scaffolds for the design of high potency monoamine oxidase (MAO) inhibitors, the present study examines the MAO inhibitory properties of a series of phthalide [2-benzofuran-1(3H)-one] analogues.", "type": "CHEMICAL", "entities": [ "monoamine", "phthalide", "2-benzofuran-1(3H)-one", "isatin", "phthalimide" ], "offsets": [ [ 128, 137 ], [ 236, 245 ], [ 247, 269 ], [ 50, 56 ], [ 61, 72 ] ] }, { "pmid": "23374869", "text": "Phthalide is structurally related to isatin and phthalimide and it is demonstrated here that substitution at C6 of the phthalide moiety yields compounds endowed with high binding affinities to both human MAO isoforms.", "type": "CHEMICAL", "entities": [ "Phthalide", "isatin", "phthalimide", "phthalide" ], "offsets": [ [ 0, 9 ], [ 37, 43 ], [ 48, 59 ], [ 119, 128 ] ] }, { "pmid": "23374869", "text": "Among the nineteen homologues evaluated, the lowest IC(50)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23374869", "text": "values recorded for the inhibition of MAO-A and -B were 0.096 and 0.0014 μM, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23374869", "text": "In most instances, C6-substituted phthalides exhibit MAO-B specific inhibition.", "type": "CHEMICAL", "entities": [ "phthalides" ], "offsets": [ [ 33, 43 ] ] }, { "pmid": "23374869", "text": "Among a series of 6-benzyloxyphthalides bearing substituents on the para position of the phenyl ring the general order of potency was CF(3) >", "type": "CHEMICAL", "entities": [ "6-benzyloxyphthalides", "phenyl", "CF(3)" ], "offsets": [ [ 17, 38 ], [ 88, 94 ], [ 133, 138 ] ] }, { "pmid": "23374869", "text": "I >", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23374869", "text": "Br >", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23374869", "text": "Cl >", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23374869", "text": "F > CH(3) >", "type": "CHEMICAL", "entities": [ "CH(3)" ], "offsets": [ [ 3, 8 ] ] }, { "pmid": "23374869", "text": "H. The results also show that the binding modes of representative phthalides are reversible and competitive at both MAO isoforms.", "type": "CHEMICAL", "entities": [ "phthalides" ], "offsets": [ [ 65, 75 ] ] }, { "pmid": "23374869", "text": "Based on these data, C6-substituted phthalides may serve as leads for the development of therapies for neurodegenerative disorders such as Parkinson's disease.", "type": "CHEMICAL", "entities": [ "C", "phthalides" ], "offsets": [ [ 20, 21 ], [ 35, 45 ] ] }, { "pmid": "23139413", "text": "Long range effect of mutations on specific conformational changes in the extracellular loop 2 of angiotensin II type 1 receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "The topology of the second extracellular loop (ECL2) and its interaction with ligands is unique in each G protein-coupled receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "When the orthosteric ligand pocket located in the transmembrane (TM) domain is occupied, ligand-specific conformational changes occur in the ECL2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "In more than 90% of G protein-coupled receptors, ECL2 is tethered to the third TM helix via a disulfide bond.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "Therefore, understanding the extent to which the TM domain and ECL2 conformations are coupled is useful.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "To investigate this, we examined conformational changes in ECL2 of the angiotensin II type 1 receptor (AT1R) by introducing mutations in distant sites that alter the activation state equilibrium of the AT1R. Differential accessibility of reporter cysteines introduced at four conformation-sensitive sites in ECL2 of these mutants was measured.", "type": "CHEMICAL", "entities": [ "cysteines" ], "offsets": [ [ 247, 256 ] ] }, { "pmid": "23139413", "text": "Binding of the agonist angiotensin II (AngII) and inverse agonist losartan in wild-type AT1R changed the accessibility of reporter cysteines, and the pattern was consistent with ligand-specific \"lid\" conformations of ECL2.", "type": "CHEMICAL", "entities": [ "losartan", "cysteines" ], "offsets": [ [ 66, 74 ], [ 131, 140 ] ] }, { "pmid": "23139413", "text": "Without agonist stimulation, the ECL2 in the gain of function mutant N111G assumed a lid conformation similar to AngII-bound wild-type AT1R. In the presence of inverse agonists, the conformation of ECL2 in the N111G mutant was similar to the inactive state of wild-type AT1R. In contrast, AngII did not induce a lid conformation in ECL2 in the loss of function D281A mutant, which is consistent with the reduced AngII binding affinity in this mutant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "However, a lid conformation was induced by [Sar(1),Gln(2),Ile(8)]", "type": "CHEMICAL", "entities": [ "Sar", "Gln", "Ile" ], "offsets": [ [ 44, 47 ], [ 51, 54 ], [ 58, 61 ] ] }, { "pmid": "23139413", "text": "AngII, a specific analog that binds to the D281A mutant with better affinity than AngII.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23139413", "text": "These results provide evidence for the emerging paradigm of domain coupling facilitated by long range interactions at distant sites on the same receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20372850", "text": "Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer.\n", "type": "CHEMICAL", "entities": [ "pyrimidine", "thymidine" ], "offsets": [ [ 40, 50 ], [ 70, 79 ] ] }, { "pmid": "20372850", "text": "Thymidine kinase-1 (TK-1) and thymidylate synthase (TS) are key enzymes for salvage and de novo pyrimidine synthesis, respectively.", "type": "CHEMICAL", "entities": [ "Thymidine", "thymidylate", "pyrimidine" ], "offsets": [ [ 0, 9 ], [ 30, 41 ], [ 96, 106 ] ] }, { "pmid": "20372850", "text": "Numerous studies have suggested that increased TS levels are associated closely with resistance to fluoropyrimidine-based chemotherapy.", "type": "CHEMICAL", "entities": [ "fluoropyrimidine" ], "offsets": [ [ 99, 115 ] ] }, { "pmid": "20372850", "text": "TAS-102 is a novel drug containing trifluorothymidine, which is phosphorylated by TK-1 to its active monophosphated form, that in turn can inhibit TS.", "type": "CHEMICAL", "entities": [ "TAS-102", "trifluorothymidine" ], "offsets": [ [ 0, 7 ], [ 35, 53 ] ] }, { "pmid": "20372850", "text": "TAS-102 has been shown to exhibit antitumor activity in fluoropyrimidine-resistant human cancer cells.", "type": "CHEMICAL", "entities": [ "TAS-102", "fluoropyrimidine" ], "offsets": [ [ 0, 7 ], [ 56, 72 ] ] }, { "pmid": "20372850", "text": "TAS-102 is currently undergoing clinical trials for use in gastrointestinal cancers.", "type": "CHEMICAL", "entities": [ "TAS-102" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "20372850", "text": "In the present study, we used immunohistochemistry to investigate the expression of TK-1 and TS in various types of cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20372850", "text": "TK-1 and TS expression was markedly different between cancer types.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20372850", "text": "High TK-1 expression was detected prominently in gastrointestinal adenocarcinomas and esophageal and uterine squamous cell carcinomas.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20372850", "text": "Gastrointestinal adenocarcinomas and squamous cell uterine carcinomas were often accompanied by high TS expression, indicating activation of pyrimidine synthesis through both the salvage and de novo pathways.", "type": "CHEMICAL", "entities": [ "pyrimidine" ], "offsets": [ [ 141, 151 ] ] }, { "pmid": "20372850", "text": "These results led us to consider that TAS-102 may also be effective for esophageal and uterine squamous cell carcinomas, as well as for gastrointestinal adenocarcinomas, even in fluoropyrimidine-resistant cases with high TS expression.", "type": "CHEMICAL", "entities": [ "TAS-102", "fluoropyrimidine" ], "offsets": [ [ 38, 45 ], [ 178, 194 ] ] }, { "pmid": "20372850", "text": "In contrast, thyroid papillary carcinomas, lung adenocarcinomas, hepatocellular carcinomas, pancreatic ductal carcinomas, and renal cell carcinomas, which exhibit low TK-1 expression, may be resistant to TAS-102.", "type": "CHEMICAL", "entities": [ "TAS-102" ], "offsets": [ [ 204, 211 ] ] }, { "pmid": "20372850", "text": "In non-small cell lung cancers, high TK-1 expression was demonstrated in squamous cell carcinomas, but not in adenocarcinomas.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20372850", "text": "This result suggests that TAS-102 efficacy and the pyrimidine synthetic pathway may differ depending on histological type.", "type": "CHEMICAL", "entities": [ "TAS-102", "pyrimidine" ], "offsets": [ [ 26, 33 ], [ 51, 61 ] ] }, { "pmid": "20372850", "text": "Our results indicate that administration of TAS-102 could be selected on the basis of the immunohistochemical evaluation of TK-1 and TS.", "type": "CHEMICAL", "entities": [ "TAS-102" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "20347047", "text": "Increased muscarinic receptor activity of airway smooth muscle isolated from a mouse model of allergic asthma.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "The mechanisms leading to airway hyper-responsiveness (AHR) in asthma are still not fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "AHR could be produced by hypersensitivity of the airway smooth muscle or hyperreactivity of the airways.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "This study was conducted to ascertain whether AHR in a murine model of asthma is produced by changes at the level of the airway smooth muscle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "Airway smooth muscle responses were characterised in vitro in isolated trachea spirals from naive mice and from an acute ovalbumin (OVA) challenge model of allergic asthma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "AHR was investigated in vivo in conscious, freely moving mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "Inflammatory cell influx into the lungs and antibody responses to the antigen were also measured.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "In vitro study of tracheal airway smooth muscle from naive mice demonstrated concentration-related contractions to methacholine and 5-HT, but no responses to histamine or adenosine or its stable analogue, 5'-N-ethyl-carboxamidoadenosine.", "type": "CHEMICAL", "entities": [ "methacholine", "5-HT", "histamine", "adenosine", "5'-N-ethyl-carboxamidoadenosine" ], "offsets": [ [ 115, 127 ], [ 132, 136 ], [ 158, 167 ], [ 171, 180 ], [ 205, 236 ] ] }, { "pmid": "20347047", "text": "The contractions to 5-HT were inhibited by ketanserin and alosetron indicating involvement of 5-HT(2A) and 5-HT(3) receptors, respectively.", "type": "CHEMICAL", "entities": [ "5-HT", "ketanserin", "alosetron" ], "offsets": [ [ 20, 24 ], [ 43, 53 ], [ 58, 67 ] ] }, { "pmid": "20347047", "text": "In an acute model of allergic asthma, OVA-treated mice were shown to be atopic by inflammatory cell influx to the lungs after OVA challenge, increases in total IgE and OVA-specific IgG levels and contractions to OVA in isolated trachea.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "In the asthmatic model, AHR to methacholine was demonstrated in conscious, freely moving mice in vivo and in isolated trachea in vitro 24 and 72h after OVA challenge.", "type": "CHEMICAL", "entities": [ "methacholine" ], "offsets": [ [ 31, 43 ] ] }, { "pmid": "20347047", "text": "No AHR in vitro was seen for 5-HT, histamine or adenosine.", "type": "CHEMICAL", "entities": [ "5-HT", "histamine", "adenosine" ], "offsets": [ [ 29, 33 ], [ 35, 44 ], [ 48, 57 ] ] }, { "pmid": "20347047", "text": "These results suggest that, in our mouse model of asthma, changes occur at the level of the muscarinic receptor transduction pathway of coupling to airway smooth muscle contraction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20347047", "text": "These changes are maintained when tissues are removed from the inflammatory environment and for at least 3 days.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357629", "text": "Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones.\n", "type": "CHEMICAL", "entities": [ "pyrazole", "flavones" ], "offsets": [ [ 78, 86 ], [ 99, 107 ] ] }, { "pmid": "23357629", "text": "A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6.", "type": "CHEMICAL", "entities": [ "pyrazole", "flavones", "1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole" ], "offsets": [ [ 18, 26 ], [ 39, 47 ], [ 87, 135 ] ] }, { "pmid": "23357629", "text": "The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments.", "type": "CHEMICAL", "entities": [ "(1)H", "(1)H", "(1)H", "(13)C", "(1)H", "(13)C" ], "offsets": [ [ 59, 63 ], [ 64, 68 ], [ 75, 79 ], [ 80, 85 ], [ 95, 99 ], [ 100, 105 ] ] }, { "pmid": "23357629", "text": "The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice.", "type": "CHEMICAL", "entities": [ "acetic acid" ], "offsets": [ [ 137, 148 ] ] }, { "pmid": "23357629", "text": "Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357629", "text": "Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23357629", "text": "The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site.", "type": "CHEMICAL", "entities": [ "keto", "phenolic", "OH" ], "offsets": [ [ 4, 8 ], [ 13, 21 ], [ 23, 25 ] ] }, { "pmid": "23627806", "text": "Superparamagnetic Hollow Hybrid Nanogels as a Potential Guidable Vehicle System of Stimuli-Mediated MR Imaging and Multiple Cancer Therapeutics.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "Hollow hybrid nanogels were prepared first by co-assembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs) (44 wt%) with the graft copolymer (56 wt%) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in aqueous phase of pH 3.0 into the hybrid vesicle structure, followed by in situ covalent stabilization via the photo-initiated polymerization of MEA residues within vesicles.", "type": "CHEMICAL", "entities": [ "iron oxide", "acrylic acid", "2-methacryloylethyl acrylate", "poly(ethylene glycol)", "poly(N-isopropylacrylamide)", "MEA", "citric acid" ], "offsets": [ [ 102, 112 ], [ 190, 202 ], [ 207, 235 ], [ 262, 283 ], [ 288, 315 ], [ 477, 480 ], [ 65, 76 ] ] }, { "pmid": "23627806", "text": "The resultant hollow nanogels, though slightly swollen, satisfactorily retain the structural integrity while the medium pH being adjusted to 7.4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "Confining SPION clusters to such a high level (44 wt%) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM-1 s-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase due to the substantial disruption of the interactions between drug molecules and copolymer components.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "With magnetic transport guidance toward the target and subsequent exposure to alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23627806", "text": "This work demonstrates that the hollow inorganic/organic hybrid nanogels show great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640331", "text": "Progesterone receptor induces bcl-x expression through intragenic binding sites favoring RNA polymerase II elongation.\n", "type": "CHEMICAL", "entities": [ "Progesterone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23640331", "text": "Steroid receptors were classically described for regulating transcription by binding to target gene promoters.", "type": "CHEMICAL", "entities": [ "Steroid" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23640331", "text": "However, genome-wide studies reveal that steroid receptors-binding sites are mainly located at intragenic regions.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 41, 48 ] ] }, { "pmid": "23640331", "text": "To determine the role of these sites, we examined the effect of progestins on the transcription of the bcl-x gene, where only intragenic progesterone receptor-binding sites (PRbs) were identified.", "type": "CHEMICAL", "entities": [ "progesterone" ], "offsets": [ [ 137, 149 ] ] }, { "pmid": "23640331", "text": "We found that in response to hormone treatment, the PR is recruited to these sites along with two histone acetyltransferases CREB-binding protein (CBP) and GCN5, leading to an increase in histone H3 and H4 acetylation and to the binding of the SWI/SNF complex.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640331", "text": "Concomitant, a more relaxed chromatin was detected along bcl-x gene mainly in the regions surrounding the intragenic PRbs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640331", "text": "PR also mediated the recruitment of the positive elongation factor pTEFb, favoring RNA polymerase II (Pol II) elongation activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640331", "text": "Together these events promoted the re-distribution of the active Pol II toward the 3'-end of the gene and a decrease in the ratio between proximal and distal transcription.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23640331", "text": "These results suggest a novel mechanism by which PR regulates gene expression by facilitating the proper passage of the polymerase along hormone-dependent genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "Lipoxygenase and urease inhibition of the aerial parts of the Polygonatum verticillatum.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "Over expression of lipoxygenase (LOX) and urease has already contributed to the pathology of different human disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "Targeting the inhibition of these enzymes has proved great clinical utility.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "The aim of the present study was to scrutinised the inhibitory profile of the aerial parts of the Polygonatum verticillatum enzyme against LOX, urease, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using standard experimental protocols.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "When checked against lipoxygenase, the extracts revealed significant attenuation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "Of the tested extracts, the ethyl acetate fraction was the most potent (half-maximal inhibitory concentration (IC50): 97 µg/mL) followed by aqueous fraction IC50: 109 µg/mL).", "type": "CHEMICAL", "entities": [ "ethyl acetate" ], "offsets": [ [ 28, 41 ] ] }, { "pmid": "23552263", "text": "Regarding urease inhibition, n-butanol was the most potent fraction (IC50: 97 µg/mL).", "type": "CHEMICAL", "entities": [ "n-butanol" ], "offsets": [ [ 27, 36 ] ] }, { "pmid": "23552263", "text": "However, the extracts did not show significant inhibition on AChE and BChE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23552263", "text": "In the preliminary phytochemical tests, the aerial parts of the plant showed the presence of saponins, alkaloids, flavonoids, phenols, tannins and terpenoids.", "type": "CHEMICAL", "entities": [ "tannins", "terpenoids", "saponins", "flavonoids", "phenols" ], "offsets": [ [ 132, 139 ], [ 144, 154 ], [ 90, 98 ], [ 111, 121 ], [ 123, 130 ] ] }, { "pmid": "23552263", "text": "The current findings could be attributed to these groups of compounds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "A physiologically based pharmacokinetic model for the oxime TMB-4: simulation of rodent and human data.\n", "type": "CHEMICAL", "entities": [ "oxime", "TMB-4" ], "offsets": [ [ 54, 59 ], [ 60, 65 ] ] }, { "pmid": "23314320", "text": "Multiple oximes have been synthesized and evaluated for use as countermeasures against chemical warfare nerve agents.", "type": "CHEMICAL", "entities": [ "oximes" ], "offsets": [ [ 9, 15 ] ] }, { "pmid": "23314320", "text": "The current U.S. military and civilian oxime countermeasure, 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride (2-PAM), is under consideration for replacement with a more effective acetylcholinesterase reactivator, 1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate (MMB-4).", "type": "CHEMICAL", "entities": [ "oxime", "2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride", "2-PAM", "1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate", "MMB-4" ], "offsets": [ [ 39, 44 ], [ 61, 116 ], [ 118, 123 ], [ 221, 289 ], [ 291, 296 ] ] }, { "pmid": "23314320", "text": "Kinetic data in the scientific literature for MMB-4 are limited; therefore, a physiologically based pharmacokinetic (PBPK) model was developed for a structurally related oxime, 1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide.", "type": "CHEMICAL", "entities": [ "MMB-4", "oxime", "1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide" ], "offsets": [ [ 46, 51 ], [ 170, 175 ], [ 177, 238 ] ] }, { "pmid": "23314320", "text": "Based on a previous model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm), as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues.", "type": "CHEMICAL", "entities": [ "organophosphate", "diisopropylfluorophosphate" ], "offsets": [ [ 44, 59 ], [ 60, 86 ] ] }, { "pmid": "23314320", "text": "All tissue compartments are diffusion limited.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "Model parameters were collected from the literature, predicted using quantitative structure-property relationships or, when necessary, fit to available pharmacokinetic data from the literature.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as well as human blood and urine data from intravenous and intramuscular administration; sensitivity analyses were performed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "The PBPK model successfully simulates rat and human data sets and has been evaluated by predicting intravenous mouse and intramuscular human data not used in the development of the model.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "Monte Carlo analyses were performed to quantify human population kinetic variability in the human evaluation data set.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "The model identifies potential pharmacokinetic differences between rodents and humans, indicated by differences in model parameters between species.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23314320", "text": "The PBPK model can be used to optimize the dosing regimen to improve oxime therapeutic efficacy in a human population.", "type": "CHEMICAL", "entities": [ "oxime" ], "offsets": [ [ 69, 74 ] ] }, { "pmid": "23493374", "text": "Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression.\n", "type": "CHEMICAL", "entities": [ "(m)CpG", "glucose" ], "offsets": [ [ 12, 18 ], [ 68, 75 ] ] }, { "pmid": "23493374", "text": "The murine neuronal facilitative glucose transporter isoform 3 (Glut3) is developmentally regulated, peaking in expression at postnatal day (PN)14.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "23493374", "text": "In the present study, we characterized a canonical CpG island spanning the 5'-flanking region of the glut3 gene.", "type": "CHEMICAL", "entities": [ "CpG" ], "offsets": [ [ 51, 54 ] ] }, { "pmid": "23493374", "text": "Methylation-specific PCR and bisulfite", "type": "CHEMICAL", "entities": [ "bisulfite" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "23493374", "text": "sequencing identified methylation of this CpG ((m)CpG) island of the glut3 gene, frequency of methylation increasing 2.5-fold with a 1.6-fold increase in DNA methyl transferase 3a concentrations noted with advancing postnatal age (PN14 vs PN3).", "type": "CHEMICAL", "entities": [ "CpG", "(m)CpG" ], "offsets": [ [ 42, 45 ], [ 47, 53 ] ] }, { "pmid": "23493374", "text": "5'-flanking region of glut3-luciferase reporter transient transfection in HT22 hippocampal neurons demonstrated that (m)CpGs inhibit glut3 transcription.", "type": "CHEMICAL", "entities": [ "(m)CpGs" ], "offsets": [ [ 117, 124 ] ] }, { "pmid": "23493374", "text": "Contrary to this biological function, glut3 expression rises synchronously with (m)CpGs in PN14 vs PN3 neurons.", "type": "CHEMICAL", "entities": [ "(m)CpGs" ], "offsets": [ [ 80, 87 ] ] }, { "pmid": "23493374", "text": "Chromatin immunoprecipitation (IP) revealed that methyl-CpG binding protein 2 (Mecp2) bound the glut3-(m)CpGs.", "type": "CHEMICAL", "entities": [ "methyl", "(m)CpGs" ], "offsets": [ [ 49, 55 ], [ 102, 109 ] ] }, { "pmid": "23493374", "text": "Depending on association with specific coregulators, Mecp2, a dual regulator of gene transcription, may repress or activate a downstream gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23493374", "text": "Sequential chromatin IP uncovered the glut3-(m)CpGs to bind Mecp2 exponentially upon recruitment of Creb1 rather than histone deacetylase 1.", "type": "CHEMICAL", "entities": [ "(m)CpGs" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "23493374", "text": "Co-IP and coimmunolocalization confirmed that Creb1 associated with Mecp2 and cotransfection with glut3-(m)CpG in HT22 cells enhanced glut3 transcription.", "type": "CHEMICAL", "entities": [ "(m)CpG" ], "offsets": [ [ 104, 110 ] ] }, { "pmid": "23493374", "text": "Separate 5-aza-2'-deoxycytidine pretreatment or in combination with trichostatin A reduced (m)CpG and specific small interference RNAs targeting Mecp2 and Creb1 separately or together depleting Mecp2 and/or Creb1 binding of glut3-(m)CpGs reduced glut3 expression in HT22 cells.", "type": "CHEMICAL", "entities": [ "5-aza-2'-deoxycytidine", "trichostatin A", "(m)CpG", "(m)CpGs" ], "offsets": [ [ 9, 31 ], [ 68, 82 ], [ 91, 97 ], [ 230, 237 ] ] }, { "pmid": "23493374", "text": "We conclude that Glut3 is a methylation-sensitive neuronal gene that recruits Mecp2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23493374", "text": "Recruitment of Creb1-Mecp2 by glut3-(m)CpG contributes towards transactivation, formulating an escape from (m)CpG-induced gene suppression, and thereby promoting developmental neuronal glut3 gene transcription and expression.", "type": "CHEMICAL", "entities": [ "(m)CpG", "(m)CpG" ], "offsets": [ [ 36, 42 ], [ 107, 113 ] ] }, { "pmid": "14676196", "text": "Structure of human microsomal cytochrome P450 2C8.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "Evidence for a peripheral fatty acid binding site.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "A 2.7-Angstrom molecular structure of human microsomal cytochrome P450 2C8 (CYP2C8) was determined by x-ray crystallography.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "The membrane protein was modified for crystallization by replacement of the hydrophobic N-terminal transmembrane domain with a short hydrophilic sequence before residue 28.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "The structure of the native sequence is complete from residue 28 to the beginning of a C-terminal histidine tag used for purification.", "type": "CHEMICAL", "entities": [ "C", "histidine" ], "offsets": [ [ 87, 88 ], [ 98, 107 ] ] }, { "pmid": "14676196", "text": "CYP2C8 is one of the principal hepatic drug-metabolizing enzymes that oxidizes therapeutic drugs such as taxol and cerivastatin and endobiotics such as retinoic acid and arachidonic acid.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "Consistent with the relatively large size of its preferred substrates, the active site volume is twice that observed for the structure of CYP2C5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "The extended active site cavity is bounded by the beta1 sheet and helix F' that have not previously been implicated in substrate recognition by mammalian P450s.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14676196", "text": "CYP2C8 crystallized as a symmetric dimer formed by the interaction of helices F, F', G', and G. Two molecules of palmitic acid are bound in the dimer interface.", "type": "CHEMICAL", "entities": [ "palmitic acid" ], "offsets": [ [ 113, 126 ] ] }, { "pmid": "14676196", "text": "The dimer is observed in solution, and mass spectrometry confirmed the association of palmitic acid with the enzyme.", "type": "CHEMICAL", "entities": [ "palmitic acid" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "14676196", "text": "This novel finding identifies a peripheral binding site in P450s that may contribute to drug-drug interactions in P450 metabolism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23371032", "text": "Resistance to conventional insecticides in Pakistani populations of Musca domestica L. (Diptera: Muscidae): a potential ectoparasite of dairy animals.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23371032", "text": "The house fly, Musca domestica L., is an important hygienic pest of humans and dairy animals with the potential to develop resistance to most chemical classes of insecticides.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23371032", "text": "Six adult house fly strains from dairy farms in Punjab, Pakistan were evaluated for resistance to selected insecticides from organochlorine, organophosphate, carbamate and pyrethroid classes.", "type": "CHEMICAL", "entities": [ "organochlorine", "organophosphate", "carbamate", "pyrethroid" ], "offsets": [ [ 125, 139 ], [ 141, 156 ], [ 158, 167 ], [ 172, 182 ] ] }, { "pmid": "23371032", "text": "For a chlorocyclodiene and two organophosphates tested, the resistance ratios (RR) at LC50 were in the range of 5.60-22.02 fold for endosulfan, 7.66-23.24 fold for profenofos and 2.47-7.44 fold for chlorpyrifos.", "type": "CHEMICAL", "entities": [ "chlorocyclodiene", "organophosphates", "endosulfan", "chlorpyrifos" ], "offsets": [ [ 6, 22 ], [ 31, 47 ], [ 132, 142 ], [ 198, 210 ] ] }, { "pmid": "23371032", "text": "For two pyrethroids and one carbamate, the RR values at LC50 were 30.22-70.02 for cypermethrin, 5.73-18.31 for deltamethrin, and 4.39-15.50 for methomyl.", "type": "CHEMICAL", "entities": [ "pyrethroids", "carbamate", "cypermethrin", "deltamethrin", "methomyl" ], "offsets": [ [ 8, 19 ], [ 28, 37 ], [ 82, 94 ], [ 111, 123 ], [ 144, 152 ] ] }, { "pmid": "23371032", "text": "This is the first report of resistance to different classes of insecticides in Pakistani dairy populations of house flies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23371032", "text": "Regular insecticide resistance monitoring programs on dairy farms are needed to prevent field control failures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23371032", "text": "Moreover, integrated approaches including the judicious use of insecticides are needed to delay the development of insecticide resistance in house flies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554743", "text": "Effect of antidepressant drugs in mice lacking the norepinephrine transporter.\n", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 51, 65 ] ] }, { "pmid": "16554743", "text": "One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap.", "type": "CHEMICAL", "entities": [ "norepinephrine", "NE" ], "offsets": [ [ 257, 271 ], [ 273, 275 ] ] }, { "pmid": "16554743", "text": "Many ADs increase synaptic NE availability by inhibition of the reuptake of NE.", "type": "CHEMICAL", "entities": [ "NE", "NE" ], "offsets": [ [ 27, 29 ], [ 76, 78 ] ] }, { "pmid": "16554743", "text": "Using mice lacking NE transporter (NET-/-) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles.", "type": "CHEMICAL", "entities": [ "NE" ], "offsets": [ [ 19, 21 ] ] }, { "pmid": "16554743", "text": "In both tests, the NET-/- mice behaved like wild-type (WT) mice acutely treated with ADs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16554743", "text": "Autoradiographic studies showed decreased binding of the beta-adrenergic ligand [3H]CGP12177 in the cerebral cortex of NET-/- mice, indicating the changes at the level of beta-adrenergic receptors similar to those obtained with ADs treatment.", "type": "CHEMICAL", "entities": [ "[3H]CGP12177" ], "offsets": [ [ 80, 92 ] ] }, { "pmid": "16554743", "text": "The binding of [3H]prazosin to alpha1-adrenergic receptors in the cerebral cortex of NET-/- mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice.", "type": "CHEMICAL", "entities": [ "NE", "[3H]prazosin" ], "offsets": [ [ 199, 201 ], [ 15, 27 ] ] }, { "pmid": "16554743", "text": "A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine.", "type": "CHEMICAL", "entities": [ "reboxetine", "desipramine", "imipramine" ], "offsets": [ [ 169, 179 ], [ 181, 192 ], [ 198, 208 ] ] }, { "pmid": "16554743", "text": "Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET-/- mice.", "type": "CHEMICAL", "entities": [ "Citalopram" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "16554743", "text": "In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET-/- mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test.", "type": "CHEMICAL", "entities": [ "reboxetine", "desipramine", "imipramine", "citalopram", "desipramine" ], "offsets": [ [ 12, 22 ], [ 24, 35 ], [ 37, 47 ], [ 53, 63 ], [ 247, 258 ] ] }, { "pmid": "16554743", "text": "From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.", "type": "CHEMICAL", "entities": [ "NE" ], "offsets": [ [ 284, 286 ] ] }, { "pmid": "16278927", "text": "In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid.\n", "type": "CHEMICAL", "entities": [ "UDP", "niflumic acid", "steroidal", "4-methylumbelliferone" ], "offsets": [ [ 131, 134 ], [ 185, 198 ], [ 35, 44 ], [ 72, 93 ] ] }, { "pmid": "16278927", "text": "The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation.", "type": "CHEMICAL", "entities": [ "4-methylumbelliferone", "4-MU", "steroidal", "UDP" ], "offsets": [ [ 177, 198 ], [ 200, 204 ], [ 32, 41 ], [ 78, 81 ] ] }, { "pmid": "16278927", "text": "4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 microM.", "type": "CHEMICAL", "entities": [ "4-MU" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "16278927", "text": "The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid.", "type": "CHEMICAL", "entities": [ "acetaminophen", "diclofenac", "diflunisal", "indomethacin", "ketoprofen", "naproxen", "niflumic acid" ], "offsets": [ [ 72, 85 ], [ 87, 97 ], [ 99, 109 ], [ 111, 123 ], [ 125, 135 ], [ 137, 145 ], [ 150, 163 ] ] }, { "pmid": "16278927", "text": "Niflumic acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 microM.", "type": "CHEMICAL", "entities": [ "Niflumic acid" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "16278927", "text": "The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition.", "type": "CHEMICAL", "entities": [ "diflunisal", "diclofenac", "indomethacin", "acetaminophen", "ketoprofen", "naproxen" ], "offsets": [ [ 19, 29 ], [ 31, 41 ], [ 46, 58 ], [ 113, 126 ], [ 128, 138 ], [ 143, 151 ] ] }, { "pmid": "16278927", "text": "Niflumic acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 microM, respectively, being similar to each IC50 value.", "type": "CHEMICAL", "entities": [ "Niflumic acid", "diflunisal", "diclofenac", "indomethacin" ], "offsets": [ [ 0, 13 ], [ 15, 25 ], [ 27, 37 ], [ 42, 54 ] ] }, { "pmid": "16278927", "text": "In conclusion, of the seven NSAIDs investigated, niflumic acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner.", "type": "CHEMICAL", "entities": [ "niflumic acid" ], "offsets": [ [ 49, 62 ] ] }, { "pmid": "9669506", "text": "Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.\n", "type": "CHEMICAL", "entities": [ "venlafaxine", "serotonin", "norepinephrine" ], "offsets": [ [ 14, 25 ], [ 66, 75 ], [ 80, 94 ] ] }, { "pmid": "9669506", "text": "In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively.", "type": "CHEMICAL", "entities": [ "serotonin", "5-hydroxytryptamine", "5-HT", "norepinephrine", "[3H]cyanoimipramine", "[3H]nisoxetine" ], "offsets": [ [ 139, 148 ], [ 150, 169 ], [ 171, 175 ], [ 185, 199 ], [ 241, 260 ], [ 265, 279 ] ] }, { "pmid": "9669506", "text": "The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter.", "type": "CHEMICAL", "entities": [ "5-HT", "paroxetine", "indalpine", "fluvoxamine", "5-HT", "norepinephrine", "desipramine", "norepinephrine" ], "offsets": [ [ 14, 18 ], [ 39, 49 ], [ 51, 60 ], [ 65, 76 ], [ 111, 115 ], [ 141, 155 ], [ 175, 186 ], [ 215, 229 ] ] }, { "pmid": "9669506", "text": "Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters.", "type": "CHEMICAL", "entities": [ "Duloxetine", "5-HT", "norepinephrine", "5-HT", "norepinephrine" ], "offsets": [ [ 0, 10 ], [ 19, 23 ], [ 28, 42 ], [ 102, 106 ], [ 115, 129 ] ] }, { "pmid": "9669506", "text": "Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (Ki = 74 nM) and a very low affinity for the norepinephrine transporter (Ki = 1.26 microM).", "type": "CHEMICAL", "entities": [ "venlafaxine", "5-HT", "norepinephrine", "5-HT", "norepinephrine" ], "offsets": [ [ 15, 26 ], [ 35, 39 ], [ 44, 58 ], [ 122, 126 ], [ 184, 198 ] ] }, { "pmid": "9669506", "text": "The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties.", "type": "CHEMICAL", "entities": [ "norepinephrine", "venlafaxine", "5-HT" ], "offsets": [ [ 87, 101 ], [ 33, 44 ], [ 78, 82 ] ] }, { "pmid": "9669506", "text": "These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [3H]cyanoimipramine and [3H]nisoxetine binding sites.", "type": "CHEMICAL", "entities": [ "5-HT", "norepinephrine", "venlafaxine", "[3H]cyanoimipramine", "[3H]nisoxetine" ], "offsets": [ [ 68, 72 ], [ 77, 91 ], [ 115, 126 ], [ 176, 195 ], [ 200, 214 ] ] }, { "pmid": "17334708", "text": "Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17334708", "text": "Massive urinary excretion of xanthurenic acid, 3-hydroxykynurenine and kynurenine, known as xanthurenic aciduria or hydroxykynureninuria, in a young Somali boy suggested kynureninase deficiency.", "type": "CHEMICAL", "entities": [ "xanthurenic acid", "3-hydroxykynurenine", "kynurenine" ], "offsets": [ [ 29, 45 ], [ 47, 66 ], [ 71, 81 ] ] }, { "pmid": "17334708", "text": "Mutation analysis of KYNU encoding kynureninase of the index case revealed homozygosity for a c.593 A > G substitution leading to a threonine-to-alanine (T198A) shift.", "type": "CHEMICAL", "entities": [ "threonine", "alanine" ], "offsets": [ [ 132, 141 ], [ 145, 152 ] ] }, { "pmid": "17334708", "text": "A younger brother was found to have a similar excretion pattern and the same genotype.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17334708", "text": "At present, neither of the two boys has symptoms of niacin deficiency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17334708", "text": "This is the first report linking xanthurenic aciduria to a mutation in the gene encoding kynureninase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "Co-C bond activation in methylmalonyl-CoA mutase by stabilization of the post-homolysis product Co2+ cobalamin.\n", "type": "CHEMICAL", "entities": [ "Co-C", "cobalamin", "methylmalonyl-CoA", "Co2+" ], "offsets": [ [ 0, 4 ], [ 101, 110 ], [ 24, 41 ], [ 96, 100 ] ] }, { "pmid": "16305240", "text": "Despite decades of research, the mechanism by which coenzyme B12 (adenosylcobalamin, AdoCbl)-dependent enzymes promote homolytic cleavage of the cofactor's Co-C bond to initiate catalysis has continued to elude researchers.", "type": "CHEMICAL", "entities": [ "Co-C", "coenzyme B12", "adenosylcobalamin", "AdoCbl" ], "offsets": [ [ 156, 160 ], [ 52, 64 ], [ 66, 83 ], [ 85, 91 ] ] }, { "pmid": "16305240", "text": "In this work, we utilized magnetic circular dichroism spectroscopy to explore how the electronic structure of the reduced B12 cofactor (i.e., the post-homolysis product Co2+ Cbl) is modulated by the enzyme methylmalonyl-CoA mutase.", "type": "CHEMICAL", "entities": [ "Co2+ Cbl", "methylmalonyl-CoA" ], "offsets": [ [ 169, 177 ], [ 206, 223 ] ] }, { "pmid": "16305240", "text": "Our data reveal a fairly uniform stabilization of the Co 3d orbitals relative to the corrin pi/pi*-based molecular orbitals when Co2+ Cbl is bound to the enzyme active site, particularly in the presence of substrate.", "type": "CHEMICAL", "entities": [ "Co2+ Cbl" ], "offsets": [ [ 129, 137 ] ] }, { "pmid": "16305240", "text": "Contrastingly, our previous studies (Brooks, A. J.; Vlasie, M.; Banerjee, R.; Brunold, T. C. J. Am.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "Chem.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "Soc.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "2004, 126, 8167-8180.) showed that when AdoCbl is bound to the MMCM active site, no enzymatic perturbation of the Co3", "type": "CHEMICAL", "entities": [ "AdoCbl" ], "offsets": [ [ 40, 46 ] ] }, { "pmid": "16305240", "text": "+", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "Cbl electronic structure occurs, even in the presence of substrate (analogues).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16305240", "text": "Collectively, these observations provide direct evidence that enzymatic Co-C bond activation involves stabilization of the post-homolysis product, Co2+ Cbl, rather than destabilization of the Co3+", "type": "CHEMICAL", "entities": [ "Co-C", "Co2+ Cbl" ], "offsets": [ [ 72, 76 ], [ 147, 155 ] ] }, { "pmid": "16305240", "text": "Cbl \"ground\" state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23194825", "text": "Neurotoxicity of \"ecstasy\" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.\n", "type": "CHEMICAL", "entities": [ "ecstasy" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "23194825", "text": "\"Ecstasy\" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans.", "type": "CHEMICAL", "entities": [ "3,4-methylenedioxymethamphetamine", "Ecstasy", "MDMA" ], "offsets": [ [ 11, 44 ], [ 1, 8 ], [ 48, 52 ] ] }, { "pmid": "23194825", "text": "MDMA metabolites can be major contributors for MDMA neurotoxicity.", "type": "CHEMICAL", "entities": [ "MDMA", "MDMA" ], "offsets": [ [ 0, 4 ], [ 47, 51 ] ] }, { "pmid": "23194825", "text": "This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate.", "type": "CHEMICAL", "entities": [ "MDMA", "catechol", "α-methyldopamine", "α-MeDA", "N-methyl-α-methyldopamine", "N-Me-α-MeDA", "retinoic acid", "12-O-tetradecanoyl-phorbol-13-acetate" ], "offsets": [ [ 39, 43 ], [ 52, 60 ], [ 74, 90 ], [ 92, 98 ], [ 104, 129 ], [ 131, 142 ], [ 200, 213 ], [ 218, 255 ] ] }, { "pmid": "23194825", "text": "Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity.", "type": "CHEMICAL", "entities": [ "dopamine", "dopamine" ], "offsets": [ [ 69, 77 ], [ 108, 116 ] ] }, { "pmid": "23194825", "text": "MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner.", "type": "CHEMICAL", "entities": [ "catechol" ], "offsets": [ [ 1, 9 ] ] }, { "pmid": "23194825", "text": "MDMA did not show a concentration- and time-dependent death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23194825", "text": "Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity.", "type": "CHEMICAL", "entities": [ "glutathione", "N-acetylcysteine", "NAC", "MDMA" ], "offsets": [ [ 35, 46 ], [ 58, 74 ], [ 76, 79 ], [ 124, 128 ] ] }, { "pmid": "23194825", "text": "Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity.", "type": "CHEMICAL", "entities": [ "superoxide", "dopamine", "GBR 12909" ], "offsets": [ [ 8, 18 ], [ 70, 78 ], [ 97, 106 ] ] }, { "pmid": "23194825", "text": "Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect.", "type": "CHEMICAL", "entities": [ "α-MeDA", "glutathione", "GSH", "γ-glutamylcysteine" ], "offsets": [ [ 13, 19 ], [ 56, 67 ], [ 69, 72 ], [ 159, 177 ] ] }, { "pmid": "23194825", "text": "Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity.", "type": "CHEMICAL", "entities": [ "buthionine sulfoximine", "BSO", "α-MeDA", "GSH" ], "offsets": [ [ 25, 47 ], [ 49, 52 ], [ 88, 94 ], [ 115, 118 ] ] }, { "pmid": "23194825", "text": "Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis.", "type": "CHEMICAL", "entities": [ "BSO", "NAC", "α-MeDA", "GSH" ], "offsets": [ [ 0, 3 ], [ 28, 31 ], [ 59, 65 ], [ 120, 123 ] ] }, { "pmid": "23194825", "text": "Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection.", "type": "CHEMICAL", "entities": [ "BSO", "N-Me-α-MeDA", "NAC" ], "offsets": [ [ 29, 32 ], [ 43, 54 ], [ 105, 108 ] ] }, { "pmid": "23194825", "text": "In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells.", "type": "CHEMICAL", "entities": [ "MDMA", "catechol" ], "offsets": [ [ 4, 8 ], [ 9, 17 ] ] }, { "pmid": "23620436", "text": "A New Proposed Rodent Model of Chemically Induced Prostate Carcinogenesis: Distinct Time-Course Prostate Cancer Progression in the Dorsolateral and Ventral Lobes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "BACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment.", "type": "CHEMICAL", "entities": [ "MNU", "testosterone" ], "offsets": [ [ 32, 35 ], [ 61, 73 ] ] }, { "pmid": "23620436", "text": "Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups.", "type": "CHEMICAL", "entities": [ "MNU" ], "offsets": [ [ 97, 100 ] ] }, { "pmid": "23620436", "text": "Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration.", "type": "CHEMICAL", "entities": [ "MNU", "testosterone" ], "offsets": [ [ 116, 119 ], [ 122, 134 ] ] }, { "pmid": "23620436", "text": "Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "Moreover, VL lesions emerged throughout the entire lobe.", "type": "CHEMICAL", "entities": [ "MNU" ], "offsets": [ [ 52, 55 ] ] }, { "pmid": "23620436", "text": "MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "There are distinct pathways involved in tumor progression in gerbil prostate lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620436", "text": "Prostate © 2013 Wiley Periodicals, Inc.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22301814", "text": "Green tea extract alleviates arsenic-induced biochemical toxicity and lipid peroxidation in rats.\n", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 29, 36 ] ] }, { "pmid": "22301814", "text": "The present work was undertaken to evaluate the protective effect of an aqueous extract of green tea (GT, Camellia sinensis) leaves against arsenic (NaAsO2)-induced biochemical toxicity and lipid peroxidation production in experimental rats.", "type": "CHEMICAL", "entities": [ "arsenic", "NaAsO2" ], "offsets": [ [ 140, 147 ], [ 149, 155 ] ] }, { "pmid": "22301814", "text": "The treatment with arsenic exhibited a significant increase in some serum hepatic and renal biochemical parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, bilirubin, cholesterol, urea and creatinine).", "type": "CHEMICAL", "entities": [ "arsenic", "alanine", "aspartate", "bilirubin", "cholesterol", "urea", "creatinine" ], "offsets": [ [ 19, 26 ], [ 116, 123 ], [ 142, 151 ], [ 216, 225 ], [ 227, 238 ], [ 240, 244 ], [ 249, 259 ] ] }, { "pmid": "22301814", "text": "But the co-administration of GT has increased the level of plasmatic concentration of biochemical parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22301814", "text": "Exposure of rats to arsenic caused also a significant increase in liver, kidney and testicular thiobarbituric acid reactive substances compared to control.", "type": "CHEMICAL", "entities": [ "arsenic", "thiobarbituric acid" ], "offsets": [ [ 20, 27 ], [ 95, 114 ] ] }, { "pmid": "22301814", "text": "However, the co-administration of GT was effective in reducing its level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22301814", "text": "To conclude, our data suggest that arsenic exposure enhanced an oxidative stress by disturbing the tissue antioxidant defense system, but the GT co-administration alleviates the toxicity induced by arsenic exposure.", "type": "CHEMICAL", "entities": [ "arsenic", "arsenic" ], "offsets": [ [ 198, 205 ], [ 35, 42 ] ] }, { "pmid": "15357957", "text": "Synthesis, receptor binding and functional studies of mesoridazine stereoisomers.\n", "type": "CHEMICAL", "entities": [ "mesoridazine" ], "offsets": [ [ 54, 66 ] ] }, { "pmid": "15357957", "text": "The four stereoisomers of mesoridazine were synthesized and evaluated in D2, 5-HT1A, 5-HT2A, 5-HT2C, D1, and D3 receptor binding and functional assays.", "type": "CHEMICAL", "entities": [ "mesoridazine" ], "offsets": [ [ 26, 38 ] ] }, { "pmid": "15357957", "text": "Two isomers demonstrated potent D2 receptor binding (Ki < 3 nM) and functional antagonism (IC50 < or = 10 nM) activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15357957", "text": "These two isomers also showed moderate affinity for the 5-HT2A and D3 receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15357957", "text": "A third isomer was devoid of significant D2 receptor binding, but did have moderate affinity for the 5-HT2A and D3 receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15357957", "text": "The fourth isomer demonstrated poor affinity for all the receptors tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15357957", "text": "Most significantly, the stereochemistry of the sulfoxide moiety played a dominant role in the observed structure-activity relationship (SAR).", "type": "CHEMICAL", "entities": [ "sulfoxide" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "23337256", "text": "Sex differences in the antidepressant-like effects of ketamine.\n", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 54, 62 ] ] }, { "pmid": "23337256", "text": "Current medications for major depression suffer from numerous limitations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23337256", "text": "Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23337256", "text": "This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23337256", "text": "However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting.", "type": "CHEMICAL", "entities": [ "ketamine", "N-methyl d-aspartate" ], "offsets": [ [ 80, 88 ], [ 93, 113 ] ] }, { "pmid": "23337256", "text": "Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects.", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 120, 128 ] ] }, { "pmid": "23337256", "text": "Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats.", "type": "CHEMICAL", "entities": [ "ketamine", "ketamine" ], "offsets": [ [ 67, 75 ], [ 174, 182 ] ] }, { "pmid": "23337256", "text": "The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats.", "type": "CHEMICAL", "entities": [ "ketamine", "estrogen", "progesterone", "ketamine" ], "offsets": [ [ 52, 60 ], [ 173, 181 ], [ 186, 198 ], [ 314, 322 ] ] }, { "pmid": "23337256", "text": "In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions.", "type": "CHEMICAL", "entities": [ "rapamycin", "ketamine" ], "offsets": [ [ 48, 57 ], [ 204, 212 ] ] }, { "pmid": "23337256", "text": "In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.", "type": "CHEMICAL", "entities": [ "ketamine" ], "offsets": [ [ 72, 80 ] ] }, { "pmid": "23574017", "text": "Effects of 17α-ethynylestradiol-induced cholestasis on the pharmacokinetics of doxorubicin in rats: reduced biliary excretion and hepatic metabolism of doxorubicin.\n", "type": "CHEMICAL", "entities": [ "17α-ethynylestradiol", "doxorubicin", "doxorubicin" ], "offsets": [ [ 11, 31 ], [ 152, 163 ], [ 79, 90 ] ] }, { "pmid": "23574017", "text": "Abstract 1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23574017", "text": "Since the prevalent hormonal combination therapy with estrogen analogues in cancer patients has frequency and possibility to induce the cholestasis, the frequent combination therapy with 17α-ethynylestradiol (EE, an oral contraceptive) and doxorubicin (an anticancer drug) might be monitored in aspect of efficacy and safety.", "type": "CHEMICAL", "entities": [ "17α-ethynylestradiol", "doxorubicin", "estrogen" ], "offsets": [ [ 186, 206 ], [ 239, 250 ], [ 53, 61 ] ] }, { "pmid": "23574017", "text": "Doxorubicin is mainly excreted into the bile via P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in hepatobiliary route and metabolized via cytochrome P450 (CYP) 3A subfamily.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23574017", "text": "Also the hepatic Mrp2 (not P-gp) and CYP3A subfamily levels were reduced in EE-induced cholestatic (EEC) rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23574017", "text": "Thus, we herein report the pharmacokinetic changes of doxorubicin with respect to the changes in its biliary excretion and hepatic metabolism in EEC rats.", "type": "CHEMICAL", "entities": [ "doxorubicin" ], "offsets": [ [ 52, 63 ] ] }, { "pmid": "23574017", "text": "2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23574017", "text": "The pharmacokinetic study of doxorubicin after intravenous administration of its hydrochloride was conducted along with the investigation of bile flow rate and hepatobiliary excretion of doxorubicin in control and EEC rats.", "type": "CHEMICAL", "entities": [ "doxorubicin", "hydrochloride", "doxorubicin" ], "offsets": [ [ 27, 38 ], [ 79, 92 ], [ 185, 196 ] ] }, { "pmid": "23574017", "text": "3. The significantly greater AUC (58.7% increase) of doxorubicin in EEC rats was due to the slower CL (32.9% decrease).", "type": "CHEMICAL", "entities": [ "doxorubicin" ], "offsets": [ [ 51, 62 ] ] }, { "pmid": "23574017", "text": "The slower CL was due to the reduction of hepatic biliary excretion (67.0% decrease) and hepatic CYP3A subfamily-mediated metabolism (21.9% decrease) of doxorubicin.", "type": "CHEMICAL", "entities": [ "doxorubicin" ], "offsets": [ [ 151, 162 ] ] }, { "pmid": "23574017", "text": "These results might have broader implications to understand the altered pharmacokinetics and/or pharmacologic effects of doxorubicin via biliary excretion and hepatic metabolism in experimental and clinical estrogen-induced cholestasis.", "type": "CHEMICAL", "entities": [ "doxorubicin", "estrogen" ], "offsets": [ [ 119, 130 ], [ 205, 213 ] ] }, { "pmid": "16534240", "text": "Corticotropin-releasing hormone reduces pressure pain sensitivity in humans without involvement of beta-endorphin(1-31), but does not reduce heat pain sensitivity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534240", "text": "In the present study the effects of intravenously administered corticotropin-releasing hormone (CRH) on the release of proopiomelanocortin (POMC) derivatives such as adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) and beta-endorphin (beta-END) as well as direct effects of CRH on pain sensitivity were examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534240", "text": "In 16 healthy volunteers we studied the effects of 100 microg intravenously administered CRH in absence or presence of 12 mg naloxone on heat or pressure pain sensitivity, using a double-blind, cross-over and placebo-controlled design.", "type": "CHEMICAL", "entities": [ "naloxone" ], "offsets": [ [ 125, 133 ] ] }, { "pmid": "16534240", "text": "To evaluate analgesic effects of CRH via release of POMC derivatives, we determined plasma concentrations of beta-END-immunoreactive material (IRM), authentic beta-END (beta-END(1-31)) and beta-LPH IRM, in parallel with heat and pressure pain tolerance thresholds before and 15 and 30 min after treatment with CRH (or placebo), and 5 min after naloxone (or placebo) administration which was administered 40 min after CRH (or placebo) injection.", "type": "CHEMICAL", "entities": [ "naloxone" ], "offsets": [ [ 344, 352 ] ] }, { "pmid": "16534240", "text": "CRH increased levels of beta-END IRM, beta-END(1-31) and beta-LPH IRM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534240", "text": "As compared to beta-END IRM levels measured by a commercial RIA kit, the beta-END(1-31) levels determined by a highly specific two-site RIA, proved to be remarkably small.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534240", "text": "Furthermore, CRH did not induce increases of heat pain tolerance thresholds, but of pressure pain tolerance thresholds, which, however, were not reversible by naloxone.", "type": "CHEMICAL", "entities": [ "naloxone" ], "offsets": [ [ 159, 167 ] ] }, { "pmid": "16534240", "text": "Neither beta-END nor beta-LPH IRM nor beta-END(1-31) levels correlated with heat or pressure pain tolerance thresholds.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534240", "text": "We conclude that CRH does not modulate heat, but pressure pain; POMC derivatives like beta-END IRM, beta-END(1-31) or beta-LPH do not mediate this effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23325562", "text": "Activation of AMP-activated Protein Kinase and Phosphorylation of Glycogen Synthase Kinase3", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "23325562", "text": "β Mediate Ursolic Acid Induced Apoptosis in HepG2 Liver Cancer Cells.\n", "type": "CHEMICAL", "entities": [ "Ursolic Acid" ], "offsets": [ [ 10, 22 ] ] }, { "pmid": "23325562", "text": "Despite the antitumour effect of ursolic acid observed in several cancers, the underlying mechanism remains unclear.", "type": "CHEMICAL", "entities": [ "ursolic acid" ], "offsets": [ [ 32, 44 ] ] }, { "pmid": "23325562", "text": "Thus, in the present study, the roles of AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 beta (GSK3β) were examined in ursolic acid induced apoptosis in HepG2 hepatocellular carcinoma cells.", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 40, 43 ] ] }, { "pmid": "23325562", "text": "Ursolic acid significantly exerted cytotoxicity, increased the sub-G1 population and the number of ethidium homodimer and terminal deoxynucleotidyl transferase(TdT) mediated dUTP nick end labeling positive cells in HepG2 cells.", "type": "CHEMICAL", "entities": [ "ethidium", "dUTP" ], "offsets": [ [ 97, 105 ], [ 172, 176 ] ] }, { "pmid": "23325562", "text": "Also, ursolic acid enhanced the cleavages of poly-ADP-ribose polymerase (PARP) and caspase3, attenuated the expression of astrocyte elevated gene (AEG1) and survivin in HepG2 cells.", "type": "CHEMICAL", "entities": [ "poly-ADP-ribose" ], "offsets": [ [ 43, 58 ] ] }, { "pmid": "23325562", "text": "Interestingly, ursolic acid increased the phosphorylation of AMPK and coenzyme A carboxylase and also enhanced phosphorylation of GSK3β at inactive form serine 9, whereas ursolic acid attenuated the phosphorylation of AKT and mTOR in HepG2 cells.", "type": "CHEMICAL", "entities": [ "ursolic acid", "serine", "ursolic acid" ], "offsets": [ [ 13, 25 ], [ 151, 157 ], [ 169, 181 ] ] }, { "pmid": "23325562", "text": "Conversely, AMPK inhibitor compound C or GSK3β inhibitor SB216763 blocked the cleavages of PARP and caspase 3 induced by ursolic acid in HepG2 cells.", "type": "CHEMICAL", "entities": [ "compound C", "SB216763", "ursolic acid" ], "offsets": [ [ 24, 34 ], [ 54, 62 ], [ 118, 130 ] ] }, { "pmid": "23325562", "text": "Furthermore, proteosomal inhibitor MG132 suppressed AMPK activation, GSK3β phosphorylation, cleaved PARP and deceased AEG-1 induced by ursolic acid in HepG2 cells.", "type": "CHEMICAL", "entities": [ "MG132", "ursolic acid" ], "offsets": [ [ 31, 36 ], [ 131, 143 ] ] }, { "pmid": "23325562", "text": "Overall, our findings suggest that ursolic acid induced apoptosis in HepG2 cells via AMPK activation and GSK3β phosphorylation as a potent chemopreventive agent.", "type": "CHEMICAL", "entities": [ "ursolic acid" ], "offsets": [ [ 30, 42 ] ] }, { "pmid": "23325562", "text": "Copyright ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23325562", "text": " 2013 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23046524", "text": "Adverse outcome pathways during zebrafish embryogenesis: a case study with paraoxon.\n", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 75, 83 ] ] }, { "pmid": "23046524", "text": "Using paraoxon as a reference acetylcholinesterase (AChE) inhibitor, the objective of this study was to develop an adverse outcome pathway (AOP) that provided quantitative linkages across levels of biological organization during zebrafish embryogenesis.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 6, 14 ] ] }, { "pmid": "23046524", "text": "Within normal zebrafish embryos, we first demonstrated that ache transcripts and AChE activity increased in a stage-dependent manner following segmentation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23046524", "text": "We then showed that static exposure of embryos to paraoxon (31.2-500 nM) from 5 to 96 hpf resulted in significant stage- and concentration-dependent AChE inhibition, albeit these effects were fully reversible within 48 h following transfer to clean water.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23046524", "text": "However, even in the presence of significant AChE inhibition, exposure to non-teratogenic paraoxon concentrations (≤250 nM) did not adversely impact secondary motoneuron development at 96 hpf.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 90, 98 ] ] }, { "pmid": "23046524", "text": "Therefore, we investigated the potential effects of paraoxon exposure on spontaneous tail contractions at 26 hpf - an early locomotor behavior that results from innervation of primary (not secondary) motoneuron axons to target axial muscles.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23046524", "text": "Based on these studies, the frequency of spontaneous tail contractions at 26 hpf - a developmental stage with minimal AChE expression and activity - was significantly higher following exposure to paraoxon concentrations as low as 31.2 nM. Overall, our data suggest that (1) normal AChE activity is not required for secondary motoneuron development and (2) spontaneous tail contractions at 26 hpf are sensitive to paraoxon exposure, an effect that may be independent of AChE inhibition.", "type": "CHEMICAL", "entities": [ "paraoxon", "paraoxon" ], "offsets": [ [ 194, 202 ], [ 411, 419 ] ] }, { "pmid": "23046524", "text": "Using a well-studied reference chemical, this study highlights the potential challenges in developing quantitative AOPs to support chemical screening and prioritization strategies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Missense mutations in the proteolipid protein 1 (PLP1) gene cause a wide spectrum of hypomyelinating disorders, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease (PMD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "However, the link between the clinical severity of PMD and the cellular response induced by mutant PLP1 remains largely unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Accumulation of misfolded proteins in the ER generally leads to up-regulation of ER chaperones to alleviate ER stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Here, we found that expression of the PLP1-A243V mutant, which causes severe disease, depletes some ER chaperones with a KDEL (Lys-Asp-Glu-Leu) motif, in HeLa cells, MO3.13 oligodendrocytic cells, and primary oligodendrocytes.", "type": "CHEMICAL", "entities": [ "Lys-Asp-Glu-Leu" ], "offsets": [ [ 127, 142 ] ] }, { "pmid": "23344956", "text": "The same PLP1 mutant also induces fragmentation of the Golgi apparatus (GA).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "These organelle changes are less prominent in cells with milder disease-associated PLP1 mutants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and GA fragmentation by inhibiting GA to ER trafficking.", "type": "CHEMICAL", "entities": [ "brefeldin A" ], "offsets": [ [ 141, 152 ] ] }, { "pmid": "23344956", "text": "We also found that mutant PLP1 disturbs localization of the KDEL receptor, which transports the chaperones with the KDEL motif from the GA to the ER.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "These data show that PLP1 mutants inhibit GA to ER trafficking, which reduces the supply of ER chaperones and induces GA fragmentation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23344956", "text": "We propose that depletion of ER chaperones and GA fragmentation induced by mutant misfolded proteins contribute to the pathogenesis of inherited ER stress-related diseases and affect the disease severity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "Endogenous opioid systems and alcohol addiction.\n", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 30, 37 ] ] }, { "pmid": "9040115", "text": "Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators.", "type": "CHEMICAL", "entities": [ "Alcohol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "9040115", "text": "Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "9040115", "text": "Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively).", "type": "CHEMICAL", "entities": [ "enkephalins" ], "offsets": [ [ 133, 144 ] ] }, { "pmid": "9040115", "text": "The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "In contrast, dysphoria results from activation of kappa-receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 105, 113 ] ] }, { "pmid": "9040115", "text": "Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway.", "type": "CHEMICAL", "entities": [ "dopamine", "alcohol" ], "offsets": [ [ 123, 131 ], [ 40, 47 ] ] }, { "pmid": "9040115", "text": "The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial.", "type": "CHEMICAL", "entities": [ "dopamine", "alcohol", "aldehyde", "tetrahydroisoquinolines" ], "offsets": [ [ 39, 47 ], [ 52, 59 ], [ 68, 76 ], [ 78, 101 ] ] }, { "pmid": "9040115", "text": "There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release).", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "9040115", "text": "In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 41, 48 ], [ 107, 114 ] ] }, { "pmid": "9040115", "text": "Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 95, 102 ] ] }, { "pmid": "9040115", "text": "Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions.", "type": "CHEMICAL", "entities": [ "naloxone", "naltrexone", "alcohol" ], "offsets": [ [ 39, 47 ], [ 52, 62 ], [ 140, 147 ] ] }, { "pmid": "9040115", "text": "Similar results have been reported when selective mu- or delta-receptor antagonists are administered.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 58, 65 ], [ 180, 187 ] ] }, { "pmid": "9040115", "text": "One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "It is suggested that alcohol interferes with this reward pathway either directly or indirectly.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 21, 28 ] ] }, { "pmid": "9040115", "text": "The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9040115", "text": "Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16690332", "text": "Dynamics of NO rebinding to the heme domain of NO synthase-like proteins from bacterial pathogens.\n", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 12, 14 ], [ 47, 49 ] ] }, { "pmid": "16690332", "text": "Some Gram-positive bacterial pathogens harbor a gene that encodes a protein (HNS, Heme domain of NO Synthase-like proteins) with striking sequence identity to the oxygenase domain of mammalian NO synthases (NOS).", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 193, 195 ], [ 97, 99 ] ] }, { "pmid": "16690332", "text": "However, they lack the N-terminal and the Zn-cysteine motif participating to the stability of an active dimer in the mammalian isoforms.", "type": "CHEMICAL", "entities": [ "N", "Zn-cysteine" ], "offsets": [ [ 23, 24 ], [ 42, 53 ] ] }, { "pmid": "16690332", "text": "The unique properties of HNS make it an excellent model system for probing how the heme environment tunes NO dynamics and for comparing it to the endothelial NO synthase heme domain (eNOS(HD)) using ultrafast transient spectroscopy.", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 106, 108 ], [ 158, 160 ] ] }, { "pmid": "16690332", "text": "NO rebinding in HNS from Staphylococcus aureus (SA-HNS) is faster than that measured for either Bacillus anthracis (BA-HNS) or for eNOS(HD) in both oxidized and reduced forms in the presence of arginine.", "type": "CHEMICAL", "entities": [ "NO", "arginine" ], "offsets": [ [ 0, 2 ], [ 194, 202 ] ] }, { "pmid": "16690332", "text": "To test whether these distinct rates arise from different energy barriers for NO recombination, we measured rebinding kinetics at several temperatures.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 78, 80 ] ] }, { "pmid": "16690332", "text": "Our data are consistent with different barriers for NO recombination in SA-HNS and BA-HNS and the presence of a second NO-binding site.", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 119, 121 ], [ 52, 54 ] ] }, { "pmid": "16690332", "text": "The hypothesis that an additional NO-binding cavity is present in BA-HNS is also consistent with the effect of the NO concentration on its rebinding.", "type": "CHEMICAL", "entities": [ "NO", "NO" ], "offsets": [ [ 34, 36 ], [ 115, 117 ] ] }, { "pmid": "16690332", "text": "The lack of the effect of NO concentration on the geminate rebinding in SA-HNS could be due to an isolated second site.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 26, 28 ] ] }, { "pmid": "16690332", "text": "We confirm the existence of a second NO site in the oxygenase domain of the reduced eNOS as previously hypothesized [A. Slama-Schwok, M. Negrerie, V. Berka, J.C. Lambry, A.L. Tsai, M.H. Vos, J.L. Martin, Nitric oxide (NO) traffic in endothelial NO synthase.", "type": "CHEMICAL", "entities": [ "NO", "Nitric oxide", "NO", "NO" ], "offsets": [ [ 37, 39 ], [ 204, 216 ], [ 218, 220 ], [ 245, 247 ] ] }, { "pmid": "16690332", "text": "Evidence for a new NO binding site dependent on tetrahydrobiopterin?", "type": "CHEMICAL", "entities": [ "NO", "tetrahydrobiopterin" ], "offsets": [ [ 19, 21 ], [ 48, 67 ] ] }, { "pmid": "16690332", "text": "J. Biol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16690332", "text": "Chem.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16690332", "text": "277 (2002) 7581-7586].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16690332", "text": "This site requires the presence of arginine and BH(4); and we propose that NO dynamic and escape from eNOS is regulated by the active site H-bonding network connecting between the heme, the substrate, and cofactor.", "type": "CHEMICAL", "entities": [ "arginine", "BH(4)", "NO", "H" ], "offsets": [ [ 35, 43 ], [ 48, 53 ], [ 75, 77 ], [ 139, 140 ] ] }, { "pmid": "2568748", "text": "Nonthrombolytic intervention in acute myocardial infarction.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568748", "text": "Alternative interventions are available for patients in whom thrombolytic therapy is inappropriate after an acute myocardial infarction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568748", "text": "Administration of a beta blocker within the first 24 hours of the patient's admission to the coronary care unit can reduce overall morbidity and mortality within the first 7 days by about 15%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568748", "text": "Maintenance therapy with an oral beta blocker can reduce mortality within the succeeding 3 years by about 25%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568748", "text": "Esmolol, a unique cardioselective beta 1-adrenergic receptor blocker with a half-life of 9 minutes, can enable some patients with relative contraindications to beta blockers to nevertheless benefit from early beta-blocking therapy.", "type": "CHEMICAL", "entities": [ "Esmolol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "2568748", "text": "It also is useful in screening patients for subsequent therapy with beta blockers.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2568748", "text": "Those who tolerate the esmolol infusion can be given a long-acting beta blocker.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 23, 30 ] ] }, { "pmid": "2568748", "text": "For patients who exhibit intolerance to esmolol, the infusion can be terminated with rapid return to baseline hemodynamics.", "type": "CHEMICAL", "entities": [ "esmolol" ], "offsets": [ [ 40, 47 ] ] }, { "pmid": "23000249", "text": "Snake venom metalloproteinases.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "Recent proteomic analyses of snake venoms show that metalloproteinases represent major components in most of the Crotalid and Viperid venoms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "In this chapter we discuss the multiple activities of the SVMPs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "In addition to hemorrhagic activity, members of the SVMP family also have fibrin(ogen)olytic activity, act as prothrombin activators, activate blood coagulation factor X, possess apoptotic activity, inhibit platelet aggregation, are pro-inflammatory and inactivate blood serine proteinase inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "Clearly the SVMPs have multiple functions in addition to their well-known hemorrhagic activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "The realization that there are structural variations in the SVMPs and the early studies that led to their classification represents an important event in our understanding of the structural forms of the SVMPs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "The SVMPs were subdivided into the P-I, P-II and P-III protein classes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "The noticeable characteristic that distinguished the different classes was their size (molecular weight) differences and domain structure:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "Class I (P-I), the small SVMPs, have molecular masses of 20-30 kDa, contain only a pro domain and the proteinase domain; Class II (P-II), the medium size SVMPs, molecular masses of 30-60 kDa, contain the pro domain, proteinase domain and disintegrin domain; Class III (P-III), the large SVMPs, have molecular masses of 60-100 kDa, contain pro, proteinase, disintegrin-like and cysteine-rich domain structure.", "type": "CHEMICAL", "entities": [ "cysteine" ], "offsets": [ [ 377, 385 ] ] }, { "pmid": "23000249", "text": "Another significant advance in the SVMP field was the characterization of the crystal structure of the first P-I class SVMP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "The structures of other P-I SVMPs soon followed and the structures of P-III SVMPs have also been determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23000249", "text": "The active site of the metalloproteinase domain has a consensus HEXXHXXGXXHD sequence and a Met-turn.", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 89, 92 ] ] }, { "pmid": "23000249", "text": "The \"Met-turn\" structure contains a conserved Met residue that forms a hydrophobic basement for the three zinc-binding histidines in the consensus sequence.", "type": "CHEMICAL", "entities": [ "Met", "Met", "zinc", "histidines" ], "offsets": [ [ 2, 5 ], [ 43, 46 ], [ 103, 107 ], [ 116, 126 ] ] }, { "pmid": "7929150", "text": "Catalytic properties of mouse carbonic anhydrase V.\nA cDNA encoding the mouse carbonic anhydrase V gene was isolated by reverse transcription and polymerase chain reaction from BALB/c mouse liver mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7929150", "text": "Vectors containing the full coding sequence as well as two different NH2-terminal truncated genes expressed enzymatically active protein in Escherichia coli.", "type": "CHEMICAL", "entities": [ "NH2" ], "offsets": [ [ 69, 72 ] ] }, { "pmid": "7929150", "text": "The carbonic anhydrase V produced by a vector containing the full coding sequence, which includes a possible NH2-terminal mitochondrial targeting signal, was proteolytically processed by E. coli and contained several amino-terminal ends.", "type": "CHEMICAL", "entities": [ "NH2", "amino" ], "offsets": [ [ 109, 112 ], [ 217, 222 ] ] }, { "pmid": "7929150", "text": "The two NH2-terminal truncated vectors deleted, respectively, 1) the 29-amino acid putative targeting sequence and 2) 51 amino acids, yielding a protein equivalent to a carbonic anhydrase (CA) V isolated from mouse liver mitochondria; and both vectors produced homogeneous protein fractions.", "type": "CHEMICAL", "entities": [ "NH2", "amino acid", "amino acids" ], "offsets": [ [ 8, 11 ], [ 72, 82 ], [ 121, 132 ] ] }, { "pmid": "7929150", "text": "These latter two forms of CA V had identical steady-state constants for the hydration of CO2, with maximal values of kcat/Km at 3 x 10(7) M-1 s-1 and kcat at 3 x 10(5) s-1 with an apparent pKa for catalysis of 7.4 determined from kcat/Km.", "type": "CHEMICAL", "entities": [ "CO2" ], "offsets": [ [ 89, 92 ] ] }, { "pmid": "7929150", "text": "In catalytic properties, mouse CA V is closest to CA I; however, in inhibition by acetazolamide, ethoxzolamide, and cyanate, CA V is very similar to CA II.", "type": "CHEMICAL", "entities": [ "acetazolamide", "ethoxzolamide", "cyanate" ], "offsets": [ [ 82, 95 ], [ 97, 110 ], [ 116, 123 ] ] }, { "pmid": "7929150", "text": "Mouse CA V has a tyrosine at position 64, where the highly active isozyme II has histidine serving as a proton shuttle in the catalytic pathway.", "type": "CHEMICAL", "entities": [ "histidine" ], "offsets": [ [ 81, 90 ] ] }, { "pmid": "7929150", "text": "Investigation of a site-specific mutant of CA V containing the replacement Tyr64-->His showed that the unique kinetic properties of CA V are not due to the presence of tyrosine at position 64.", "type": "CHEMICAL", "entities": [ "His", "tyrosine" ], "offsets": [ [ 83, 86 ], [ 168, 176 ] ] }, { "pmid": "17929831", "text": "Kinetic characterization of adenylosuccinate synthetase from the thermophilic archaea Methanocaldococcus jannaschii.\n", "type": "CHEMICAL", "entities": [ "adenylosuccinate" ], "offsets": [ [ 28, 44 ] ] }, { "pmid": "17929831", "text": "Adenylosuccinate synthetase (AdSS) catalyzes the Mg2+ dependent condensation of a molecule of IMP with aspartate to form adenylosuccinate, in a reaction driven by the hydrolysis of GTP to GDP.", "type": "CHEMICAL", "entities": [ "Adenylosuccinate", "aspartate", "adenylosuccinate", "GTP", "GDP", "Mg2+" ], "offsets": [ [ 0, 16 ], [ 103, 112 ], [ 121, 137 ], [ 181, 184 ], [ 188, 191 ], [ 49, 53 ] ] }, { "pmid": "17929831", "text": "AdSS from the thermophilic archaea, Methanocaldococcus jannaschii (MjAdSS) is 345 amino acids long against an average length of 430-457 amino acids for most mesophilic AdSS.", "type": "CHEMICAL", "entities": [ "amino acids", "amino acids" ], "offsets": [ [ 82, 93 ], [ 136, 147 ] ] }, { "pmid": "17929831", "text": "This short AdSS has two large deletions that map to the middle and C-terminus of the protein.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 67, 68 ] ] }, { "pmid": "17929831", "text": "This article discusses the detailed kinetic characterization of MjAdSS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17929831", "text": "Initial velocity and product inhibition studies, carried out at 70 degrees C, suggest a rapid equilibrium random AB steady-state ordered C kinetic mechanism for the MjAdSS catalyzed reaction.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17929831", "text": "AdSS are known to exhibit monomer-dimer equilibrium with the dimer being implicated in catalysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17929831", "text": "In contrast, our studies show that MjAdSS is an equilibrium mixture of dimers and tetramers with the tetramer being the catalytically active form.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17929831", "text": "The tetramer dissociates into dimers with a minor increase in ionic strength of the buffer, while the dimer is extremely stable and does not dissociate even at 1.2 M NaCl.", "type": "CHEMICAL", "entities": [ "NaCl" ], "offsets": [ [ 166, 170 ] ] }, { "pmid": "17929831", "text": "Phosphate, a product of the reaction, was found to be a potent inhibitor of MjAdSS showing biphasic inhibition of enzyme activity.", "type": "CHEMICAL", "entities": [ "Phosphate" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17929831", "text": "The inhibition was competitive with IMP and noncompetitive with GTP.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 64, 67 ] ] }, { "pmid": "17929831", "text": "MjAdSS, like the mouse acidic isozyme, exhibits substrate inhibition, with IMP inhibiting enzyme activity at subsaturating GTP concentrations.", "type": "CHEMICAL", "entities": [ "acidic", "GTP" ], "offsets": [ [ 23, 29 ], [ 123, 126 ] ] }, { "pmid": "17929831", "text": "Regulation of enzyme activity by the glycolytic intermediate, fructose 1,6 bisphosphate, was also observed with the inhibition being competitive with IMP and noncompetitive against GTP.", "type": "CHEMICAL", "entities": [ "fructose", "1,6 bisphosphate", "GTP" ], "offsets": [ [ 62, 70 ], [ 71, 87 ], [ 181, 184 ] ] }, { "pmid": "8052854", "text": "Inhibition of NF-kappa B by sodium salicylate and aspirin.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8052854", "text": "The transcription factor nuclear factor-kappa B (NF-kappa B) is critical for the inducible expression of multiple cellular and viral genes involved in inflammation and infection including interleukin-1 (IL-1), IL-6, and adhesion molecules.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8052854", "text": "The anti-inflammatory drugs sodium salicylate and aspirin inhibited the activation of NF-kappa B, which further explains the mechanism of action of these drugs.", "type": "CHEMICAL", "entities": [ "sodium salicylate", "aspirin" ], "offsets": [ [ 28, 45 ], [ 50, 57 ] ] }, { "pmid": "8052854", "text": "This inhibition prevented the degradation of the NF-kappa B inhibitor, I kappa B, and therefore NF-kappa B was retained in the cytosol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8052854", "text": "Sodium salicylate and aspirin also inhibited NF-kappa B-dependent transcription from the Ig kappa enhancer and the human immunodeficiency virus (HIV) long terminal repeat (LTR) in transfected T cells.", "type": "CHEMICAL", "entities": [ "Sodium salicylate", "aspirin" ], "offsets": [ [ 0, 17 ], [ 22, 29 ] ] }, { "pmid": "16417577", "text": "Galanin attenuates cyclic AMP regulatory element-binding protein (CREB) phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures.\n", "type": "CHEMICAL", "entities": [ "morphine", "naloxone", "cyclic AMP" ], "offsets": [ [ 107, 115 ], [ 120, 128 ], [ 19, 29 ] ] }, { "pmid": "16417577", "text": "Repeated morphine administration leads to molecular alterations of the neural circuitry in the locus coeruleus and nucleus accumbens.", "type": "CHEMICAL", "entities": [ "morphine" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "16417577", "text": "These changes include increased activity of several components of the cAMP signaling pathway that are thought to be associated with psychological and somatic signs of opiate withdrawal.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 70, 74 ] ] }, { "pmid": "16417577", "text": "The neuropeptide galanin has been shown to attenuate cAMP signaling in multiple cell types.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "16417577", "text": "The current study demonstrates that acute galanin treatment blocks the consequences of increased cAMP signaling following chronic opiate administration and withdrawal in Cath.a cells and primary cultures of striatal neurons as measured by phosphorylation of the transcription factor cAMP regulatory element-binding protein (CREB).", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP" ], "offsets": [ [ 97, 101 ], [ 283, 287 ] ] }, { "pmid": "16417577", "text": "In addition, galanin-mediated attenuation of CREB phosphorylation is independent of galanin-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in Cath.a cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16417577", "text": "These data suggest that galanin receptors may serve as an additional potential therapeutic target for the treatment of opiate withdrawal.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17896959", "text": "Na+/Ca2+ exchange inhibitors: a new class of calcium regulators.\n", "type": "CHEMICAL", "entities": [ "Na+", "calcium", "Ca2+" ], "offsets": [ [ 0, 3 ], [ 45, 52 ], [ 4, 8 ] ] }, { "pmid": "17896959", "text": "The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that normally extrudes Ca(2+) from the cell (forward mode), but also brings Ca(2+) into the cell (reverse mode) under special conditions such as intracellular Na(+)", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)", "Na(+)", "Na(+)", "Ca(2+)" ], "offsets": [ [ 10, 16 ], [ 140, 146 ], [ 223, 228 ], [ 4, 9 ], [ 87, 93 ] ] }, { "pmid": "17896959", "text": "(Na(+)(i)) accumulation or membrane depolarization.", "type": "CHEMICAL", "entities": [ "Na(+)" ], "offsets": [ [ 1, 6 ] ] }, { "pmid": "17896959", "text": "There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17896959", "text": "The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996.", "type": "CHEMICAL", "entities": [ "KB-R7943", "benzyloxyphenyl" ], "offsets": [ [ 89, 97 ], [ 111, 126 ] ] }, { "pmid": "17896959", "text": "Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769.", "type": "CHEMICAL", "entities": [ "SEA0400", "SN-6", "YM-244769" ], "offsets": [ [ 80, 87 ], [ 89, 93 ], [ 99, 108 ] ] }, { "pmid": "17896959", "text": "Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na(+)(i)-dependent inactivation.", "type": "CHEMICAL", "entities": [ "benzyloxyphenyl", "Na(+)" ], "offsets": [ [ 40, 55 ], [ 106, 111 ] ] }, { "pmid": "17896959", "text": "Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na(+)(i)), but become effective during the reverse mode under pathological conditions (high Na(+)(i)).", "type": "CHEMICAL", "entities": [ "Na(+)", "Na(+)", "benzyloxyphenyl" ], "offsets": [ [ 118, 123 ], [ 210, 215 ], [ 15, 30 ] ] }, { "pmid": "17896959", "text": "This should be an ideal profile for calcium regulators against Na(+)(i)-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia.", "type": "CHEMICAL", "entities": [ "calcium", "Na(+)" ], "offsets": [ [ 36, 43 ], [ 63, 68 ] ] }, { "pmid": "17896959", "text": "Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action.", "type": "CHEMICAL", "entities": [ "amiodarone", "dronedarone", "bepridil", "aprindine", "cibenzoline" ], "offsets": [ [ 39, 49 ], [ 51, 62 ], [ 64, 72 ], [ 74, 83 ], [ 89, 100 ] ] }, { "pmid": "17896959", "text": "It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17896959", "text": "This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 129, 136 ] ] }, { "pmid": "17593236", "text": "Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.\n", "type": "CHEMICAL", "entities": [ "glimepiride", "glimepiride", "metformin", "sitagliptin" ], "offsets": [ [ 143, 154 ], [ 167, 178 ], [ 183, 192 ], [ 61, 72 ] ] }, { "pmid": "17593236", "text": "AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 67, 78 ] ] }, { "pmid": "17593236", "text": "(DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c))", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": ">or=7.5% and or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "mg/day) plus metformin (>or=1,500 mg/day) combination therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17593236", "text": "The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409864", "text": "Compound and compositions as TGR5 agonists: WO2012082947.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409864", "text": "The patent application WO2012082947 claims novel compounds as agonists of a plasma membrane-bound bile acid receptor TGR5.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409864", "text": "By activating TGR5, the agonists improve glycemic control and enhance energy expenditure.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409864", "text": "The basic generic claim of the patent covers pyrazole derivatives, different permutations on the core pyrazole ring are covered in the subsidiary claims.", "type": "CHEMICAL", "entities": [ "pyrazole", "pyrazole" ], "offsets": [ [ 45, 53 ], [ 102, 110 ] ] }, { "pmid": "23409864", "text": "The claimed compounds are human TGR5 agonists having potency in the nM range.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23160090", "text": "Hydroxysafflor yellow a inhibits lipopolysaccharide-induced inflammatory signal transduction in human alveolar epithelial A549 cells.\n", "type": "CHEMICAL", "entities": [ "Hydroxysafflor yellow a" ], "offsets": [ [ 0, 23 ] ] }, { "pmid": "23160090", "text": "Hydroxysafflor yellow A (HSYA) is an active ingredient obtained from the flower of Carthamus tinctorius", "type": "CHEMICAL", "entities": [ "Hydroxysafflor yellow A", "HSYA" ], "offsets": [ [ 0, 23 ], [ 25, 29 ] ] }, { "pmid": "23160090", "text": "L.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23160090", "text": "The present study investigated the effects of HSYA on lipopolysaccharide (LPS)-induced inflammatory signal transduction in human alveolar epithelial A549 cells.", "type": "CHEMICAL", "entities": [ "HSYA" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "23160090", "text": "A549 cells stimulated with LPS were incubated with three doses of HSYA (1, 4 and 16μmol/L).", "type": "CHEMICAL", "entities": [ "HSYA" ], "offsets": [ [ 66, 70 ] ] }, { "pmid": "23160090", "text": "HSYA suppressed the expression of TLR-4, Myd88, ICAM-1, TNFα, IL-1β and IL-6 at the mRNA and protein level, and inhibited the adhesion of leukocytes to A549 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23160090", "text": "HSYA treatment also decreased NF-κB p65 nuclear translocation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23160090", "text": "These findings suggest that HSYA effectively inhibits LPS-induced inflammatory signal transduction in A549 cells.", "type": "CHEMICAL", "entities": [ "HSYA" ], "offsets": [ [ 24, 28 ] ] }, { "pmid": "23601990", "text": "Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase.\n", "type": "CHEMICAL", "entities": [ "cholesterol", "phosphorylated flavonoids" ], "offsets": [ [ 103, 114 ], [ 39, 64 ] ] }, { "pmid": "23601990", "text": "A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE).", "type": "CHEMICAL", "entities": [ "cholesterol", "phosphorylated flavonoids" ], "offsets": [ [ 109, 120 ], [ 12, 37 ] ] }, { "pmid": "23601990", "text": "The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids.", "type": "CHEMICAL", "entities": [ "flavonoids" ], "offsets": [ [ 128, 138 ] ] }, { "pmid": "23601990", "text": "Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE.", "type": "CHEMICAL", "entities": [ "phosphorylated flavonoids" ], "offsets": [ [ 18, 43 ] ] }, { "pmid": "23601990", "text": "The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase.", "type": "CHEMICAL", "entities": [ "hydroxyl", "phosphate", "phosphorylated flavonoids" ], "offsets": [ [ 58, 66 ], [ 91, 100 ], [ 128, 153 ] ] }, { "pmid": "23601990", "text": "The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16855178", "text": "5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity.\nH(2)S functions as a neuromodulator and exerts anti-inflammatory activities.", "type": "CHEMICAL", "entities": [ "H(2)S", "5-Amino-2-hydroxybenzoic acid", "mesalamine", "4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester", "ATB-429", "hydrogen sulfide" ], "offsets": [ [ 222, 227 ], [ 0, 29 ], [ 130, 140 ], [ 30, 75 ], [ 77, 84 ], [ 89, 105 ] ] }, { "pmid": "16855178", "text": "Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16855178", "text": "In this study, we have investigated the role of a novel H(2)S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats.", "type": "CHEMICAL", "entities": [ "H(2)S", "mesalamine", "5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester", "ATB-429" ], "offsets": [ [ 56, 61 ], [ 86, 96 ], [ 98, 173 ], [ 175, 182 ] ] }, { "pmid": "16855178", "text": "Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16855178", "text": "In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect.", "type": "CHEMICAL", "entities": [ "ATB-429", "mesalamine" ], "offsets": [ [ 17, 24 ], [ 190, 200 ] ] }, { "pmid": "16855178", "text": "ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor.", "type": "CHEMICAL", "entities": [ "K(+)", "K", "ATP", "ATB-429", "glibenclamide", "ATP" ], "offsets": [ [ 79, 83 ], [ 85, 86 ], [ 87, 90 ], [ 0, 7 ], [ 48, 61 ], [ 65, 68 ] ] }, { "pmid": "16855178", "text": "The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction).", "type": "CHEMICAL", "entities": [ "ATB-429" ], "offsets": [ [ 30, 37 ] ] }, { "pmid": "16855178", "text": "At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats.", "type": "CHEMICAL", "entities": [ "ATB-429" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "16855178", "text": "Colonic cyclooxygenase-2 and interkeukin-1beta mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine.", "type": "CHEMICAL", "entities": [ "ATB-429", "mesalamine" ], "offsets": [ [ 122, 129 ], [ 142, 152 ] ] }, { "pmid": "16855178", "text": "ATB-429, but not mesalamine, increased blood concentrations of H(2)S in both healthy and postcolitic rats.", "type": "CHEMICAL", "entities": [ "ATB-429", "mesalamine", "H(2)S" ], "offsets": [ [ 0, 7 ], [ 17, 27 ], [ 63, 68 ] ] }, { "pmid": "16855178", "text": "Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K(ATP) channel-mediated mechanism.", "type": "CHEMICAL", "entities": [ "ATB-429", "K", "ATP" ], "offsets": [ [ 40, 47 ], [ 142, 143 ], [ 144, 147 ] ] }, { "pmid": "16855178", "text": "This study provides evidence that H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.", "type": "CHEMICAL", "entities": [ "H(2)S" ], "offsets": [ [ 34, 39 ] ] }, { "pmid": "15066664", "text": "Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin.\n", "type": "CHEMICAL", "entities": [ "sodium", "alpha-hydroxyphenylamide", "phenytoin" ], "offsets": [ [ 22, 28 ], [ 47, 71 ], [ 85, 94 ] ] }, { "pmid": "15066664", "text": "Voltage-gated sodium (Na) channels are a critical component of electrically excitable cells.", "type": "CHEMICAL", "entities": [ "sodium", "Na" ], "offsets": [ [ 14, 20 ], [ 22, 24 ] ] }, { "pmid": "15066664", "text": "Phenytoin (diphenylhydantoin, DPH) is an established sodium channel blocker and is a useful anticonvulsant and class", "type": "CHEMICAL", "entities": [ "diphenylhydantoin", "DPH", "sodium", "Phenytoin" ], "offsets": [ [ 11, 28 ], [ 30, 33 ], [ 53, 59 ], [ 0, 9 ] ] }, { "pmid": "15066664", "text": "1b antiarrhythmic, and has been effectively used in the treatment of neuropathic pain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15066664", "text": "In this study, we have synthesized novel alpha-hydroxyphenylamide analogues of diphenylhydantoin and examined their ability to inhibit human Na(V)1.5 sodium channels expressed in Chinese Hamster Ovary (CHO-K1) cells.", "type": "CHEMICAL", "entities": [ "alpha-hydroxyphenylamide", "diphenylhydantoin", "sodium" ], "offsets": [ [ 41, 65 ], [ 79, 96 ], [ 150, 156 ] ] }, { "pmid": "15066664", "text": "Phenyl ring substitutions were examined including para-methyl, para-fluoro, para-chloro, ortho-chloro and meta-chloro.", "type": "CHEMICAL", "entities": [ "Phenyl", "para-methyl", "para-fluoro", "para-chloro", "ortho-chloro", "meta-chloro" ], "offsets": [ [ 0, 6 ], [ 50, 61 ], [ 63, 74 ], [ 76, 87 ], [ 89, 101 ], [ 106, 117 ] ] }, { "pmid": "15066664", "text": "We have found that phenyl ring substitutions with electron withdrawing properties resulted in compounds with greater activity.", "type": "CHEMICAL", "entities": [ "phenyl" ], "offsets": [ [ 19, 25 ] ] }, { "pmid": "15066664", "text": "In comparison to diphenylhydantoin, the novel chloro-substituted alpha-hydroxyphenylamide compounds produced as much as a 20-fold greater tonic and frequency-dependent blockade of Na(V)1.5 channels with an IC(50) value of 14.5 microM.", "type": "CHEMICAL", "entities": [ "diphenylhydantoin", "chloro", "alpha-hydroxyphenylamide" ], "offsets": [ [ 17, 34 ], [ 46, 52 ], [ 65, 89 ] ] }, { "pmid": "15066664", "text": "In addition, the chloro-substitutions have position specific state dependent blocking properties.", "type": "CHEMICAL", "entities": [ "chloro" ], "offsets": [ [ 17, 23 ] ] }, { "pmid": "15066664", "text": "The ortho-, meta- and para-chloro substitutions have an 8-, 13- and 3-fold increased affinity for the inactivated state, respectively.", "type": "CHEMICAL", "entities": [ "ortho-, meta- and para-chloro" ], "offsets": [ [ 4, 33 ] ] }, { "pmid": "15066664", "text": "Molecular modeling suggests that these differences in affinity are due to a direct interaction with the receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15066664", "text": "Comparing models of diphenylhydantoin to the novel alpha-hydroxyphenlyamide compound suggests that the increased activity may be due to an optimized phenyl ring position and increased molecular volume.", "type": "CHEMICAL", "entities": [ "diphenylhydantoin", "alpha-hydroxyphenlyamide", "phenyl" ], "offsets": [ [ 20, 37 ], [ 51, 75 ], [ 149, 155 ] ] }, { "pmid": "15066664", "text": "This information may be useful in the development of more potent sodium channel blockers.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 65, 71 ] ] }, { "pmid": "11034583", "text": "Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans.\n", "type": "CHEMICAL", "entities": [ "serotonin", "SB-207266" ], "offsets": [ [ 13, 22 ], [ 51, 60 ] ] }, { "pmid": "11034583", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "Serotonin 5-HT(4) receptors are located on enteric cholinergic neurones and may regulate peristalsis.", "type": "CHEMICAL", "entities": [ "Serotonin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11034583", "text": "5-HT(4) receptors on primary afferent neurones have been postulated to modulate visceral sensation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "While 5-HT(4) agonists are used as prokinetic agents, the physiological role of 5-HT(4) receptors in the human gut is unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "AIMS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "Our aim was to characterise the role of 5-HT(4) receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT(4) receptor antagonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "Part A compared the effects of placebo to four doses of a 5-HT(4) receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT(4) mediated response) and orocaecal transit in 18 subjects.", "type": "CHEMICAL", "entities": [ "SB-207266", "cisapride", "aldosterone" ], "offsets": [ [ 87, 96 ], [ 105, 114 ], [ 143, 154 ] ] }, { "pmid": "11034583", "text": "In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12.", "type": "CHEMICAL", "entities": [ "SB-207266" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "11034583", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11034583", "text": "Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit.", "type": "CHEMICAL", "entities": [ "SB-207266", "aldosterone" ], "offsets": [ [ 35, 44 ], [ 152, 163 ] ] }, { "pmid": "11034583", "text": "Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation.", "type": "CHEMICAL", "entities": [ "SB-207266" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "11034583", "text": "CONCLUSION: 5-HT(4) receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects.", "type": "CHEMICAL", "entities": [ "cisapride", "SB 207266" ], "offsets": [ [ 64, 73 ], [ 104, 113 ] ] }, { "pmid": "16455797", "text": "Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target.\n", "type": "CHEMICAL", "entities": [ "spermidine", "spermine" ], "offsets": [ [ 41, 51 ], [ 52, 60 ] ] }, { "pmid": "16455797", "text": "Spermidine/spermine N1-acetyltransferase (SSAT) is a key enzyme in the control of polyamine levels in human cells, as acetylation of spermidine and spermine triggers export or degradation.", "type": "CHEMICAL", "entities": [ "Spermidine", "spermine", "spermidine", "spermine", "polyamine" ], "offsets": [ [ 0, 10 ], [ 11, 19 ], [ 133, 143 ], [ 148, 156 ], [ 82, 91 ] ] }, { "pmid": "16455797", "text": "Increased intracellular polyamine levels accompany several types of cancers as well as other human diseases, and compounds that affect the expression, activity, or stability of SSAT are being explored as potential therapeutic drugs.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "16455797", "text": "We have expressed human SSAT from the cloned cDNA in Escherichia coli and have determined high-resolution structures of wild-type and mutant SSAT, as the free dimer and in binary and ternary complexes with CoA, acetyl-CoA (AcCoA), spermine, and the inhibitor N1,N11bis-(ethyl)-norspermine (BE-3-3-3).", "type": "CHEMICAL", "entities": [ "CoA", "acetyl-CoA", "AcCoA", "spermine", "N1,N11bis-(ethyl)-norspermine" ], "offsets": [ [ 206, 209 ], [ 211, 221 ], [ 223, 228 ], [ 231, 239 ], [ 259, 288 ] ] }, { "pmid": "16455797", "text": "These structures show details of binding sites for cofactor, substrates, and inhibitor and provide a framework to understand enzymatic activity, mutations, and the action of potential drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16455797", "text": "Two dimer conformations were observed: a symmetric form with two open surface channels capable of binding substrate or cofactor, and an asymmetric form in which only one of the surface channels appears capable of binding and acetylating polyamines.", "type": "CHEMICAL", "entities": [ "polyamines" ], "offsets": [ [ 237, 247 ] ] }, { "pmid": "16455797", "text": "SSAT was found to self-acetylate lysine-26 in the presence of AcCoA and absence of substrate, a reaction apparently catalzyed by AcCoA bound in the second channel of the asymmetric dimer.", "type": "CHEMICAL", "entities": [ "acetylate", "lysine", "AcCoA", "AcCoA" ], "offsets": [ [ 23, 32 ], [ 33, 39 ], [ 62, 67 ], [ 129, 134 ] ] }, { "pmid": "16455797", "text": "These unexpected and intriguing complexities seem likely to have some as yet undefined role in regulating SSAT activity or stability as a part of polyamine homeostasis.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 146, 155 ] ] }, { "pmid": "16455797", "text": "Sequence signatures group SSAT with proteins that appear to have thialysine Nepsilon-acetyltransferase activity.", "type": "CHEMICAL", "entities": [ "thialysine" ], "offsets": [ [ 65, 75 ] ] }, { "pmid": "23570914", "text": "Suppression of nuclear factor erythroid 2-related factor 2 via extracellular signal-regulated kinase contributes to bleomycin-induced oxidative stress and fibrogenesis.\n", "type": "CHEMICAL", "entities": [ "bleomycin" ], "offsets": [ [ 116, 125 ] ] }, { "pmid": "23570914", "text": "Pulmonary fibrosis is a serious and irreversible lung injury with obscure etiologic mechanisms and no effective treatment to date.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23570914", "text": "This study explored a crucial link between oxidative stress and pulmonary fibrogenesis, focusing on nuclear factor erythroid 2-related factor 2 (Nrf2), a core transcription factor in antioxidative regulation systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23570914", "text": "Treatment of C57 BL/6 mice with bleomycin increased fibroblast viability and collagen production and significantly downregulated Nrf2.", "type": "CHEMICAL", "entities": [ "bleomycin" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "23570914", "text": "In addition, prominent oxidative stress was indicated by changes in superoxide dismutase, catalase activity, and glutathione and thiobarbituric acid-reactive substance levels.", "type": "CHEMICAL", "entities": [ "superoxide", "glutathione", "thiobarbituric acid" ], "offsets": [ [ 68, 78 ], [ 113, 124 ], [ 129, 148 ] ] }, { "pmid": "23570914", "text": "In a cell-based model, bleomycin suppressed Nrf2 activation via extracellular signal-related kinase phosphorylation, enhancing intracellular reactive oxygen species in lung fibroblasts and stimulating abnormal cell proliferation and collagen secretion.", "type": "CHEMICAL", "entities": [ "bleomycin", "oxygen" ], "offsets": [ [ 23, 32 ], [ 150, 156 ] ] }, { "pmid": "23570914", "text": "To confirm this novel mechanism of bleomycin-induced fibrogenesis, we attempted to upregulate Nrf2 and related antioxidant proteins in bleomycin-treated fibroblasts using a putative Nrf2 activator, caffeic acid phenethyl ester, and the results showed that bleomycin-induced fibroblast proliferation and collagen content were attenuated through improved redox balance.", "type": "CHEMICAL", "entities": [ "caffeic acid phenethyl ester", "bleomycin", "bleomycin" ], "offsets": [ [ 198, 226 ], [ 256, 265 ], [ 35, 44 ] ] }, { "pmid": "23570914", "text": "Collectively, these results disclose a potential regulatory mechanism in pulmonary fibrosis that will aid the development of new therapies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298863", "text": "Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice.\n", "type": "CHEMICAL", "entities": [ "TAK-441" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "23298863", "text": "6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (TAK-441) is a potent, selective hedgehog signaling pathway inhibitor that binds to Smo and is being developed for the treatment of cancer.", "type": "CHEMICAL", "entities": [ "6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide", "TAK-441" ], "offsets": [ [ 0, 160 ], [ 162, 169 ] ] }, { "pmid": "23298863", "text": "The objectives of these studies were to explore the possibility of establishing of a link between the pharmacokinetics of TAK-441 and the responses of Gli1 mRNA in tumor-associated stromal or skin cells and the antitumor effect of hedgehog inhibition.", "type": "CHEMICAL", "entities": [ "TAK-441" ], "offsets": [ [ 122, 129 ] ] }, { "pmid": "23298863", "text": "To this end, we built pharmacokinetic and pharmacodynamic models that describe the relationship of the concentrations of TAK-441 plasma to the responses of Gli1 mRNA in the tumor (target) and skin (surrogate) and to tumor growth inhibition in mice bearing xenografts of human pancreatic tumors (PAN-04).", "type": "CHEMICAL", "entities": [ "TAK-441" ], "offsets": [ [ 121, 128 ] ] }, { "pmid": "23298863", "text": "The responses of Gli1 mRNA and tumor growth were described by an indirect response model and an exponential tumor growth model, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298863", "text": "The IC50 values for Gli1 mRNA inhibition in the tumor and skin by TAK-441 were estimated to be 0.0457 and 0.113 μg/ml, respectively.", "type": "CHEMICAL", "entities": [ "TAK-441" ], "offsets": [ [ 66, 73 ] ] }, { "pmid": "23298863", "text": "The IC90 value for tumor growth inhibition was estimated to be 0.68 μg/ml.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298863", "text": "These results suggest that a >83% inhibition of Gli1 mRNA expression in the skin or a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth in the xenografted model mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298863", "text": "We conclude that Gli1 mRNA expression in the tumor and skin could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "Non-small cell lung cancer (NSCLC) cells have constitutively high expression of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX) 2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "These NSCLC cells also have increased prostaglandin expression (PGE2).", "type": "CHEMICAL", "entities": [ "prostaglandin", "PGE2" ], "offsets": [ [ 38, 51 ], [ 64, 68 ] ] }, { "pmid": "10626810", "text": "Many lung cancers also express 12-lipoxygenase RNA and 12-lipoxygenase protein and biosynthesize 12(S)-hydroxyeicosatetraenoic acid, which correlates with their metastatic potential.", "type": "CHEMICAL", "entities": [ "12(S)-hydroxyeicosatetraenoic acid" ], "offsets": [ [ 97, 131 ] ] }, { "pmid": "10626810", "text": "Several studies have demonstrated that COX-1 and COX-2 inhibitors could inhibit the in vitro growth of human lung cancer cell lines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "In this report, we evaluated the growth-inhibitory effects of sulindac sulfide, a COX-1 and COX-2 inhibitor; exisulind (sulindac sulfone), a novel proapoptotic agent that does not inhibit COX enzymes; and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor on human lung cancer cell lines.", "type": "CHEMICAL", "entities": [ "sulindac sulfide", "exisulind", "sulindac sulfone", "nordihydroguaiaretic acid", "NDGA" ], "offsets": [ [ 62, 78 ], [ 109, 118 ], [ 120, 136 ], [ 205, 230 ], [ 232, 236 ] ] }, { "pmid": "10626810", "text": "We compared these effects with those of 13-cis-retinoic acid, a chemoprevention agent, and with the cytotoxic chemotherapeutic agents paclitaxel and cisplatin, alone or in combination.", "type": "CHEMICAL", "entities": [ "13-cis-retinoic acid", "paclitaxel", "cisplatin" ], "offsets": [ [ 40, 60 ], [ 134, 144 ], [ 149, 158 ] ] }, { "pmid": "10626810", "text": "Our goal was to develop new chemoprevention and treatment strategies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "Each of the six agents tested inhibited the in vitro growth of three NSCLC and three SCLC cell lines at the highest concentration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10626810", "text": "Paclitaxel was the most potent agent (IC50 = 0.003-0.150 microM); sulindac sulfide, NDGA, and 13-cis-retinoic acid had intermediate potency (IC50 = 4-80 microM), and cisplatin and exisulind were the least potent (IC50 = 150-500 microM).", "type": "CHEMICAL", "entities": [ "Paclitaxel", "sulindac sulfide", "NDGA", "13-cis-retinoic acid", "cisplatin", "exisulind" ], "offsets": [ [ 0, 10 ], [ 66, 82 ], [ 84, 88 ], [ 94, 114 ], [ 166, 175 ], [ 180, 189 ] ] }, { "pmid": "10626810", "text": "Combination studies showed synergistic interactions for sulindac sulfide, exisulind, and NDGA with paclitaxel, cisplatin, and 13-cis-retinoic acid, regardless of drug-resistance phenotype.", "type": "CHEMICAL", "entities": [ "sulindac sulfide", "exisulind", "NDGA", "paclitaxel", "cisplatin", "13-cis-retinoic acid" ], "offsets": [ [ 56, 72 ], [ 74, 83 ], [ 89, 93 ], [ 99, 109 ], [ 111, 120 ], [ 126, 146 ] ] }, { "pmid": "10626810", "text": "At high concentrations, the combination of 13-cis-retinoic acid and each of the five other drugs resulted in a strong synergistic effect.", "type": "CHEMICAL", "entities": [ "13-cis-retinoic acid" ], "offsets": [ [ 43, 63 ] ] }, { "pmid": "10626810", "text": "These studies provide a rationale for chemoprevention (exisulind +/- retinoic acid +/- NDGA) and therapeutic (exisulind +/- paclitaxel +/- cisplatin) studies in patients at risk for, or with, lung cancer.", "type": "CHEMICAL", "entities": [ "exisulind", "retinoic acid", "NDGA", "exisulind", "paclitaxel", "cisplatin" ], "offsets": [ [ 55, 64 ], [ 69, 82 ], [ 87, 91 ], [ 110, 119 ], [ 124, 134 ], [ 139, 148 ] ] }, { "pmid": "20421509", "text": "Phenothiazines inhibit S100A4 function by inducing protein oligomerization.\nS100A4, a member of the S100 family of Ca(2+)-binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Phenothiazines" ], "offsets": [ [ 115, 121 ], [ 0, 14 ] ] }, { "pmid": "20421509", "text": "Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20421509", "text": "These observations suggest that S100A4 is an excellent target for therapeutic intervention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20421509", "text": "Using a unique biosensor-based assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction.", "type": "CHEMICAL", "entities": [ "trifluoperazine", "TFP" ], "offsets": [ [ 38, 53 ], [ 55, 58 ] ] }, { "pmid": "20421509", "text": "To examine the interaction of S100A4 with TFP, we determined the 2.3 A crystal structure of human Ca(2+)-S100A4 bound to TFP.", "type": "CHEMICAL", "entities": [ "TFP", "Ca(2+)", "TFP" ], "offsets": [ [ 42, 45 ], [ 98, 104 ], [ 121, 124 ] ] }, { "pmid": "20421509", "text": "Two TFP molecules bind within the hydrophobic target binding pocket of Ca(2+)-S100A4 with no significant conformational changes observed in the protein upon complex formation.", "type": "CHEMICAL", "entities": [ "TFP", "Ca(2+)" ], "offsets": [ [ 4, 7 ], [ 71, 77 ] ] }, { "pmid": "20421509", "text": "NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution.", "type": "CHEMICAL", "entities": [ "TFP" ], "offsets": [ [ 96, 99 ] ] }, { "pmid": "20421509", "text": "Remarkably, TFP binding results in the assembly of five Ca(2+)-S100A4/TFP dimers into a tightly packed pentameric ring.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "TFP" ], "offsets": [ [ 56, 62 ], [ 12, 15 ] ] }, { "pmid": "20421509", "text": "Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties.", "type": "CHEMICAL", "entities": [ "TFP" ], "offsets": [ [ 83, 86 ] ] }, { "pmid": "20421509", "text": "The Ca(2+)-S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "prochlorperazine", "PCP" ], "offsets": [ [ 4, 10 ], [ 18, 34 ], [ 36, 39 ] ] }, { "pmid": "20421509", "text": "Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution.", "type": "CHEMICAL", "entities": [ "TFP" ], "offsets": [ [ 118, 121 ] ] }, { "pmid": "20421509", "text": "Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization.", "type": "CHEMICAL", "entities": [ "TFP", "TFP" ], "offsets": [ [ 32, 35 ], [ 171, 174 ] ] }, { "pmid": "20421509", "text": "Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.", "type": "CHEMICAL", "entities": [ "phenothiazines" ], "offsets": [ [ 68, 82 ] ] }, { "pmid": "23201124", "text": "Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase, the NEDDylator.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "Inhibitors of Apoptosis Protein (IAPs) are guardian ubiquitin ligases that keep classic proapoptotic proteins in check.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "Systematic identification of additional IAP substrates is challenged by the heterogeneity and sheer number of ubiquitinated proteins (>5,000).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "Here we report a powerful catalytic tagging tool, the NEDDylator, which fuses a NEDD8 E2-conjugating enzyme, Ubc12, to the ubiquitin ligase, XIAP or cIAP1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "This permits transfer of the rare ubiquitin homolog NEDD8 to the ubiquitin E3 substrates, allowing them to be efficiently purified for LC-MS/MS identification.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "We have identified >50 potential IAP substrates of both cytosolic and mitochondrial origin that bear hallmark N-terminal IAP binding motifs.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 110, 111 ] ] }, { "pmid": "23201124", "text": "These substrates include the recently discovered protein phosphatase PGAM5, which we show is proteolytically processed, accumulates in cytosol during apoptosis, and sensitizes cells to death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23201124", "text": "These studies reveal mechanisms and antagonistic partners for specific IAPs, and provide a powerful technology for labeling binding partners in transient protein-protein complexes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "Cloning and expression of the liver and muscle isoforms of ovine carnitine palmitoyltransferase 1: residues within the N-terminus of the muscle isoform influence the kinetic properties of the enzyme.\n", "type": "CHEMICAL", "entities": [ "N", "carnitine" ], "offsets": [ [ 119, 120 ], [ 65, 74 ] ] }, { "pmid": "12662154", "text": "The nucleotide sequence data reported will appear in DDBJ, EMBL, GenBank(R) and GSDB Nucleotide Sequence Databases; the sequences of ovine CPT1A and CPT1B cDNAs have the accession numbers Y18387 and AJ272435 respectively and the partial adipose tissue and liver CPT1A clones have the accession numbers Y18830 and Y18829 respectively.", "type": "CHEMICAL", "entities": [ "nucleotide", "Nucleotide" ], "offsets": [ [ 4, 14 ], [ 85, 95 ] ] }, { "pmid": "12662154", "text": "Fatty acid and ketone body metabolism differ considerably between monogastric and ruminant species.", "type": "CHEMICAL", "entities": [ "Fatty acid", "ketone" ], "offsets": [ [ 0, 10 ], [ 15, 21 ] ] }, { "pmid": "12662154", "text": "The regulation of the key enzymes involved may differ accordingly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "Carnitine palmitoyltransferase 1 (CPT 1) is the key locus for the control of long-chain fatty acid beta-oxidation and liver ketogenesis.", "type": "CHEMICAL", "entities": [ "Carnitine", "fatty acid" ], "offsets": [ [ 0, 9 ], [ 88, 98 ] ] }, { "pmid": "12662154", "text": "Previously we showed that CPT 1 kinetics in sheep and rat liver mitochondria differ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "We cloned cDNAs for both isoforms [liver- (L-) and muscle- (M-)] of ovine CPT 1 in order to elucidate the structural features of these proteins and their genes ( CPT1A and CPT1B ).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "Their deduced amino acid sequences show a high degree of conservation compared with orthologues from other mammalian species, with the notable exception of the N-terminus of ovine M-CPT 1.", "type": "CHEMICAL", "entities": [ "N", "amino acid" ], "offsets": [ [ 160, 161 ], [ 14, 24 ] ] }, { "pmid": "12662154", "text": "These differences were also present in bovine M-CPT 1, whose N-terminal sequence we determined.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 61, 62 ] ] }, { "pmid": "12662154", "text": "In addition, the 5'-end of the sheep CPT1B cDNA suggested a different promoter architecture when compared with previously characterized CPT1B genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "Northern blotting revealed differences in tissue distribution for both CPT1A and CPT1B transcripts compared with other species.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12662154", "text": "In particular, ovine CPT1B mRNA was less tissue restricted, and the predominant transcript in the pancreas was CPT1B. Expression in yeast allowed kinetic characterization of the two native enzymes, and of a chimaera in which the distinctive N-terminal segment of ovine M-CPT 1 was replaced with that from rat M-CPT 1.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 241, 242 ] ] }, { "pmid": "12662154", "text": "The ovine N-terminal segment influences the kinetics of the enzyme for both its substrates, such that the K (m) for palmitoyl-CoA is decreased and that for carnitine is increased for the chimaera, relative to the parental ovine M-CPT 1.", "type": "CHEMICAL", "entities": [ "N", "palmitoyl-CoA", "carnitine" ], "offsets": [ [ 10, 11 ], [ 116, 129 ], [ 156, 165 ] ] }, { "pmid": "7912539", "text": "Cardiac effects of the beta 3-adrenoceptor agonist BRL35135 in man.\n", "type": "CHEMICAL", "entities": [ "BRL35135" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "7912539", "text": "The aim of the present study was to evaluate the cardiac effects of the beta 3-adrenoceptor agonist BRL35135, and determine whether beta 3-receptors are involved in mediating chronotropic or inotropic responses in man.", "type": "CHEMICAL", "entities": [ "BRL35135" ], "offsets": [ [ 100, 108 ] ] }, { "pmid": "7912539", "text": "Eight normal males received single oral doses of BRL35135 8 mg (BRL) or the selective beta 2-adrenoceptor agonist salbutamol 8 mg (SAL), after pretreatment with either placebo (PL), bisoprolol 5 mg (B5) as a selective beta 1-adrenoceptor antagonist, or nadolol 20 mg (N20) to block beta", "type": "CHEMICAL", "entities": [ "BRL35135", "BRL", "salbutamol", "SAL", "bisoprolol", "nadolol" ], "offsets": [ [ 49, 57 ], [ 64, 67 ], [ 114, 124 ], [ 131, 134 ], [ 182, 192 ], [ 253, 260 ] ] }, { "pmid": "7912539", "text": "1- and beta", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7912539", "text": "2- but not beta 3-receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7912539", "text": "Both BRL and SAL produced a significant increase in postural finger tremor in keeping with beta 2-adrenoceptor stimulation, and this response was totally abolished by pretreatment with N20.", "type": "CHEMICAL", "entities": [ "BRL", "SAL" ], "offsets": [ [ 5, 8 ], [ 13, 16 ] ] }, { "pmid": "7912539", "text": "Significant increases in systolic blood pressure and Doppler stroke distance occurred with BRL and SAL which were unaffected by pretreatment with B5 and completely blocked by N20, in keeping with beta 2-mediated effects.", "type": "CHEMICAL", "entities": [ "BRL", "SAL" ], "offsets": [ [ 91, 94 ], [ 99, 102 ] ] }, { "pmid": "7912539", "text": "BRL and SAL produced significant chronotropic and minute distance responses which were unaffected by beta 1-adrenoceptor blockade.", "type": "CHEMICAL", "entities": [ "BRL", "SAL" ], "offsets": [ [ 0, 3 ], [ 8, 11 ] ] }, { "pmid": "7912539", "text": "However, whereas N20 blocked these responses to SAL, a small but significant response occurred with BRL in comparison with placebo despite complete blockade of co-existing beta 2-mediated effects.", "type": "CHEMICAL", "entities": [ "SAL", "BRL" ], "offsets": [ [ 48, 51 ], [ 100, 103 ] ] }, { "pmid": "7912539", "text": "Compared with PL, the mean responses to N20/BRL, and the 95% confidence interval for the differences between the means were 7.4 beats min-1", "type": "CHEMICAL", "entities": [ "BRL" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "7912539", "text": "[3.2 to 11.6] (P = 0.002) for heart rate, and 208.8 cm", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7912539", "text": "[38.3 to 379.3] (P = 0.02) for minute distance responses.(ABSTRACT TRUNCATED AT 250 WORDS)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085979", "text": "Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication.\n", "type": "CHEMICAL", "entities": [ "Aryl hydrocarbon" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23085979", "text": "The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation.", "type": "CHEMICAL", "entities": [ "aryl hydrocarbon" ], "offsets": [ [ 4, 20 ] ] }, { "pmid": "23085979", "text": "In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085979", "text": "The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085979", "text": "Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner.", "type": "CHEMICAL", "entities": [ "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD", "polycyclic aromatic hydrocarbons" ], "offsets": [ [ 73, 108 ], [ 110, 114 ], [ 119, 151 ] ] }, { "pmid": "23085979", "text": "Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells.", "type": "CHEMICAL", "entities": [ "TCDD" ], "offsets": [ [ 119, 123 ] ] }, { "pmid": "23085979", "text": "Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23085979", "text": "This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "Heteromtoxin (HmTx), a novel heterodimeric phospholipase A(2) from Heterometrus laoticus scorpion venom.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "Heteromtoxin (HmTx) is a group III phospholipase A(2) produced in Heterometrus laoticus, in Thailand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "In this study, HmTx was purified from venom by separation chromatography, and the PLA(2) activity of the fractions was determined by lecithin agar assay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "The enzyme is an acidic protein with a pI of 5.6 and an apparent molecular weight of 14018.4 Da.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "The nucleotide sequence of HmTx contains 649 bp, and the mature protein is predicted to have 131 amino acid residues-104 of which make up the large subunit, and 27 of which make up the small subunit.", "type": "CHEMICAL", "entities": [ "nucleotide", "amino acid" ], "offsets": [ [ 4, 14 ], [ 97, 107 ] ] }, { "pmid": "23142507", "text": "The subunit structure of HmTx is highly similar to that of the other toxin, Pandinus imperator imperatoxin I (IpTx(i)) and to Mesobuthus tamulus phospholipase A(2) (MtPLA(2)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23142507", "text": "The 3D-structure of HmTx consists of three conserved alpha-helices: h1 (Lys24-His34), h2 (Cys59-Asp71), and h3 (Ala80-Phe89).", "type": "CHEMICAL", "entities": [ "Lys", "His", "Cys", "Asp", "Ala", "Phe" ], "offsets": [ [ 72, 75 ], [ 78, 81 ], [ 90, 93 ], [ 96, 99 ], [ 112, 115 ], [ 118, 121 ] ] }, { "pmid": "23142507", "text": "The beta-sheet consisted of a single stranded anti-parallel beta-sheet (b1.1 at Glu43-Lys45 and b1.2 at Lys48-Asn50) that was highly similar to the conserved sequences (-CGXG-, -CCXXHDXC- and CXCEXXXXXC-) of Apis mellifera (bee) phospholipases.", "type": "CHEMICAL", "entities": [ "Glu", "Lys", "Lys", "Asn" ], "offsets": [ [ 80, 83 ], [ 86, 89 ], [ 104, 107 ], [ 110, 113 ] ] }, { "pmid": "23612710", "text": "Comparative phosphoproteomic analysis of checkpoint recovery identifies new regulators of the DNA damage response.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612710", "text": "How cells recover from a DNA damage-induced arrest is currently poorly understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612710", "text": "We performed large-scale quantitative phosphoproteomics to identify changes in protein phosphorylation that occurred during recovery from arrest in the G2 phase of the cell cycle caused by DNA damage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612710", "text": "We identified 154 proteins that were differentially phosphorylated, and systematic depletion of each of these differentially phosphorylated proteins by small interfering RNA (siRNA) identified at least 10 potential regulators of recovery.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612710", "text": "Astrin, a protein associated with the mitotic spindle, was among the potential regulators of recovery.", "type": "CHEMICAL", "entities": [ "Astrin" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23612710", "text": "We found that astrin controlled the abundance of the cell cycle regulator p53 during DNA damage-induced arrest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612710", "text": "Cells in which astrin was depleted had decreased murine double minute 2 (MDM2) abundance and increased p53 at the later stages of the DNA damage response.", "type": "CHEMICAL", "entities": [ "astrin" ], "offsets": [ [ 15, 21 ] ] }, { "pmid": "23612710", "text": "Astrin was required for continued expression of genes encoding proteins that promote cell cycle progression in arrested cells.", "type": "CHEMICAL", "entities": [ "Astrin" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23612710", "text": "Thus, by controlling p53 abundance in cells recovering from DNA damage, astrin maintains the cells in a state competent to resume the cell cycle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14638499", "text": "Molecular mechanism of terbinafine resistance in Saccharomyces cerevisiae.\n", "type": "CHEMICAL", "entities": [ "terbinafine" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "14638499", "text": "Ten mutants of the yeast Saccharomyces cerevisiae resistant to the antimycotic terbinafine were isolated after chemical or UV mutagenesis.", "type": "CHEMICAL", "entities": [ "terbinafine" ], "offsets": [ [ 79, 90 ] ] }, { "pmid": "14638499", "text": "Molecular analysis of these mutants revealed single base pair exchanges in the ERG1 gene coding for squalene epoxidase, the target of terbinafine.", "type": "CHEMICAL", "entities": [ "squalene", "terbinafine" ], "offsets": [ [ 100, 108 ], [ 134, 145 ] ] }, { "pmid": "14638499", "text": "The mutants did not show cross-resistance to any of the substrates of various pleiotropic drug resistance efflux pumps tested.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14638499", "text": "The ERG1 mRNA levels in the mutants did not differ from those in the wild-type parent strains.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14638499", "text": "Terbinafine resistance was transmitted with the mutated alleles in gene replacement experiments, proving that single amino acid substitutions in the Erg1 protein were sufficient to confer the resistance phenotype.", "type": "CHEMICAL", "entities": [ "Terbinafine", "amino acid" ], "offsets": [ [ 0, 11 ], [ 117, 127 ] ] }, { "pmid": "14638499", "text": "The amino acid changes caused by the point mutations were clustered in two regions of the Erg1 protein.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 4, 14 ] ] }, { "pmid": "14638499", "text": "Seven mutants carried the amino acid substitutions F402L", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "14638499", "text": "(one mutant), F420L (one mutant), and P430S (five mutants) in the C-terminal part of the protein; and three mutants carried an L251F exchange in the central part of the protein.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 66, 67 ] ] }, { "pmid": "14638499", "text": "Interestingly, all exchanges identified involved amino acids which are conserved in the squalene epoxidases of yeasts and mammals.", "type": "CHEMICAL", "entities": [ "amino acids", "squalene" ], "offsets": [ [ 49, 60 ], [ 88, 96 ] ] }, { "pmid": "14638499", "text": "Two mutations that were generated by PCR mutagenesis of the ERG1 gene and that conferred terbinafine resistance mapped in the same regions of the Erg1 protein, with one resulting in an L251F exchange and the other resulting in an F433S exchange.", "type": "CHEMICAL", "entities": [ "terbinafine" ], "offsets": [ [ 89, 100 ] ] }, { "pmid": "14638499", "text": "The results strongly indicate that these regions are responsible for the interaction of yeast squalene epoxidase with terbinafine.", "type": "CHEMICAL", "entities": [ "squalene", "terbinafine" ], "offsets": [ [ 94, 102 ], [ 118, 129 ] ] }, { "pmid": "14871882", "text": "Ornithine metabolism in male and female rat kidney: mitochondrial expression of ornithine aminotransferase and arginase II.\n", "type": "CHEMICAL", "entities": [ "Ornithine", "ornithine" ], "offsets": [ [ 0, 9 ], [ 80, 89 ] ] }, { "pmid": "14871882", "text": "In the kidney, L-ornithine is reabsorbed along the proximal convoluted tubule (PCT), transported by basolateral carriers, and produced by arginase II (AII).", "type": "CHEMICAL", "entities": [ "L-ornithine" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "14871882", "text": "Here, the renal metabolic fate of L-ornithine was analyzed in male and female rats.", "type": "CHEMICAL", "entities": [ "L-ornithine" ], "offsets": [ [ 34, 45 ] ] }, { "pmid": "14871882", "text": "Kidneys and renal zones were dissected and used for Western blot analysis, immunofluorescence, and electron microscopic studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "Ornithine aminotransferase (OAT) and AII were localized using specific antibodies.", "type": "CHEMICAL", "entities": [ "Ornithine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "14871882", "text": "Ornithine oxidation was determined by incubating microdissected tubules with L-[1-14C] or L-[U-14C]ornithine in the presence or absence of energy-providing substrates.", "type": "CHEMICAL", "entities": [ "Ornithine", "L-[1-14C]", "L-[U-14C]ornithine" ], "offsets": [ [ 0, 9 ], [ 77, 86 ], [ 90, 108 ] ] }, { "pmid": "14871882", "text": "Ornithine decarboxylase (ODC) mRNAs were localized by in situ hybridization.", "type": "CHEMICAL", "entities": [ "Ornithine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "14871882", "text": "The 48-kDa OAT protein was detected in male and female kidneys, but its level was fourfold higher in the latter.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "OAT relative distribution increased from the superficial cortex toward the outer medulla to reach its highest level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "Almost all OAT protein was localized in cortical and medullary proximal straight tubules (CPST and OSPST, respectively).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "In proximal straight tubule (PST), AII protein distribution overlapped that of OAT.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "No gender difference in AII protein level was found.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "OAT and AII were colocalized within PST mitochondria.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "L-[1-14C]ornithine decarboxylation occurred in all tubules, but predominantly in proximal tubules.", "type": "CHEMICAL", "entities": [ "L-[1-14C]ornithine" ], "offsets": [ [ 0, 18 ] ] }, { "pmid": "14871882", "text": "L-[1-14C]ornithine decarboxylation was enhanced when L-[1-14C]ornithine was given to tubules as the sole substrate.", "type": "CHEMICAL", "entities": [ "L-[1-14C]ornithine", "L-[1-14C]ornithine" ], "offsets": [ [ 0, 18 ], [ 53, 71 ] ] }, { "pmid": "14871882", "text": "The use of L-[U-14C]ornithine demonstrated the complete oxidation of ornithine.", "type": "CHEMICAL", "entities": [ "L-[U-14C]ornithine", "ornithine" ], "offsets": [ [ 11, 29 ], [ 69, 78 ] ] }, { "pmid": "14871882", "text": "In conclusion, the OAT gene was expressed more in female rat proximal tubules than in male.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14871882", "text": "Because OAT and AII proteins overlapped in PST mitochondria, L-arginine-derived ornithine may be preferentially converted to L-glutamate, as proven by ornithine oxidation.", "type": "CHEMICAL", "entities": [ "L-arginine", "ornithine", "L-glutamate", "ornithine" ], "offsets": [ [ 61, 71 ], [ 80, 89 ], [ 125, 136 ], [ 151, 160 ] ] }, { "pmid": "14871882", "text": "However, the coexpression of ODC, glutamate decarboxylase, and glutamine synthetase in PST suggests that L-ornithine can also be metabolized to putrescine, GABA, and L-glutamine.", "type": "CHEMICAL", "entities": [ "glutamate", "glutamine", "L-ornithine", "putrescine", "GABA", "L-glutamine" ], "offsets": [ [ 34, 43 ], [ 63, 72 ], [ 105, 116 ], [ 144, 154 ], [ 156, 160 ], [ 166, 177 ] ] }, { "pmid": "14871882", "text": "The fate of L-ornithine may depend on the cellular context.", "type": "CHEMICAL", "entities": [ "L-ornithine" ], "offsets": [ [ 12, 23 ] ] }, { "pmid": "17075268", "text": "Dexamethasone suppresses histamine synthesis by repressing both transcription and activity of HDC in allergic rats.\n", "type": "CHEMICAL", "entities": [ "Dexamethasone", "histamine" ], "offsets": [ [ 0, 13 ], [ 25, 34 ] ] }, { "pmid": "17075268", "text": "BACKGROUND: Histamine synthesized by histidine decarboxylase (HDC) from L-histidine is a major chemical mediator in the development of nasal allergy which is characterized by nasal hypersensitivity.", "type": "CHEMICAL", "entities": [ "Histamine", "histidine", "L-histidine" ], "offsets": [ [ 12, 21 ], [ 37, 46 ], [ 72, 83 ] ] }, { "pmid": "17075268", "text": "However the regulatory mechanism of histamine synthesis by HDC remains to be elucidated.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "17075268", "text": "The objectives of the present study were to examine the changes of histamine content, HDC activity and HDC mRNA expression in the nasal mucosa of allergy model rats sensitized by the exposure to toluene diisocyanate (TDI) and to investigate the effect of dexamethasone on the above mentioned allergic parameters.", "type": "CHEMICAL", "entities": [ "histamine", "toluene diisocyanate", "TDI", "dexamethasone" ], "offsets": [ [ 67, 76 ], [ 195, 215 ], [ 217, 220 ], [ 255, 268 ] ] }, { "pmid": "17075268", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17075268", "text": "Rats were sensitized and provocated by TDI and the nasal allergy-like behaviors were scored during a 10 minute period after provocation.", "type": "CHEMICAL", "entities": [ "TDI" ], "offsets": [ [ 39, 42 ] ] }, { "pmid": "17075268", "text": "Histamine content and HDC activity in the nasal mucosa were determined using fluorometric high performance liquid chromatography.", "type": "CHEMICAL", "entities": [ "Histamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17075268", "text": "The expression of HDC mRNA in nasal mucosa was determined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17075268", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17075268", "text": "In TDI-sensitized rats, nasal allergy-like behaviors such as sneezing and watery rhinorrhea were induced.", "type": "CHEMICAL", "entities": [ "TDI" ], "offsets": [ [ 3, 6 ] ] }, { "pmid": "17075268", "text": "Histamine content, HDC activity and HDC mRNA expression in nasal mucosa were also significantly increased after TDI provocation.", "type": "CHEMICAL", "entities": [ "Histamine", "TDI" ], "offsets": [ [ 0, 9 ], [ 112, 115 ] ] }, { "pmid": "17075268", "text": "Pretreatment with dexamethasone significantly suppressed nasal allergy-like behaviors, up-regulation of histamine content, HDC activity and HDC mRNA induced by TDI in TDI-sensitized rats.", "type": "CHEMICAL", "entities": [ "dexamethasone", "histamine", "TDI", "TDI" ], "offsets": [ [ 18, 31 ], [ 104, 113 ], [ 160, 163 ], [ 167, 170 ] ] }, { "pmid": "17075268", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17075268", "text": "These findings indicate that increased synthesis of histamine through up-regulation of HDC gene expression and HDC activity in nasal mucosa plays an important role in the development of nasal hypersensitivity.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 52, 61 ] ] }, { "pmid": "17075268", "text": "Repression of HDC gene expression and HDC activity by dexamethasone may underlie its therapeutic effect in the treatment of allergy.", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 54, 67 ] ] }, { "pmid": "23223345", "text": "The Effects of Carbohydrate, Unsaturated Fat, and Protein Intake on Measures of Insulin Sensitivity: Results from the OmniHeart Trial.\n", "type": "CHEMICAL", "entities": [ "Carbohydrate" ], "offsets": [ [ 15, 27 ] ] }, { "pmid": "23223345", "text": "OBJECTIVE Impaired insulin sensitivity increases the risk of cardiovascular disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "Although calorie restriction and weight loss increase insulin sensitivity, the effects of modifying macronutrient composition on insulin sensitivity are uncertain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "The purpose of this study is to determine the effects on insulin sensitivity of a carbohydrate-rich diet (CARB; similar to the Dietary Approaches to Stop Hypertension [DASH] diet), a protein-rich diet (PROT; protein predominantly from plant sources), and an unsaturated fat-rich diet (UNSAT; predominantly monounsaturated).", "type": "CHEMICAL", "entities": [ "carbohydrate", "CARB" ], "offsets": [ [ 82, 94 ], [ 106, 110 ] ] }, { "pmid": "23223345", "text": "RESEARCH DESIGN AND METHODS", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "This study was a randomized, controlled, three-period, crossover feeding study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "The study participants were 164 individuals with prehypertension or stage 1 hypertension without diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "Diets were administered for 6 weeks each, with a washout period between diets of 2-4 weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "Weight was held constant throughout the study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "For our primary outcome, we calculated the quantitative insulin sensitivity check index (QUICKI) using the end-of-period fasting serum glucose and insulin.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 135, 142 ] ] }, { "pmid": "23223345", "text": "QUICKI is a validated measure of insulin sensitivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "The primary analyses used generalized estimating equations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "RESULTS At baseline, mean (SD) BMI was 30.2 (6.1) kg/m(2), and mean (SD) QUICKI was 0.35 (0.04).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23223345", "text": "The UNSAT diet increased QUICKI by 0.005, more than the CARB diet (P = 0.04).", "type": "CHEMICAL", "entities": [ "CARB" ], "offsets": [ [ 56, 60 ] ] }, { "pmid": "23223345", "text": "PROT had no significant effect compared with CARB.", "type": "CHEMICAL", "entities": [ "CARB" ], "offsets": [ [ 45, 49 ] ] }, { "pmid": "23223345", "text": "CONCLUSIONS A diet that partially replaces carbohydrate with unsaturated fat may improve insulin sensitivity in a population at risk for cardiovascular disease.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 43, 55 ] ] }, { "pmid": "23223345", "text": "Given the well-recognized challenges of sustaining weight loss, our results suggest an alternative approach for improving insulin sensitivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "BACKGROUND: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity.", "type": "CHEMICAL", "entities": [ "kaolin" ], "offsets": [ [ 179, 185 ] ] }, { "pmid": "16534527", "text": "METHODS AND RESULTS: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Food intake and body weight were assessed weekly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "At 4 weeks, body composition and plasma metabolic profiles were measured.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg).", "type": "CHEMICAL", "entities": [ "Kaolin" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "16534527", "text": "Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05).", "type": "CHEMICAL", "entities": [ "cholesterol", "triglycerides" ], "offsets": [ [ 7, 18 ], [ 20, 33 ] ] }, { "pmid": "16534527", "text": "Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake.", "type": "CHEMICAL", "entities": [ "kaolin" ], "offsets": [ [ 90, 96 ] ] }, { "pmid": "16534527", "text": "In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16534527", "text": "Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23381968", "text": "Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.\n", "type": "CHEMICAL", "entities": [ "clopidogrel", "clarithromycin", "sibutramine" ], "offsets": [ [ 21, 32 ], [ 37, 51 ], [ 96, 107 ] ] }, { "pmid": "23381968", "text": "In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans.", "type": "CHEMICAL", "entities": [ "racemic sibutramine", "clopidogrel", "clarithromycin" ], "offsets": [ [ 162, 181 ], [ 42, 53 ], [ 58, 72 ] ] }, { "pmid": "23381968", "text": "Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers.", "type": "CHEMICAL", "entities": [ "Sibutramine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23381968", "text": "Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively.", "type": "CHEMICAL", "entities": [ "Clopidogrel", "clarithromycin", "sibutramine" ], "offsets": [ [ 0, 11 ], [ 16, 30 ], [ 59, 70 ] ] }, { "pmid": "23381968", "text": "The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P < .001 and P < .001, respectively) but not during the clarithromycin phase (P = .099 and P = .090, respectively).", "type": "CHEMICAL", "entities": [ "clopidogrel", "clarithromycin" ], "offsets": [ [ 76, 87 ], [ 151, 165 ] ] }, { "pmid": "23381968", "text": "Exposure to sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23381968", "text": "These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo.", "type": "CHEMICAL", "entities": [ "sibutramine" ], "offsets": [ [ 47, 58 ] ] }, { "pmid": "23506002", "text": "New selective inhibitors of MMP-13 for inflammatory diseases: a patent evaluation (W02012151158).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506002", "text": "A series of compounds incorporating an aromatic scaffold based on isoxazolines were prepared in the patent application (WO2012151158).", "type": "CHEMICAL", "entities": [ "isoxazolines" ], "offsets": [ [ 66, 78 ] ] }, { "pmid": "23506002", "text": "The new compounds from the patent are defined to be biologically active metabolites, prodrugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts, they are claimed to be useful for treating immunological conditions because of their inhibitory activities on matrix metalloproteinase (MMP-13), although no specific MMP-13 inhibition data or other rationale to explain their biological effects is provided.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506002", "text": "The compounds have a broad potential utility with osteoarthritis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, degenerative joint disease or systemic lupus erythematosus among the likely preferred indications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609963", "text": "LIVER X RECEPTORS, NERVOUS SYSTEM AND LIPID METABOLISM.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609963", "text": "Lipids in the nervous system are represented by cholesterol and phospholipids as constituents of cell membranes and, in particular, of myelin.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 48, 59 ] ] }, { "pmid": "23609963", "text": "Therefore, lipids are finely regulated to guarantee physiological functions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609963", "text": "In the central nervous system, cholesterol is locally synthesized due to the presence of the blood brain barrier.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "23609963", "text": "In the peripheral nervous system cholesterol is either uptaken by lipoproteins and/or produced by de novo biosynthesis.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 33, 44 ] ] }, { "pmid": "23609963", "text": "Defects in lipid homeostasis in these tissues lead to structural and functional changes that often result in different pathological conditions depending on the affected pathways (i.e. cholesterol biosynthesis, cholesterol efflux, fatty acid biosynthesis etc.).", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "fatty acid" ], "offsets": [ [ 184, 195 ], [ 210, 221 ], [ 230, 240 ] ] }, { "pmid": "23609963", "text": "Alterations in cholesterol metabolism in the central nervous system are linked to several disorders such as Alzheimer's disease, Huntington disease, Parkinson disease, Multiple Sclerosis, Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and glioblastoma.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 15, 26 ] ] }, { "pmid": "23609963", "text": "In the peripheral nervous system changes in lipid metabolism are associated with the development of peripheral neuropathy that may be caused by metabolic disorders, injuries, therapeutics and autoimmune diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609963", "text": "Transcription factors, such as the Liver X receptors (LXRs), regulate both cholesterol and fatty acid metabolism in several tissues including the nervous system.", "type": "CHEMICAL", "entities": [ "cholesterol", "fatty acid" ], "offsets": [ [ 75, 86 ], [ 91, 101 ] ] }, { "pmid": "23609963", "text": "In the last few years several studies elucidated the biology of LXRs in nervous system due to the availability of knock-out mice and the development of synthetic ligands.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23609963", "text": "Here, we review a survey of the literature focused on central and peripheral nervous system and in physiological and pathological settings with particular attention on the roles played by LXRs in both districts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "Cysteinyl leukotriene-dependent interleukin-5 production leading to eosinophilia during late asthmatic response in guinea-pigs.\n", "type": "CHEMICAL", "entities": [ "Cysteinyl leukotriene" ], "offsets": [ [ 0, 21 ] ] }, { "pmid": "11972613", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "Allergic airway eosinophilia is suppressed by cysteinyl leukotriene (CysLT) receptor (CysLT1 receptor) antagonists in several species including humans and guinea-pigs, suggesting that CysLTs are directly or indirectly involved in induction of the response.", "type": "CHEMICAL", "entities": [ "CysLTs", "cysteinyl leukotriene", "CysLT" ], "offsets": [ [ 184, 190 ], [ 46, 67 ], [ 69, 74 ] ] }, { "pmid": "11972613", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "We examined the effect of CysLT antagonists (pranlukast and MCI-826) on antigen inhalation-induced eosinophilia in peripheral blood and lung, and on IL-5 activity in serum during late increase of airway resistance (late asthmatic response, LAR) in sensitized guinea-pigs.", "type": "CHEMICAL", "entities": [ "CysLT", "pranlukast", "MCI-826" ], "offsets": [ [ 26, 31 ], [ 45, 55 ], [ 60, 67 ] ] }, { "pmid": "11972613", "text": "METHODS: Guinea-pigs inhaled ovalbumin (OVA) + Al(OH)3 and OVA mists alternately for sensitization and challenge, respectively, once every 2 weeks.", "type": "CHEMICAL", "entities": [ "Al(OH)3" ], "offsets": [ [ 47, 54 ] ] }, { "pmid": "11972613", "text": "At the fifth challenge, the effects of CysLT antagonists and an anti-IL-5 antibody (TRFK-5) on the occurrence of LAR, and blood and lung eosinophilia, which appeared at 5 h after challenge, were examined.", "type": "CHEMICAL", "entities": [ "CysLT" ], "offsets": [ [ 39, 44 ] ] }, { "pmid": "11972613", "text": "The time-course of IL-5 activity in the serum after the challenge was evaluated by measuring in vitro 'eosinophil survival prolongation activity'.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "The influence of CysLT antagonists on IL-5 activity was assessed.", "type": "CHEMICAL", "entities": [ "CysLT" ], "offsets": [ [ 17, 22 ] ] }, { "pmid": "11972613", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "CysLT antagonists and TRFK-5 completely abolished blood and lung eosinophilia.", "type": "CHEMICAL", "entities": [ "CysLT" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "11972613", "text": "LAR was suppressed by both MCI-826 and TRFK-5 by 40-50%.", "type": "CHEMICAL", "entities": [ "MCI-826" ], "offsets": [ [ 27, 34 ] ] }, { "pmid": "11972613", "text": "Sera obtained from sensitized, challenged animals 3 h and 4 h after challenge induced an obvious prolongation of eosinophil survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "The activity of the sera was completely neutralized by prior exposure to TRFK-5, suggesting that it reflected IL-5 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11972613", "text": "Increased IL-5 activity in the serum was inhibited by both pranlukast and MCI-826 by over 90%.", "type": "CHEMICAL", "entities": [ "pranlukast", "MCI-826" ], "offsets": [ [ 59, 69 ], [ 74, 81 ] ] }, { "pmid": "11972613", "text": "CONCLUSIONS: CysLTs produced after antigen provocation sequentially induced IL-5 production from some immune component cells via CysLT1 receptor activation.", "type": "CHEMICAL", "entities": [ "CysLTs" ], "offsets": [ [ 13, 19 ] ] }, { "pmid": "11972613", "text": "Thus, it is likely that CysLTs indirectly cause antigen-induced eosinophilia through IL-5 production.", "type": "CHEMICAL", "entities": [ "CysLTs" ], "offsets": [ [ 24, 30 ] ] }, { "pmid": "22890749", "text": "Theoretical study of the decomposition of ethyl and ethyl 3-phenyl glycidate.\n", "type": "CHEMICAL", "entities": [ "ethyl and ethyl 3-phenyl glycidate" ], "offsets": [ [ 42, 76 ] ] }, { "pmid": "22890749", "text": "The mechanism of the decomposition of ethyl and ethyl 3-phenyl glycidate in gas phase was studied by density functional theory (DFT) and MP2 methods.", "type": "CHEMICAL", "entities": [ "ethyl and ethyl 3-phenyl glycidate" ], "offsets": [ [ 38, 72 ] ] }, { "pmid": "22890749", "text": "A proposed mechanism for the reaction indicates that the ethyl side of the ester is eliminated as ethylene through a concerted six-membered cyclic transition state, and the unstable intermediate glycidic acid decarboxylates rapidly to give the corresponding aldehyde.", "type": "CHEMICAL", "entities": [ "ethyl", "ethylene", "glycidic acid", "aldehyde" ], "offsets": [ [ 57, 62 ], [ 98, 106 ], [ 195, 208 ], [ 258, 266 ] ] }, { "pmid": "22890749", "text": "Two possible pathways for glycidic acid decarboxylation were studied: one via a five-membered cyclic transition state, and the other via a four-membered cyclic transition state.", "type": "CHEMICAL", "entities": [ "glycidic acid" ], "offsets": [ [ 26, 39 ] ] }, { "pmid": "22890749", "text": "The results of the calculations indicate that the decarboxylation reaction occurs via a mechanism with five-membered cyclic transition state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties.\n", "type": "CHEMICAL", "entities": [ "Meclofenamic acid", "diclofenac", "potassium" ], "offsets": [ [ 0, 17 ], [ 22, 32 ], [ 62, 71 ] ] }, { "pmid": "15598972", "text": "The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing.", "type": "CHEMICAL", "entities": [ "potassium" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "15598972", "text": "The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "Furthermore, the KCNQ2 and KCNQ3 channel alpha subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development.", "type": "CHEMICAL", "entities": [ "potassium" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "15598972", "text": "Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers.", "type": "CHEMICAL", "entities": [ "meclofenamic acid", "meclofenamate", "diclofenac" ], "offsets": [ [ 19, 36 ], [ 38, 51 ], [ 57, 67 ] ] }, { "pmid": "15598972", "text": "Extracellular application of meclofenamate (EC(50) = 25 microM) and diclofenac (EC(50) = 2.6 microM) resulted in the activation of KCNQ2/Q3 K(+) currents, heterologously expressed in Chinese hamster ovary cells.", "type": "CHEMICAL", "entities": [ "meclofenamate", "diclofenac" ], "offsets": [ [ 29, 42 ], [ 68, 78 ] ] }, { "pmid": "15598972", "text": "Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 and -15 mV, respectively) and by markedly slowing the deactivation kinetics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel alpha subunits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "In contrast, they did not enhance KCNQ1 K(+) currents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15598972", "text": "In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED(50) = 43 mg/kg).", "type": "CHEMICAL", "entities": [ "meclofenamate", "diclofenac", "diclofenac" ], "offsets": [ [ 30, 43 ], [ 48, 58 ], [ 152, 162 ] ] }, { "pmid": "15598972", "text": "These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12431845", "text": "Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.\n", "type": "CHEMICAL", "entities": [ "Atomoxetine", "norepinephrine", "dopamine" ], "offsets": [ [ 0, 11 ], [ 46, 60 ], [ 65, 73 ] ] }, { "pmid": "12431845", "text": "The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD).", "type": "CHEMICAL", "entities": [ "norepinephrine", "NE", "atomoxetine", "tomoxetine", "LY139603" ], "offsets": [ [ 14, 28 ], [ 30, 32 ], [ 56, 67 ], [ 85, 95 ], [ 99, 107 ] ] }, { "pmid": "12431845", "text": "We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions.", "type": "CHEMICAL", "entities": [ "atomoxetine", "atomoxetine", "monoamine", "monoamines" ], "offsets": [ [ 43, 54 ], [ 96, 107 ], [ 113, 122 ], [ 176, 186 ] ] }, { "pmid": "12431845", "text": "Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters.", "type": "CHEMICAL", "entities": [ "Atomoxetine", "NE", "serotonin", "5-HT", "dopamine", "DA", "NE" ], "offsets": [ [ 0, 11 ], [ 90, 92 ], [ 94, 103 ], [ 105, 109 ], [ 115, 123 ], [ 125, 127 ], [ 250, 252 ] ] }, { "pmid": "12431845", "text": "In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels.", "type": "CHEMICAL", "entities": [ "atomoxetine", "NE" ], "offsets": [ [ 26, 37 ], [ 77, 79 ] ] }, { "pmid": "12431845", "text": "Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12431845", "text": "In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level.", "type": "CHEMICAL", "entities": [ "methylphenidate" ], "offsets": [ [ 33, 48 ] ] }, { "pmid": "12431845", "text": "The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX).", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 84, 95 ] ] }, { "pmid": "12431845", "text": "We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD.", "type": "CHEMICAL", "entities": [ "atomoxetine", "catecholamines", "atomoxetine" ], "offsets": [ [ 24, 35 ], [ 56, 70 ], [ 158, 169 ] ] }, { "pmid": "12431845", "text": "In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.", "type": "CHEMICAL", "entities": [ "methylphenidate", "atomoxetine", "DA" ], "offsets": [ [ 15, 30 ], [ 32, 43 ], [ 61, 63 ] ] }, { "pmid": "23298698", "text": "Locally administered prostaglandin E2 prevents aeroallergen-induced airway sensitization in mice through immunomodulatory mechanisms.\n", "type": "CHEMICAL", "entities": [ "prostaglandin E2" ], "offsets": [ [ 21, 37 ] ] }, { "pmid": "23298698", "text": "Prostaglandin E2 attenuates airway pathology in asthmatic patients and exerts a protective effect in antigen-sensitized mice when administered systemically.", "type": "CHEMICAL", "entities": [ "Prostaglandin E2" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23298698", "text": "We aimed to establish the consequences of intranasal PGE2 administration on airway reactivity to aeroallergens in mice and reveal the underlying immunoinflammatory mechanisms.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "23298698", "text": "PGE2 was administered either daily during a 10-day exposure to house dust mite (HDM) extracts or for limited intervals.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23298698", "text": "Airway hyperreactivity was measured by whole-body and invasive plethysmography.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298698", "text": "The phenotypes of lung immune cells and cytokine production were analysed by flow cytometry and ELISA, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298698", "text": "Airway hyperreactivity was sustainably reduced only when PGE2 administration was restricted to the initial 5 days of exposure to HDM.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 57, 61 ] ] }, { "pmid": "23298698", "text": "Lung inflammation, IL-4 production, and airway mast cell activity were also prevented under this early short-term treatment with PGE2.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 129, 133 ] ] }, { "pmid": "23298698", "text": "Interestingly, a Th2 response was already committed on day 5 of exposure to HDM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298698", "text": "This was paralleled by GM-CSF and osteopontin upregulation and a decreased number of plasmacytoid dendritic and T regulatory cells, as well as a trend towards reduced IL-10 expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298698", "text": "Local PGE2 administration prevented the increase of airway IL-13 and osteopontin and kept lung plasmacytoid dendritic cell counts close to baseline.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 6, 10 ] ] }, { "pmid": "23298698", "text": "GM-CSF and Tregs were unaffected by the treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23298698", "text": "These findings suggest that the protection provided by PGE2 is a result of the modulation of early lung immunomodulatory mechanisms, and possibly a shift in the balance of dendritic cells towards a tolerogenic profile.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 55, 59 ] ] }, { "pmid": "23220589", "text": "In vitro investigation of efficacy of new reactivators on OPC inhibited rat brain acetylcholinesterase.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "Organophosphorus compounds (OPC) were developed as warfare nerve agents.", "type": "CHEMICAL", "entities": [ "Organophosphorus" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23220589", "text": "They are also widely used as pesticides.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "The drug therapy of intoxication with OPC includes mainly combination of cholinesterase (ChE) reactivators and cholinolytics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "There is no single ChE reactivator having an ability to reactivate sufficiently the inhibited enzyme due to the high variability of chemical structure of the inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "The difficulties in reactivation of ChE activity and slight antidote effect regarding intoxication with some OPC are some of the reasons for continuous efforts to obtain new reactivators of ChE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "The aim of the present study was to evaluate the efficacy of some ChE reactivators against OPC intoxication (tabun, paraoxon and dichlorvos) in in vitro experiments and to compare their activity to that known for some currently used oximes (obidoxime, HI-6, 2-PAM).", "type": "CHEMICAL", "entities": [ "tabun", "paraoxon", "dichlorvos", "oximes", "obidoxime", "HI-6", "2-PAM" ], "offsets": [ [ 109, 114 ], [ 116, 124 ], [ 129, 139 ], [ 233, 239 ], [ 241, 250 ], [ 252, 256 ], [ 258, 263 ] ] }, { "pmid": "23220589", "text": "Experiments were carried out using rat brain acetylcholinesterase (AChE).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23220589", "text": "Reactivators showed different activity in the reactivation of rat brain AChE after dichlorvos, paraoxon and tabun inhibition.", "type": "CHEMICAL", "entities": [ "dichlorvos", "paraoxon", "tabun" ], "offsets": [ [ 83, 93 ], [ 95, 103 ], [ 108, 113 ] ] }, { "pmid": "23220589", "text": "AChE was easier reactivated after paraoxon treatment.", "type": "CHEMICAL", "entities": [ "paraoxon" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "23220589", "text": "The best effect showed BT-07-4M, obidoxime, TMB-4 and BT-08 from the group of symmetric oximes, and Toxidin, BT-05 and BT-03 from asymmetric compounds.", "type": "CHEMICAL", "entities": [ "BT-07-4M", "obidoxime", "TMB-4", "BT-08", "oximes", "Toxidin", "BT-05", "BT-03" ], "offsets": [ [ 23, 31 ], [ 33, 42 ], [ 44, 49 ], [ 54, 59 ], [ 88, 94 ], [ 100, 107 ], [ 109, 114 ], [ 119, 124 ] ] }, { "pmid": "23220589", "text": "The reactivation of brain AChE inhibited with tabun demonstrated better activity of new compound BT-07-4M, TMB-4 and obidoxime from symmetric oximes, and BT-05 and BT-03 possessing asymmetric structure.", "type": "CHEMICAL", "entities": [ "BT-07-4M", "TMB-4", "obidoxime", "oximes", "BT-05", "BT-03" ], "offsets": [ [ 97, 105 ], [ 107, 112 ], [ 117, 126 ], [ 142, 148 ], [ 154, 159 ], [ 164, 169 ] ] }, { "pmid": "23220589", "text": "All compounds showed low activity toward inhibition of AChE caused by dichlorvos.", "type": "CHEMICAL", "entities": [ "dichlorvos" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "23220589", "text": "Comparison of two main structure types (symmetric/asymmetric) showed that the symmetric compounds reactivated better AChE, inhibited with this OPC, than asymmetric ones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15562257", "text": "State-dependent mibefradil block of Na+ channels.\n", "type": "CHEMICAL", "entities": [ "mibefradil", "Na+" ], "offsets": [ [ 16, 26 ], [ 36, 39 ] ] }, { "pmid": "15562257", "text": "Mibefradil is a T-type Ca2+ channel antagonist with reported cross-reactivity with other classes of ion channels, including K+, Cl-, and Na+ channels.", "type": "CHEMICAL", "entities": [ "Mibefradil", "K+", "Cl-", "Na+", "Ca2+" ], "offsets": [ [ 0, 10 ], [ 124, 126 ], [ 128, 131 ], [ 137, 140 ], [ 23, 27 ] ] }, { "pmid": "15562257", "text": "Using whole-cell voltage clamp, we examined mibefradil block of four Na+ channel isoforms expressed in human embryonic kidney cells: Nav1.5 (cardiac), Nav1.4 (skeletal muscle), Nav1.2 (brain), and Nav1.7 (peripheral nerve).", "type": "CHEMICAL", "entities": [ "mibefradil", "Na+" ], "offsets": [ [ 44, 54 ], [ 69, 72 ] ] }, { "pmid": "15562257", "text": "Mibefradil blocked Nav1.5 in a use/frequency-dependent manner, indicating preferential binding to states visited during depolarization.", "type": "CHEMICAL", "entities": [ "Mibefradil" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15562257", "text": "Mibefradil blocked currents of all Na+ channel isoforms with similar affinity and a dependence on holding potential, and drug off-rate was slowed at depolarized potentials (k(off) was 0.024/s at -130 mV and 0.007/s at -100 mV for Nav1.5).", "type": "CHEMICAL", "entities": [ "Mibefradil", "Na+" ], "offsets": [ [ 0, 10 ], [ 35, 38 ] ] }, { "pmid": "15562257", "text": "We further probed the interaction of mibefradil with inactivated Nav1.5 channels.", "type": "CHEMICAL", "entities": [ "mibefradil" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "15562257", "text": "Neither the degree nor the time course of block was dependent on the stimulus duration, which dramatically changed the residency time of channels in the fast-inactivated state.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15562257", "text": "In addition, inhibiting the binding of the fast inactivation lid (Nav1.5 ICM + MTSET) did not alter mibefradil block, confirming that the drug does not preferentially interact with the fast-inactivated state.", "type": "CHEMICAL", "entities": [ "mibefradil" ], "offsets": [ [ 100, 110 ] ] }, { "pmid": "15562257", "text": "We also tested whether mibefradil interacted with slow-inactivated state(s).", "type": "CHEMICAL", "entities": [ "mibefradil" ], "offsets": [ [ 23, 33 ] ] }, { "pmid": "15562257", "text": "When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely.", "type": "CHEMICAL", "entities": [ "mibefradil" ], "offsets": [ [ 99, 109 ] ] }, { "pmid": "15562257", "text": "Our results suggest that mibefradil blocks Na+ channels in a state-dependent manner that does not depend on fast inactivation but probably involves interaction with one or more slow-inactivated state(s).", "type": "CHEMICAL", "entities": [ "mibefradil", "Na+" ], "offsets": [ [ 25, 35 ], [ 43, 46 ] ] }, { "pmid": "23154865", "text": "Enhanced heterodimerization of Bax by Bcl-2 mutants improves irradiated cell survival.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "B Cell Lymphoma-2 (Bcl-2) protein suppresses ionizing radiation-induced apoptosis in hemato-lymphoid system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "To enhance the survival of irradiated cells, we have compared the effects and mechanism of Bcl-2 and its functional variants, D34A (caspase-3 resistant) and S70E (mimics phosphorylation on S70).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "Bcl-2 and its mutants were transfected into hematopoietic cell line and assessed for cell survival, clonogenicity and cell cycle perturbations upon exposure to ionizing radiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "The electrostatic potential of BH3 cleft of Bcl-2/mutants and their heterodimerization with Bcl-2 associated X protein (Bax) were computationally evaluated.", "type": "CHEMICAL", "entities": [ "BH3" ], "offsets": [ [ 31, 34 ] ] }, { "pmid": "23154865", "text": "Correspondingly, these results were verified by co-immunoprecipitation and western blotting.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "The mutants afford higher radioprotective effect than Bcl-2 in apoptotic and clonogenic assays at D(0) (radiation dose at which 37 % cell survival was observed).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "The computational and functional analysis indicates that mutants have higher propensity to neutralize Bax protein by heterodimerization and have increased caspase-9 suppression capability, which is responsible for enhanced survival.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23154865", "text": "This study implies potential of Bcl-2 mutants or their chemical/peptide mimics to elicit radioprotective effect in cells exposed to radiation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15714982", "text": "[Treatment of androgen-independent hormone refractory prostate cancer using docetaxel].\n", "type": "CHEMICAL", "entities": [ "androgen", "docetaxel" ], "offsets": [ [ 14, 22 ], [ 76, 85 ] ] }, { "pmid": "15714982", "text": "Although prostate cancer patients with metastatic lesion initially respond to androgen ablation therapy, almost patients develop to hormone-refractory states.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "15714982", "text": "The optimal treatment for men with hormone refractory prostate cancer (HRPC) has not been established.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15714982", "text": "Docetaxel is a semisynthetic taxane that inhibit tumor growth by induction of microtubule stabilization and promotion of bcl-2 inactivation, which induce apoptosis.", "type": "CHEMICAL", "entities": [ "Docetaxel", "taxane" ], "offsets": [ [ 0, 9 ], [ 29, 35 ] ] }, { "pmid": "15714982", "text": "Docetaxel as single agent has significant anti-tumor effect in HRPC patients.", "type": "CHEMICAL", "entities": [ "Docetaxel" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15714982", "text": "Docetaxel combined with estramustine or other antimicrotubular agents have shown further significant cytotoxicity in HRPC patients.", "type": "CHEMICAL", "entities": [ "Docetaxel", "estramustine" ], "offsets": [ [ 0, 9 ], [ 24, 36 ] ] }, { "pmid": "15714982", "text": "In the United States, Food and Drug Administration (FDA) approved docetaxel, injection in combination with prednisone for the treatment of patients with advanced metastatic prostate cancer in 2004.", "type": "CHEMICAL", "entities": [ "docetaxel", "prednisone" ], "offsets": [ [ 66, 75 ], [ 107, 117 ] ] }, { "pmid": "18708991", "text": "ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety.\n", "type": "CHEMICAL", "entities": [ "9-hydroxyrisperidone", "risperidone" ], "offsets": [ [ 60, 80 ], [ 85, 96 ] ] }, { "pmid": "18708991", "text": "Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4.", "type": "CHEMICAL", "entities": [ "Risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 0, 11 ], [ 53, 73 ] ] }, { "pmid": "18708991", "text": "Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 92, 103 ], [ 108, 128 ] ] }, { "pmid": "18708991", "text": "Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 5, 16 ], [ 21, 41 ] ] }, { "pmid": "18708991", "text": "The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 155, 166 ], [ 168, 188 ] ] }, { "pmid": "18708991", "text": "Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured.", "type": "CHEMICAL", "entities": [ "risperidone", "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 57, 68 ], [ 161, 172 ], [ 177, 197 ] ] }, { "pmid": "18708991", "text": "Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 46, 57 ], [ 59, 79 ] ] }, { "pmid": "18708991", "text": "Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18708991", "text": "The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 38, 49 ], [ 51, 71 ] ] }, { "pmid": "18708991", "text": "The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 67, 78 ], [ 108, 128 ] ] }, { "pmid": "18708991", "text": "Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes.", "type": "CHEMICAL", "entities": [ "9-hydroxyrisperidone" ], "offsets": [ [ 94, 114 ] ] }, { "pmid": "18708991", "text": "In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 116, 127 ], [ 199, 219 ] ] }, { "pmid": "15133083", "text": "Polyamine metabolism in a member of the phylum Microspora (Encephalitozoon cuniculi): effects of polyamine analogues.\n", "type": "CHEMICAL", "entities": [ "Polyamine", "polyamine" ], "offsets": [ [ 0, 9 ], [ 97, 106 ] ] }, { "pmid": "15133083", "text": "The uptake, biosynthesis and catabolism of polyamines in the microsporidian parasite Encephalitozoon cuniculi are detailed with reference to the effects of oligoamine and arylamine analogues of polyamines.", "type": "CHEMICAL", "entities": [ "oligoamine", "arylamine", "polyamines", "polyamines" ], "offsets": [ [ 156, 166 ], [ 171, 180 ], [ 194, 204 ], [ 43, 53 ] ] }, { "pmid": "15133083", "text": "Enc. cuniculi, an intracellular parasite of mammalian cells, has both biosynthetic and catabolic enzymes of polyamine metabolism, as demonstrated in cell-free extracts of mature spores.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 108, 117 ] ] }, { "pmid": "15133083", "text": "The uptake of polyamines was measured in immature, pre-emergent spores isolated from host cells by Percoll gradient.", "type": "CHEMICAL", "entities": [ "polyamines" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "15133083", "text": "Spermine was rapidly taken up and metabolized to spermidine and an unknown, possibly acetamidopropanal, by spermidine/spermine N(1)-acetyltransferase (SSAT) and polyamine oxidase (PAO).", "type": "CHEMICAL", "entities": [ "N(1)", "polyamine" ], "offsets": [ [ 127, 131 ], [ 161, 170 ] ] }, { "pmid": "15133083", "text": "Most of the spermidine and the unknown product were found in the cell incubation medium, indicating they were released from the cell.", "type": "CHEMICAL", "entities": [ "spermidine" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "15133083", "text": "bis(Ethyl) oligoamine analogues of polyamines, such as SL-11144 and SL-11158, as well as arylamine analogues", "type": "CHEMICAL", "entities": [ "bis(Ethyl) oligoamine", "polyamines", "SL-11144", "SL-11158", "arylamine" ], "offsets": [ [ 0, 21 ], [ 35, 45 ], [ 55, 63 ], [ 68, 76 ], [ 89, 98 ] ] }, { "pmid": "15133083", "text": "[BW-1, a bis(phenylbenzyl) 3-7-3 analogue] blocked uptake and interconversion of spermine at micromolar levels and, in the case of BW-1, acted as substrate for PAO.", "type": "CHEMICAL", "entities": [ "spermine", "BW-1", "BW-1", "bis(phenylbenzyl)" ], "offsets": [ [ 81, 89 ], [ 131, 135 ], [ 1, 5 ], [ 9, 26 ] ] }, { "pmid": "15133083", "text": "The Enc. cuniculi PAO activity differed from that found in mammalian cells with respect to pH optimum, substrate specificity and sensitivity to known PAO inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15133083", "text": "SL-11158 inhibited SSAT activity with a mixed type of inhibition in which the analogue had a 70-fold higher affinity for the enzyme than the natural substrate, spermine.", "type": "CHEMICAL", "entities": [ "SL-11158", "spermine" ], "offsets": [ [ 0, 8 ], [ 160, 168 ] ] }, { "pmid": "15133083", "text": "The interest in Enc. cuniculi polyamine metabolism and the biochemical effects of these polyamine analogues is warranted since they cure model infections of Enc. cuniculi in mice and are potential candidates for human clinical trials.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 88, 97 ] ] }, { "pmid": "23497227", "text": "Synthesis and in vitro evaluation of N-Aryl pyrido-quinazolines derivatives as potent EGFR inhibitors.\n", "type": "CHEMICAL", "entities": [ "N-Aryl pyrido-quinazolines" ], "offsets": [ [ 37, 63 ] ] }, { "pmid": "23497227", "text": "A series of pyrido-quinazolines have been synthesised, characterised and tested for their in vitro EGFR tyrosine kinase inhibitory activity.", "type": "CHEMICAL", "entities": [ "tyrosine", "pyrido-quinazolines" ], "offsets": [ [ 104, 112 ], [ 12, 31 ] ] }, { "pmid": "23497227", "text": "The compounds were prepared from Alkylideno/arylideno-bis-ureas.", "type": "CHEMICAL", "entities": [ "Alkylideno/arylideno-bis-ureas" ], "offsets": [ [ 33, 63 ] ] }, { "pmid": "23497227", "text": "Their final structure of the compounds were elucidated on the basis of spectral studies (IR., 1H NMR, FT-IR and EI-MS).", "type": "CHEMICAL", "entities": [ "1H" ], "offsets": [ [ 94, 96 ] ] }, { "pmid": "23497227", "text": "The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23497227", "text": "Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity and structurally halogenated derivatives had a pronounced effect in inhibiting EGFR internalization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23497227", "text": "", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23497227", "text": " 2013 John Wiley & Sons A/S.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17600786", "text": "A fluorescent polymeric heparin sensor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17600786", "text": "Linear copolymers have been developed which carry binding sites tailored for sulfated sugars.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17600786", "text": "All binding monomers are based on the methacrylamide skeleton and ensure statistical radical copolymerization.", "type": "CHEMICAL", "entities": [ "methacrylamide" ], "offsets": [ [ 38, 52 ] ] }, { "pmid": "17600786", "text": "They are decorated with o-aminomethylphenylboronates for covalent ester formation and/or alkylammonium ions for noncovalent Coulomb attraction.", "type": "CHEMICAL", "entities": [ "o-aminomethylphenylboronates", "alkylammonium" ], "offsets": [ [ 24, 52 ], [ 89, 102 ] ] }, { "pmid": "17600786", "text": "Alcohol sidechains maintain a high water solubility; a dansyl monomer was constructed as a fluorescence label.", "type": "CHEMICAL", "entities": [ "Alcohol", "dansyl" ], "offsets": [ [ 0, 7 ], [ 55, 61 ] ] }, { "pmid": "17600786", "text": "Statistical copolymerization of comonomer mixtures with optimized ratios was started by AIBN (AIBN=2,2'-azoisobutyronitrile) and furnished water-soluble comonomers with an exceptionally high affinity for glucosaminoglucans.", "type": "CHEMICAL", "entities": [ "AIBN", "AIBN", "2,2'-azoisobutyronitrile" ], "offsets": [ [ 88, 92 ], [ 94, 98 ], [ 99, 123 ] ] }, { "pmid": "17600786", "text": "Heparin can be quantitatively detected with an unprecedented 30 nM sensitivity, and a neutral polymer without any ammonium cation is still able to bind the target with almost micromolar affinity.", "type": "CHEMICAL", "entities": [ "ammonium cation" ], "offsets": [ [ 114, 129 ] ] }, { "pmid": "17600786", "text": "From this unexpected result, we propose a new binding scheme between the boronate and a sulfated ethylene glycol or aminoethanol unit.", "type": "CHEMICAL", "entities": [ "boronate", "ethylene glycol", "aminoethanol" ], "offsets": [ [ 73, 81 ], [ 97, 112 ], [ 116, 128 ] ] }, { "pmid": "17600786", "text": "Although the mechanism of heparin binding involves covalent boronate ester formation, it can be completely reversed by protamine addition, similar to heparin's complex formation with antithrombin III.", "type": "CHEMICAL", "entities": [ "boronate ester" ], "offsets": [ [ 60, 74 ] ] }, { "pmid": "23397052", "text": "Impaired cliff avoidance reaction in dopamine transporter knockout mice.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "23397052", "text": "RATIONALE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.", "type": "CHEMICAL", "entities": [ "Dopamine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23397052", "text": "OBJECTIVES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Impulsivity of DAT-KO mice was assessed in the CAR paradigm.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "As expected, DAT-KO mice showed PPI deficits compared to WT mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice.", "type": "CHEMICAL", "entities": [ "methylphenidate", "nisoxetine" ], "offsets": [ [ 15, 30 ], [ 34, 44 ] ] }, { "pmid": "23397052", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397052", "text": "Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.", "type": "CHEMICAL", "entities": [ "monoamine", "norepinephrine" ], "offsets": [ [ 12, 21 ], [ 51, 65 ] ] }, { "pmid": "10702256", "text": "SPACRCAN, a novel human interphotoreceptor matrix hyaluronan-binding proteoglycan synthesized by photoreceptors and pinealocytes.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "The interphotoreceptor matrix is a unique extracellular complex occupying the interface between photoreceptors and the retinal pigment epithelium in the fundus of the eye.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "Because of the putative supportive role in photoreceptor maintenance, it is likely that constituent molecules play key roles in photoreceptor function and may be targets for inherited retinal disease.", "type": "CHEMICAL", "entities": [ "retinal" ], "offsets": [ [ 184, 191 ] ] }, { "pmid": "10702256", "text": "In this study we identify and characterize SPACRCAN, a novel chondroitin proteoglycan in this matrix.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "SPACRCAN was cloned from a human retinal cDNA library and the gene localized to chromosome 3q11.2.", "type": "CHEMICAL", "entities": [ "retinal" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "10702256", "text": "Analysis of SPACRCAN mRNA and protein revealed that SPACRCAN is expressed exclusively by photoreceptors and pinealocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "SPACRCAN synthesized by photoreceptors is localized to the interphotoreceptor matrix where it surrounds both rods and cones.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "The functional protein contains 1160 amino acids with a large central mucin domain, three consensus sites for glycosaminoglycan attachment, two epidermal growth factor-like repeats, a putative hyaluronan-binding motif, and a potential transmembrane domain near the C-terminal.", "type": "CHEMICAL", "entities": [ "C", "amino acids" ], "offsets": [ [ 265, 266 ], [ 37, 48 ] ] }, { "pmid": "10702256", "text": "Lectin and Western blotting indicate an M(r) around 400,000 before and 230,000 after chondroitinase ABC digestion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10702256", "text": "Removal of N- and O-linked oligosaccharides reduces the M(r) to approximately 160,000, suggesting that approximately 60% of the mass of SPACRCAN is carbohydrate.", "type": "CHEMICAL", "entities": [ "N", "O", "carbohydrate" ], "offsets": [ [ 11, 12 ], [ 18, 19 ], [ 148, 160 ] ] }, { "pmid": "10702256", "text": "Finally, we demonstrate that SPACRCAN binds hyaluronan and propose that associations between SPACRCAN and hyaluronan may be involved in organization of the insoluble interphotoreceptor matrix, particularly as SPACRCAN is the major proteoglycan present in this matrix.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22981796", "text": "Validation of an in vitro exposure system for toxicity assessment of air-delivered nanomaterials.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22981796", "text": "To overcome the limitations of in vitro exposure of submerged lung cells to nanoparticles (NPs), we validated an integrated low flow system capable of generating and depositing airborne NPs directly onto cells at an air-liquid interface (ALI).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22981796", "text": "The in vitro exposure system was shown to provide uniform and controlled dosing of particles with 70.3% efficiency to epithelial cells grown on transwells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22981796", "text": "This system delivered a continuous airborne exposure of NPs to lung cells without loss of cell viability in repeated 4h exposure periods.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22981796", "text": "We sequentially exposed cells to air-delivered copper (Cu) NPs in vitro to compare toxicity results to our prior in vivo inhalation studies.", "type": "CHEMICAL", "entities": [ "copper", "Cu" ], "offsets": [ [ 47, 53 ], [ 55, 57 ] ] }, { "pmid": "22981796", "text": "The evaluation of cellular dosimetry indicated that a large amount of Cu was taken up, dissolved and released into the basolateral medium (62% of total mass).", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 70, 72 ] ] }, { "pmid": "22981796", "text": "Exposure to Cu NPs decreased cell viability to 73% (p<0.01) and significantly (p<0.05) elevated levels of lactate dehydrogenase, intracellular reactive oxygen species and interleukin-8 that mirrored our findings from subacute in vivo inhalation studies in mice.", "type": "CHEMICAL", "entities": [ "Cu", "lactate", "oxygen" ], "offsets": [ [ 12, 14 ], [ 106, 113 ], [ 152, 158 ] ] }, { "pmid": "22981796", "text": "Our results show that this exposure system is useful for screening of NP toxicity in a manner that represents cellular responses of the pulmonary epithelium in vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327993", "text": "Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells.\n", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "23327993", "text": "The thioredoxin reductase/thioredoxin system (TrxR/Trx1) plays a major role in protecting cells from oxidative stress.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327993", "text": "Disruption of the TrxR-Trx1 system keeps Trx1 in the oxidized state leading to cell death through activation of the ASK1-Trx1 apoptotic pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327993", "text": "The potential mechanism and ability of tri- and tetra-oligopeptides derived from the canonical -CxxC- motif of the Trx1-active site to mimic and enhance Trx1 cellular activity was examined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327993", "text": "The Trx mimetics peptides (TXM) protected insulinoma INS 832/13 cells from oxidative stress induced by selectively inhibiting TrxR with auranofin (AuF).", "type": "CHEMICAL", "entities": [ "auranofin", "AuF" ], "offsets": [ [ 136, 145 ], [ 147, 150 ] ] }, { "pmid": "23327993", "text": "TXM reversed the AuF-effects preventing apoptosis, and increasing cell-viability.", "type": "CHEMICAL", "entities": [ "AuF" ], "offsets": [ [ 17, 20 ] ] }, { "pmid": "23327993", "text": "The TXM peptides were effective in inhibiting AuF-induced MAPK, JNK and p38(MAPK) phosphorylation, in correlation with preventing caspase-3 cleavage and thereby PARP-1 dissociation.", "type": "CHEMICAL", "entities": [ "AuF" ], "offsets": [ [ 46, 49 ] ] }, { "pmid": "23327993", "text": "The ability to form a disulfide-bridge-like conformation was estimated from molecular dynamics simulations.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "23327993", "text": "The TXM peptides restored insulin secretion and displayed Trx1 denitrosylase activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23327993", "text": "Their potency was 10-100-fold higher than redox reagents like NAC, AD4, or ascorbic acid.", "type": "CHEMICAL", "entities": [ "NAC", "AD4", "ascorbic acid" ], "offsets": [ [ 62, 65 ], [ 67, 70 ], [ 75, 88 ] ] }, { "pmid": "23327993", "text": "Unable to reverse ERK1/2 phosphorylation, TXM-CB3 (NAc-Cys-Pro-Cys amide) appeared to function in part, through inhibiting ASK1-Trx dissociation.", "type": "CHEMICAL", "entities": [ "NAc-Cys-Pro-Cys amide" ], "offsets": [ [ 51, 72 ] ] }, { "pmid": "23327993", "text": "These highly effective anti-apoptotic effects of Trx1 mimetic peptides exhibited in INS 832/13 cells could become valuable in treating adverse oxidative-stress related disorders such as diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10617684", "text": "Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide.\n", "type": "CHEMICAL", "entities": [ "flecainide", "sodium" ], "offsets": [ [ 103, 113 ], [ 27, 33 ] ] }, { "pmid": "10617684", "text": "Flecainide block of Na(+) current (I(Na)) was investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium channel alpha subunit mutation with three amino acids deleted (DeltaKPQ) stably transfected into human embryonic kidney 293 cells using whole-cell, patch-clamp recordings.", "type": "CHEMICAL", "entities": [ "Flecainide", "sodium", "amino acids", "Na(+)", "Na" ], "offsets": [ [ 0, 10 ], [ 110, 116 ], [ 159, 170 ], [ 20, 25 ], [ 37, 39 ] ] }, { "pmid": "10617684", "text": "Flecainide (1-300 mM) caused tonic and use-dependent block (UDB) of I(Na) in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "Flecainide", "Na" ], "offsets": [ [ 0, 10 ], [ 70, 72 ] ] }, { "pmid": "10617684", "text": "Compared with WT, DeltaKPQ I(Na) was more sensitive to flecainide, and flecainide preferentially inhibited late I(Na) (mean current between 20 and 23.5 ms after depolarization) compared with peak I(Na).", "type": "CHEMICAL", "entities": [ "Na", "flecainide", "flecainide", "Na", "Na" ], "offsets": [ [ 29, 31 ], [ 55, 65 ], [ 71, 81 ], [ 114, 116 ], [ 198, 200 ] ] }, { "pmid": "10617684", "text": "The IC(50) value of peak and late I(Na) for WT was 127 +/- 6 and 44 +/- 2 microM (n = 20) and for DeltaKPQ was 80 +/- 9 and 19 +/- 2 microM (n = 31) respectively.", "type": "CHEMICAL", "entities": [ "Na" ], "offsets": [ [ 36, 38 ] ] }, { "pmid": "10617684", "text": "UDB of peak I(Na) was greater and developed more slowly during pulse trains for DeltaKPQ than for WT.", "type": "CHEMICAL", "entities": [ "Na" ], "offsets": [ [ 14, 16 ] ] }, { "pmid": "10617684", "text": "The IC(50) value for UDB of peak I(Na) for WT was 29 +/- 4 microM (n = 20) and for DeltaKPQ was 11", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10617684", "text": "+/- 1 microM (n = 26).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10617684", "text": "For DeltaKPQ, UDB of late I(Na) was greater than for peak I(Na).", "type": "CHEMICAL", "entities": [ "Na", "Na" ], "offsets": [ [ 28, 30 ], [ 60, 62 ] ] }, { "pmid": "10617684", "text": "Recovery from block was slower for DeltaKPQ than for WT.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10617684", "text": "We conclude that DeltaKPQ interacts differently with flecainide than with WT, leading to increased block and slowed recovery, especially for late I(Na).", "type": "CHEMICAL", "entities": [ "flecainide", "Na" ], "offsets": [ [ 53, 63 ], [ 148, 150 ] ] }, { "pmid": "10617684", "text": "These data provide insights into mechanisms for flecainide block and provide a rationale at the cellular and molecular level that open channel block may be a useful pharmacological property for treatment of LQT3.", "type": "CHEMICAL", "entities": [ "flecainide" ], "offsets": [ [ 48, 58 ] ] }, { "pmid": "23118019", "text": "In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor.\n", "type": "CHEMICAL", "entities": [ "naltrindole" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "23118019", "text": "Accumulating evidence supports a role for κ-opioid receptor antagonists in the treatment of mood disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23118019", "text": "Standard κ-antagonists have an unusual pharmacodynamic action, with a single injection blocking receptor signaling for several weeks.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23118019", "text": "Here, we have characterized the κ-selective properties of two ligands, 5'-(2-aminomethyl) naltrindole (5'-AMN) and N-((Naltrindol-5-yl) methyl) pentanimidamide (5'-MABN), to identify whether modifications of the naltrindole side chain produces short-acting κ-antagonists.", "type": "CHEMICAL", "entities": [ "5'-(2-aminomethyl) naltrindole", "5'-AMN", "N-((Naltrindol-5-yl) methyl) pentanimidamide", "5'-MABN", "naltrindole" ], "offsets": [ [ 68, 98 ], [ 100, 106 ], [ 112, 156 ], [ 158, 165 ], [ 209, 220 ] ] }, { "pmid": "23118019", "text": "Opioid receptor binding affinity and activity were assessed using [(3)H]-diprenorphine binding, guanosine-5'-O-(3-[35S]-thio) triphosphate ([(35)S]-GTPγS) binding and isolated guinea-pig ileum.", "type": "CHEMICAL", "entities": [ "[(3)H]-diprenorphine", "guanosine-5'-O-(3-[35S]-thio) triphosphate", "[(35)S]-GTPγS" ], "offsets": [ [ 61, 81 ], [ 91, 133 ], [ 135, 148 ] ] }, { "pmid": "23118019", "text": "Pharmacodynamic profiles of 5'-AMN and 5'-MABN (1-10 mg/kg) were investigated using the tail-withdrawal assay and diuresis.", "type": "CHEMICAL", "entities": [ "5'-AMN", "5'-MABN" ], "offsets": [ [ 22, 28 ], [ 33, 40 ] ] }, { "pmid": "23118019", "text": "Efficacy was also determined in depression- and anxiety-related behavioral paradigms in CD-1 mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23118019", "text": "Both 5'-AMN and 5'-MABN had high affinity for κ-receptors (K (i) 1.36 ± 0.98 and 0.27 ± 0.08, respectively) and were revealed as potent κ-antagonists (pA(2) 7.43 and 8.18, respectively) and μ-receptor antagonists (pA(2) 7.62 and 7.85, respectively) in the ileum.", "type": "CHEMICAL", "entities": [ "5'-MABN" ], "offsets": [ [ 10, 17 ] ] }, { "pmid": "23118019", "text": "Contrary to our hypothesis, in vivo, 5'-AMN and 5'-MABN displayed long-lasting antagonist effects in mice, reducing the antinociceptive actions of U50,488 (10 mg/kg) at 28 and 21 days post-injection, respectively.", "type": "CHEMICAL", "entities": [ "5'-AMN", "5'-MABN", "U50,488" ], "offsets": [ [ 26, 32 ], [ 37, 44 ], [ 136, 143 ] ] }, { "pmid": "23118019", "text": "Interestingly, while 5'-AMN and 5'-MABN were not κ-selective, both compounds did show significant antidepressant- and anxiolytic-like effects at 7-14 days post-injection in mice.", "type": "CHEMICAL", "entities": [ "5'-AMN", "5'-MABN" ], "offsets": [ [ 10, 16 ], [ 21, 28 ] ] }, { "pmid": "23522834", "text": "Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23522834", "text": "Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors.", "type": "CHEMICAL", "entities": [ "dihydropteridinone" ], "offsets": [ [ 134, 152 ] ] }, { "pmid": "23522834", "text": "By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23522834", "text": "When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "Effect of bioactive peptide of Carapax Trionycis on TGF-β1-induced intracellular events in hepatic stellate cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "ETHNOPHARMACOLOGICAL RELEVANCE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "In traditional Chinese medicines for hepatic fibrosis therapy, Carapax Trionycis is used usually as an indispensable component and has a long history of medical use in China.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "Previous studies have demonstrated that extracts of Carapax Trionycis were able to protect liver against fibrosis in CCl4 animal models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "AIM OF THE STUDY: The purpose of this study is to verify the inhibitory effect and the underlying mechanisms of Carapax Trionycis extract peptide (CTEP) on activated hepatic stellate cells which play a central role in liver fibrogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "MATERIALS AND METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "Hepatic stellate cells induced by TGF-β1 were applied to evaluate the anti-fibrotic effect of CTEP in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "MTS assay, enzyme-linked immunosorbent assay and western blotting were then used to further investigate the molecular mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "The results show that the contents of collagen I, collagen III and TIMP-1 were significantly inhibited and the level of collagen I, collagen III, p-Smad 3, TIMP-1 and α-SMA proteins decreased significantly in a concentration-dependence manner after treatment with CTEP.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "Interestingly, the level of Smad 3 protein was not different significantly.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23583903", "text": "Our data indicate that CTEP efficiently inhibits cultured HSC-T6 cell activation and proliferation via the TGF-β1/Smad pathway as well as by the elimination of the extracellular matrix.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612487", "text": "Sphingosine-1-phosphate promotes the nuclear translocation of β-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines.\n", "type": "CHEMICAL", "entities": [ "Sphingosine-1-phosphate" ], "offsets": [ [ 0, 23 ] ] }, { "pmid": "23612487", "text": "Sphingosine-1-phosphate (S1P) is a well-known signaling sphingolipid and bioactive lipid mediator.", "type": "CHEMICAL", "entities": [ "S1P", "sphingolipid" ], "offsets": [ [ 24, 27 ], [ 55, 67 ] ] }, { "pmid": "23612487", "text": "Recently, it was reported that S1P inhibits osteoclast differentiation and bone resorption.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 30, 33 ] ] }, { "pmid": "23612487", "text": "On the other hand, S1P effects on osteoblasts and bone formation are little known.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 18, 21 ] ] }, { "pmid": "23612487", "text": "In this study, we investigated the effects of S1P on osteoblasts, using two osteoblast-like cell lines, SaOS-2 and MC3T3-E1.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 45, 48 ] ] }, { "pmid": "23612487", "text": "S1P activated phosphatidylinositol 3-kinase (PI3K)/Akt signaling, leading to the inhibition of glycogen synthase kinase-3β and the nuclear translocation of β-catenin, followed by the increase of the transcriptional activity by β-catenin/T-cell factor complex formation in both SaOS-2 cells and MC3T3-E1 cells.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 13, 33 ] ] }, { "pmid": "23612487", "text": "The inhibitors of PI3K and Akt suppressed S1P-induced nuclear localization of β-catenin.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 38, 41 ] ] }, { "pmid": "23612487", "text": "We further investigated the effects of PI3K/Akt signaling on the Wnt/β-catenin signaling pathway, since β-catenin takes a central role in this signaling pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612487", "text": "Both inhibitors for PI3K and Akt suppressed the nuclear localization of β-catenin and T-cell factor transcriptional activity induced by Wnt-3a.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 137, 140 ] ] }, { "pmid": "23612487", "text": "S1P increased the amount of osteoprotegerin at both mRNA and protein levels, and increased the activity of alkaline phosphatase, leading to the mineralization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23612487", "text": "These findings suggest that S1P activates the PI3K/Akt signaling pathway leading to the promotion of nuclear translocation of β-catenin in osteoblast-like cells, resulting in the upregulation of osteoptotegerin and osteoblast differentiation markers including alkaline phosphatase, probably relating to the inhibition of osteoclast formation and the mineralization, respectively.", "type": "CHEMICAL", "entities": [ "S1P" ], "offsets": [ [ 20, 23 ] ] }, { "pmid": "18847313", "text": "Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells.\n", "type": "CHEMICAL", "entities": [ "Plerixafor" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18847313", "text": "Stem cells harvested from peripheral blood are the most commonly used graft source in hematopoietic stem cell transplantation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18847313", "text": "While G-CSF is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients undergoing autologous transplantation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18847313", "text": "Plerixafor (AMD3100, Genzyme Corporation) is a bicyclam molecule that antagonizes the binding of the chemokine stromal cell-derived factor-1 (SDF-1) to its cognate receptor CXCR4.", "type": "CHEMICAL", "entities": [ "Plerixafor", "AMD3100", "bicyclam" ], "offsets": [ [ 0, 10 ], [ 12, 19 ], [ 47, 55 ] ] }, { "pmid": "18847313", "text": "Plerixafor results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF.", "type": "CHEMICAL", "entities": [ "Plerixafor" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18847313", "text": "In clinical studies of autologous stem cell transplantation, the combination of plerixafor and G-CSF allows the collection of large numbers of stem cells in fewer apheresis sessions and can salvage those who fail G-CSF mobilization alone.", "type": "CHEMICAL", "entities": [ "plerixafor" ], "offsets": [ [ 80, 90 ] ] }, { "pmid": "23164618", "text": "Supra-normal stimulation of dopamine D1 receptors in the prelimbic cortex blocks behavioral expression of both aversive and rewarding associative memories through a cyclic-AMP-dependent signaling pathway.\n", "type": "CHEMICAL", "entities": [ "cyclic-AMP", "dopamine" ], "offsets": [ [ 165, 175 ], [ 28, 36 ] ] }, { "pmid": "23164618", "text": "Dopamine (DA) receptor transmission through either D(1) or D(2)-like subtypes is involved critically in the processing of emotional information within the medial prefrontal cortex (mPFC).", "type": "CHEMICAL", "entities": [ "Dopamine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23164618", "text": "However the functional role of specific DA D(1)-like receptor transmission in the expression of emotionally salient associative memories (either aversive or rewarding) is not currently understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164618", "text": "Here we demonstrate that specific activation of DA D(1) receptors in the prelimbic (PLC) division of the mPFC causes a transient block in the behavioral expression of both aversive and rewarding associative memories.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164618", "text": "We report that intra-PLC microinfusions of a selective D(1) receptor agonist block the spontaneous expression of an associative olfactory fear memory, without altering the stability of the original memory trace.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164618", "text": "Furthermore, using an unbiased place conditioning procedure (CPP), intra-PLC D(1) receptor activation blocks the spontaneous expression of an associative morphine (5 mg/kg; i.p.)", "type": "CHEMICAL", "entities": [ "morphine" ], "offsets": [ [ 154, 162 ] ] }, { "pmid": "23164618", "text": "reward memory, while leaving morphine-primed memory expression intact.", "type": "CHEMICAL", "entities": [ "morphine" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "23164618", "text": "Interestingly, both intra-PLC D(1)-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cyclic-AMP (cAMP) signaling as both effects were rescued by co-administration of a cAMP signaling inhibitor.", "type": "CHEMICAL", "entities": [ "cyclic-AMP", "cAMP", "cAMP" ], "offsets": [ [ 151, 161 ], [ 163, 167 ], [ 234, 238 ] ] }, { "pmid": "23164618", "text": "The blockade of both rewarding and aversive associative memories is mediated through a D(1)-specific signaling pathway, as neither forms of spontaneous memory expression were blocked by intra-PLC microinfusions of a D(2)-like receptor agonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164618", "text": "Our results demonstrate that the spontaneous expression of either rewarding or aversive emotionally salient memories shares a common, D(1)-receptor mediated substrate within the mPFC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23183186", "text": "P21-activated protein kinase 1 (Pak1) mediates the cross talk between insulin and β-catenin on proglucagon gene expression and its ablation affects glucose homeostasis in male C57BL/6 mice.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 148, 155 ] ] }, { "pmid": "23183186", "text": "In gut endocrine L cells, the Wnt signaling pathway effector β-catenin", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23183186", "text": "(β-cat)/transcription factor 7-like 2 mediates the stimulatory effect of insulin on proglucagon (gcg) expression and glucagon-like peptide-1 (GLP-1) production.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23183186", "text": "In several other cell lineages, insulin is able to stimulate p21-activated protein kinase 1 (Pak1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23183186", "text": "Here we determined the role of Pak1 in gcg expression and the effect of Pak1 deletion on glucose homeostasis.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 86, 93 ] ] }, { "pmid": "23183186", "text": "Insulin stimulated Pak1 activation through increasing its Thr423 phosphorylation in gut gcg-expressing cell lines, associated with increased gcg mRNA levels.", "type": "CHEMICAL", "entities": [ "Thr" ], "offsets": [ [ 55, 58 ] ] }, { "pmid": "23183186", "text": "This stimulation was attenuated by the Pak inhibitor 2,2'-dihydroxy-1,1'-dinaphthyldisulfide (IPA3) or dominant-negative Pak1.", "type": "CHEMICAL", "entities": [ "2,2'-dihydroxy-1,1'-dinaphthyldisulfide", "IPA3" ], "offsets": [ [ 50, 89 ], [ 91, 95 ] ] }, { "pmid": "23183186", "text": "Both insulin and cAMP-promoting agents activated β-cat Ser675 phosphorylation, which was attenuated by IPA3 or protein kinase A inhibition, respectively.", "type": "CHEMICAL", "entities": [ "cAMP", "Ser" ], "offsets": [ [ 14, 18 ], [ 52, 55 ] ] }, { "pmid": "23183186", "text": "Gut gcg levels were reduced in male Pak1(-/-)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23183186", "text": "mice, associated with impaired glucose tolerance after an ip or oral glucose challenge.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 27, 34 ], [ 65, 72 ] ] }, { "pmid": "23183186", "text": "These mice had lower circulating active GLP-1 levels after a glucose challenge as well as reduced distal ileum GLP-1 content after insulin treatment.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "23183186", "text": "Finally, the Pak1(-/-) mice exhibited reduced brainstem gcg level and abolished β-cat Ser675 phosphorylation in brain neurons after insulin treatment.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 82, 85 ] ] }, { "pmid": "23183186", "text": "We suggest that Pak1 mediates the cross talk between insulin and Wnt signaling pathways on gut and brain gcg expression, and its ablation impairs glucose homeostasis.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 141, 148 ] ] }, { "pmid": "17018843", "text": "Characterization of the regulation of renal Na+/H+ exchanger NHE3 by insulin.\n", "type": "CHEMICAL", "entities": [ "Na+", "H+" ], "offsets": [ [ 44, 47 ], [ 48, 50 ] ] }, { "pmid": "17018843", "text": "Insulin receptors are widely distributed in the kidney and affect multiple aspects of renal function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "In the proximal tubule, insulin regulates volume and acid-base regulation through stimulation of the Na(+)/H(+) exchanger NHE3.", "type": "CHEMICAL", "entities": [ "Na(+)", "H(+)" ], "offsets": [ [ 101, 106 ], [ 107, 111 ] ] }, { "pmid": "17018843", "text": "This paper characterizes the signaling pathway by which insulin stimulates NHE3 in a cell culture model [opossum kidney (OK) cell].", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "Insulin has two distinct phases of action on NHE3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "Chronic insulin (24 h) activates NHE3 through the classic phosphatidylinositol 3-kinase-serum- and glucocorticoid-dependent kinase 1 (PI3K-SGK1) pathway as insulin stimulates SGK1 phosphorylation and the insulin effect can be blocked by the PI3K inhibitor wortmannin or a dominant-negative SGK1.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol", "wortmannin" ], "offsets": [ [ 58, 78 ], [ 256, 266 ] ] }, { "pmid": "17018843", "text": "We showed that SGK1 transcript and protein are expressed in rat proximal tubule and OK cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "We previously showed that glucocorticoids augment the effect of insulin on NHE3 (Klisic J, Hu MC, Nief V, Reyes L, Fuster D, Moe OW, Ambuhl PM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "Am J Physiol Renal Physiol 283: F532-F539, 2002).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "Part of this can be mediated via induction of SGK1 by glucocorticoids, and indeed the insulin effect on NHE3 can also be amplified by overexpression of SGK1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "We next addressed the acute effect of insulin (1-2 h) on NHE3 by systematically examining the candidate signaling cascades and activation mechanisms of NHE3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "We ruled out the PI3K-SGK1-Akt and TC10 pathways, increased surface NHE3, NHE3 phosphorylation, NHE3 association with calcineurin homologous protein 1 or megalin as mechanisms of acute activation of NHE3 by insulin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "In summary, insulin stimulates NHE3 acutely via yet undefined pathways and mechanisms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17018843", "text": "The chronic effect of insulin is mediated by the classic PI3K-SGK1 route.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17067304", "text": "The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole.\n", "type": "CHEMICAL", "entities": [ "quinpirole", "olanzapine" ], "offsets": [ [ 151, 161 ], [ 25, 35 ] ] }, { "pmid": "17067304", "text": "Male and female Sprague-Dawley rats were administered quinpirole (1 mg/kg, i.p.) or saline once daily from postnatal day (P)1 to P21.", "type": "CHEMICAL", "entities": [ "quinpirole" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "17067304", "text": "This drug treatment has been shown to produce long-term priming of the D2 receptor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17067304", "text": "Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days.", "type": "CHEMICAL", "entities": [ "olanzapine" ], "offsets": [ [ 68, 78 ] ] }, { "pmid": "17067304", "text": "One day after olanzapine treatment ceased, rats were tested on the place and match-to-place versions of the Morris water maze (MWM) for seven consecutive days.", "type": "CHEMICAL", "entities": [ "olanzapine" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "17067304", "text": "Dopamine D2 receptor priming was verified through a yawning behavioural test, a D2 receptor-mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete.", "type": "CHEMICAL", "entities": [ "Dopamine", "olanzapine", "olanzapine" ], "offsets": [ [ 0, 8 ], [ 115, 125 ], [ 160, 170 ] ] }, { "pmid": "17067304", "text": "Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment.", "type": "CHEMICAL", "entities": [ "quinpirole", "olanzapine" ], "offsets": [ [ 29, 39 ], [ 92, 102 ] ] }, { "pmid": "17067304", "text": "On the MWM place version, D2-primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM.", "type": "CHEMICAL", "entities": [ "olanzapine", "olanzapine" ], "offsets": [ [ 102, 112 ], [ 128, 138 ] ] }, { "pmid": "17067304", "text": "There were no significant deficits on the match-to-place version.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17067304", "text": "Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment.", "type": "CHEMICAL", "entities": [ "quinpirole", "olanzapine" ], "offsets": [ [ 45, 55 ], [ 155, 165 ] ] }, { "pmid": "17067304", "text": "Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment.", "type": "CHEMICAL", "entities": [ "quinpirole", "olanzapine" ], "offsets": [ [ 9, 19 ], [ 124, 134 ] ] }, { "pmid": "17067304", "text": "These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.", "type": "CHEMICAL", "entities": [ "olanzapine" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "23397359", "text": "Temperature Effects of Sputtering of Langmuir-Blodgett Multilayers.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397359", "text": "Time-of-flight secondary ion mass spectrometry (TOF-SIMS) and atomic force microscopy (AFM) are employed to characterize a wedge-shaped crater eroded by a 40 keV C(60)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397359", "text": "(+) cluster ion beam on an organic thin film of 402 nm of barium arachidate (AA) multilayers prepared by the Langmuir-Blodgett (LB) technique.", "type": "CHEMICAL", "entities": [ "barium arachidate" ], "offsets": [ [ 58, 75 ] ] }, { "pmid": "23397359", "text": "Sample cooling to 90 K was used to help reduce chemical damage, improve depth resolution and maintain constant erosion rate during depth profiling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397359", "text": "The film was characterized at 90 K, 135 K, 165 K, 205 K, 265 K and 300 K. It is shown that sample cooling to 205 K or lower helps to inhibit erosion rate decay, whereas at 300 K and 265 K the erosion rate continues to drop after 250 nm of erosion, reaching about half of the initial value after removal of the entire film.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397359", "text": "Depth profiles are acquired from the SIMS images of the eroded wedge crater.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23397359", "text": "The results suggest that sample cooling only slightly improves the altered layer thickness, but eliminates the decrease in erosion rate observed above 265 K.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "An engineered human follistatin variant: insights into the pharmacokinetic and pharmocodynamic relationships of a novel molecule with broad therapeutic potential.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, wound-healing properties, and muscle-stimulating effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential disease-modifying agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG(1) Fc and removing the intrinsic heparan sulfate-binding activity of follistatin.", "type": "CHEMICAL", "entities": [ "sulfate" ], "offsets": [ [ 169, 176 ] ] }, { "pmid": "23249626", "text": "The engineered variant molecule had ~100- and ~1600-fold improvements in terminal half-life and exposure, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23249626", "text": "Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333577", "text": "Suppression of Src/ERK and GSK-3/β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells.\n", "type": "CHEMICAL", "entities": [ "pinosylvin" ], "offsets": [ [ 56, 66 ] ] }, { "pmid": "23333577", "text": "Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, has exhibited a potential cancer chemopreventive activity.", "type": "CHEMICAL", "entities": [ "trans-stilbenoid" ], "offsets": [ [ 33, 49 ] ] }, { "pmid": "23333577", "text": "However, the growth inhibitory activity against cancer cells and the underlying molecular mechanisms remain to be elucidated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333577", "text": "Therefore, the anti-proliferative activity of pinosylvin was investigated in human colorectal HCT 116 cancer cells.", "type": "CHEMICAL", "entities": [ "pinosylvin" ], "offsets": [ [ 45, 55 ] ] }, { "pmid": "23333577", "text": "Pinosylvin inhibited the proliferation of HCT 116 cells by arresting transition of cell cycle from G1 to S phase along with the downregulation of cyclin D1, cyclin E, cyclin A, cyclin dependent kinase 2 (CDK2), CDK4, c-Myc, and retinoblastoma protein (pRb), and the upregulation of p21(WAF1/CIP1) and p53.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23333577", "text": "Pinosylvin was also found to attenuate the activation of proteins involved in focal adhesion kinase (FAK)/c-Src/extracellular signal-regulated kinase (ERK) signaling, and phosphoinositide 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3β (GSK-3β) signaling pathway.", "type": "CHEMICAL", "entities": [ "phosphoinositide" ], "offsets": [ [ 170, 186 ] ] }, { "pmid": "23333577", "text": "Subsequently, pinosylvin suppressed the nuclear translocation of β-catenin, one of downstream molecules of PI3K/Akt/GSK-3β signaling, and these events led to the sequential downregulation of β-catenin-mediated transcription of target genes including BMP4, ID2, survivin, cyclin D1, MMP7, and c-Myc.", "type": "CHEMICAL", "entities": [ "pinosylvin" ], "offsets": [ [ 11, 21 ] ] }, { "pmid": "23333577", "text": "These findings demonstrate that the anti-proliferative activity of pinosylvin might be associated with the cell cycle arrest and downregulation of cell proliferation regulating signaling pathways in human colorectal cancer cells.", "type": "CHEMICAL", "entities": [ "pinosylvin" ], "offsets": [ [ 61, 71 ] ] }, { "pmid": "23434647", "text": "The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "Tumor-associated macrophages (TAMs) are correlated with poor prognosis in many human cancers; however, the mechanism by which TAMs facilitate ovarian cancer cell migration and invasion remains unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "This study was aimed to examine the function of adrenomedullin (ADM) in macrophage polarization and their further effects on the migration of ovarian cancer cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "Exogenous ADM antagonist and small interfering RNA (siRNA) specific for ADM expression were treated to macrophages and EOC cell line HO8910, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "Then macrophages were cocultured with HO8910 cells without direct contact.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "Flow cytometry, Western blot and real-time PCR were used to detect macrophage phenotype and cytokine production.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "The migration ability and cytoskeleton rearrangement of ovarian cancer cells were determined by Transwell migration assay and phalloidin staining.", "type": "CHEMICAL", "entities": [ "phalloidin" ], "offsets": [ [ 126, 136 ] ] }, { "pmid": "23434647", "text": "Western blot was performed to evaluate the activity status of signaling molecules in the process of ovarian cancer cell migration.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "The results showed that ADM induced macrophage phenotype and cytokine production similar to TAMs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "Macrophages polarized by ADM promoted the migration and cytoskeleton rearrangement of HO8910 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "The expression of RhoA and its downstream effector, cofilin, were upregulated in macrophage-induced migration of HO8910 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23434647", "text": "In conclusion, ADM could polarize macrophages similar to TAMs, and then polarized macrophages promote the migration of ovarian cancer cells via activation of RhoA signaling pathway in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265543", "text": "Influence of nitrogen supply on the production of higher alcohols/esters and expression of flavour-related genes in cachaça fermentation.\n", "type": "CHEMICAL", "entities": [ "nitrogen", "alcohols", "esters" ], "offsets": [ [ 13, 21 ], [ 57, 65 ], [ 66, 72 ] ] }, { "pmid": "23265543", "text": "This study provides the first attempt to analyse the influence of ammonium supplements on sugar-cane juice fermentation and the flavour profile in a cachaça industrial process.", "type": "CHEMICAL", "entities": [ "ammonium", "sugar" ], "offsets": [ [ 65, 73 ], [ 89, 94 ] ] }, { "pmid": "23265543", "text": "The objective was to find a relationship between higher alcohol/ester content and the transcription levels of the main genes involved in production of these compounds under cachaça fermentation.", "type": "CHEMICAL", "entities": [ "alcohol", "ester" ], "offsets": [ [ 54, 61 ], [ 62, 67 ] ] }, { "pmid": "23265543", "text": "Sugar-cane juice with a low amount of assimilable nitrogen (81 mg N/L), was further supplemented with mid-range or high concentrations of ammonium sulfate.", "type": "CHEMICAL", "entities": [ "nitrogen", "ammonium sulfate" ], "offsets": [ [ 47, 55 ], [ 135, 151 ] ] }, { "pmid": "23265543", "text": "Overall, higher alcohol production was reduced by ammonium supplementation, and this can be correlated with a general downregulation of genes encoding decarboxylases and dehydrogenases of the Ehrlich pathway.", "type": "CHEMICAL", "entities": [ "alcohol", "ammonium" ], "offsets": [ [ 13, 20 ], [ 47, 55 ] ] }, { "pmid": "23265543", "text": "The production of acetate esters was enhanced by mid-range ammonium supplementation and the production of acyl esters by high ammonium supplementation.", "type": "CHEMICAL", "entities": [ "acetate esters", "ammonium", "acyl esters", "ammonium" ], "offsets": [ [ 15, 29 ], [ 56, 64 ], [ 103, 114 ], [ 123, 131 ] ] }, { "pmid": "23265543", "text": "The acyl esters could be correlated with expression of alcohol acyl-transferase EEB1 and the acyl esterase IAH1.", "type": "CHEMICAL", "entities": [ "acyl esters", "alcohol", "acyl", "acyl" ], "offsets": [ [ 1, 12 ], [ 52, 59 ], [ 60, 64 ], [ 90, 94 ] ] }, { "pmid": "23534442", "text": "Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors.\n", "type": "CHEMICAL", "entities": [ "nitric oxide", "1,5-diarylpyrrole nitrooxyalkyl ethers" ], "offsets": [ [ 134, 146 ], [ 42, 80 ] ] }, { "pmid": "23534442", "text": "A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed.", "type": "CHEMICAL", "entities": [ "3-substituted 1,5-diarylpyrroles", "nitrooxyalkyl" ], "offsets": [ [ 12, 44 ], [ 55, 68 ] ] }, { "pmid": "23534442", "text": "New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported.", "type": "CHEMICAL", "entities": [ "pyrrole", "nitrooxyalkyl", "esters", "carbonates", "ethers", "NO" ], "offsets": [ [ 15, 22 ], [ 31, 44 ], [ 53, 59 ], [ 61, 71 ], [ 77, 83 ], [ 125, 127 ] ] }, { "pmid": "23534442", "text": "By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied.", "type": "CHEMICAL", "entities": [ "nitrooxyalkyl ethers", "alcohols" ], "offsets": [ [ 51, 71 ], [ 99, 107 ] ] }, { "pmid": "23534442", "text": "Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models.", "type": "CHEMICAL", "entities": [ "Nitrooxy", "NO" ], "offsets": [ [ 0, 8 ], [ 28, 30 ] ] }, { "pmid": "23534442", "text": "Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534442", "text": "Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23534442", "text": "Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.", "type": "CHEMICAL", "entities": [ "nitrooxyalkyl ester and ether", "(1)H", "(13)C" ], "offsets": [ [ 133, 162 ], [ 30, 34 ], [ 40, 45 ] ] }, { "pmid": "12184062", "text": "The clinical profile of the angiotensin II receptor blocker eprosartan.\n", "type": "CHEMICAL", "entities": [ "angiotensin II", "eprosartan" ], "offsets": [ [ 28, 42 ], [ 60, 70 ] ] }, { "pmid": "12184062", "text": "Angiotensin II receptor antagonists block angiotensin II type 1 (AT1) receptors and reduce the pressor effects of angiotensin in the vasculature.", "type": "CHEMICAL", "entities": [ "Angiotensin II", "angiotensin", "angiotensin II" ], "offsets": [ [ 0, 14 ], [ 114, 125 ], [ 42, 56 ] ] }, { "pmid": "12184062", "text": "By this mechanism, they induce similar pharmacological effects to angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure (BP).", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 66, 77 ] ] }, { "pmid": "12184062", "text": "However, AT1 antagonists differ from ACE inhibitors with respect to side effects, and induce less cough, which is related to bradykinin activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12184062", "text": "Within the class of angiotensin II antagonists, eprosartan differs from other currently clinically available agents in terms of its chemical structure and its dual pharmacological mode of action.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 20, 34 ] ] }, { "pmid": "12184062", "text": "Eprosartan acts not only at vascular AT1 receptors but also at presynaptic AT1 receptors, causing inhibition of sympathetically stimulated noradrenaline release.", "type": "CHEMICAL", "entities": [ "Eprosartan", "noradrenaline" ], "offsets": [ [ 0, 10 ], [ 139, 152 ] ] }, { "pmid": "12184062", "text": "Eprosartan is not metabolized by cytochrome P450 enzymes and therefore has a low potential for metabolic drug interactions, which may be of importance when treating the elderly and patients on multiple drugs.", "type": "CHEMICAL", "entities": [ "Eprosartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12184062", "text": "In clinical trials eprosartan has proven to be at least as effective as the ACE inhibitor enalapril in reducing BP, but with a significantly lower incidence of side effects.", "type": "CHEMICAL", "entities": [ "eprosartan" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "12184062", "text": "Eprosartan is safe, effective and well tolerated in long-term treatment, either as monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.", "type": "CHEMICAL", "entities": [ "Eprosartan", "hydrochlorothiazide" ], "offsets": [ [ 0, 10 ], [ 155, 174 ] ] }, { "pmid": "22815248", "text": "Protective Effects of a Purified Saponin Mixture from Astragalus corniculatus Bieb., in vivo Hepatotoxicity Models.\n", "type": "CHEMICAL", "entities": [ "Saponin" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "22815248", "text": "In this study, the in vivo effects of a purified saponin mixture (PSM), obtained from Astragalus corniculatus Bieb., were investigated using two in vivo hepatotoxicity models based on liver damage caused by paracetamol (PC) and carbon tetrachloride (CCl4 ).", "type": "CHEMICAL", "entities": [ "paracetamol", "carbon tetrachloride", "CCl4", "saponin" ], "offsets": [ [ 207, 218 ], [ 228, 248 ], [ 250, 254 ], [ 49, 56 ] ] }, { "pmid": "22815248", "text": "The effects of PSM were compared with silymarin.", "type": "CHEMICAL", "entities": [ "silymarin" ], "offsets": [ [ 38, 47 ] ] }, { "pmid": "22815248", "text": "Male Wistar rats were challenged orally with 20% CCl4 or PC (2 g/kg) four days after being pre-treated with PSM (100 mg/kg) or silymarin (200 mg/kg).", "type": "CHEMICAL", "entities": [ "CCl4", "silymarin" ], "offsets": [ [ 49, 53 ], [ 127, 136 ] ] }, { "pmid": "22815248", "text": "A significant decrease of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) activities and glutathione (GSH) levels and an increase of malondialdehyde (MDA) quantity was observed after CCl4 and PC administration alone.", "type": "CHEMICAL", "entities": [ "aspartate", "alanine", "lactate", "glutathione", "GSH", "malondialdehyde", "MDA", "CCl4" ], "offsets": [ [ 26, 35 ], [ 54, 61 ], [ 80, 87 ], [ 123, 134 ], [ 136, 139 ], [ 167, 182 ], [ 184, 187 ], [ 217, 221 ] ] }, { "pmid": "22815248", "text": "PSM pre-treatment decreased serum transaminases and LDH activities and MDA levels and increased the levels of cell protector GSH.", "type": "CHEMICAL", "entities": [ "MDA", "GSH" ], "offsets": [ [ 71, 74 ], [ 125, 128 ] ] }, { "pmid": "22815248", "text": "Biotransformation phase I enzymes were also assessed in both models.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22815248", "text": "In the CCl4 hepatotoxicity model, pre-treatment with PSM or silymarin resulted in significantly increased activities of ethylmorphine-N-demethylase and aniline 4-hydroxylase activity and cytochrome P450, compared to the CCl4 only group.", "type": "CHEMICAL", "entities": [ "ethylmorphine", "N", "aniline", "CCl4", "CCl4", "silymarin" ], "offsets": [ [ 120, 133 ], [ 134, 135 ], [ 152, 159 ], [ 220, 224 ], [ 7, 11 ], [ 60, 69 ] ] }, { "pmid": "22815248", "text": "Neither silymarin nor PSM influenced PC biotransformation.", "type": "CHEMICAL", "entities": [ "silymarin" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "22815248", "text": "Our results suggest that PSM, obtained from A. corniculatus, Bieb. showed in vivo hepatoprotective and antioxidant activities against CCl4 and PC-induced liver damage comparable to that of silymarin.", "type": "CHEMICAL", "entities": [ "CCl4", "silymarin" ], "offsets": [ [ 134, 138 ], [ 189, 198 ] ] }, { "pmid": "22815248", "text": "Copyright © 2012 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15114505", "text": "In vitro inhibition of diacylglycerol acyltransferase by prenylflavonoids from Sophora flavescens.\n", "type": "CHEMICAL", "entities": [ "diacylglycerol", "prenylflavonoids" ], "offsets": [ [ 23, 37 ], [ 57, 73 ] ] }, { "pmid": "15114505", "text": "Four prenylflavonoids, kurarinone ( 1), a chalcone of 1, kuraridin ( 2), kurarinol ( 3), kushenol H ( 4) and kushenol K ( 5) isolated from the roots of Sophora flavescens were investigated for their inhibitory effects on diacylglycerol acyltransferase (DGAT).", "type": "CHEMICAL", "entities": [ "kushenol K", "diacylglycerol", "kurarinone", "chalcone", "prenylflavonoids", "kuraridin", "kurarinol", "kushenol H" ], "offsets": [ [ 109, 119 ], [ 221, 235 ], [ 23, 33 ], [ 42, 50 ], [ 5, 21 ], [ 57, 66 ], [ 73, 82 ], [ 89, 99 ] ] }, { "pmid": "15114505", "text": "The flavonoids inhibited DGAT activity in a dose-dependent manner with IC50 values of 10.9 microM ( 1), 9.8 microM ( 2), 8.6 microM ( 3), 142.0 microM ( 4) and 250 microM ( 5).", "type": "CHEMICAL", "entities": [ "flavonoids" ], "offsets": [ [ 4, 14 ] ] }, { "pmid": "15114505", "text": "The prenylflavonoids without C3-OH ( 1, 2, 3) showed stronger inhibition than those with C3-OH ( 4, 5).", "type": "CHEMICAL", "entities": [ "prenylflavonoids", "C3-OH", "C3-OH" ], "offsets": [ [ 4, 20 ], [ 29, 34 ], [ 89, 94 ] ] }, { "pmid": "15114505", "text": "On the other hand, flavonoids without side chains (hesperetin, naringenin, quercetin and kaempferol) did not inhibit the enzyme activity at a final concentration of 800 microM.", "type": "CHEMICAL", "entities": [ "flavonoids", "hesperetin", "naringenin", "quercetin", "kaempferol" ], "offsets": [ [ 19, 29 ], [ 51, 61 ], [ 63, 73 ], [ 75, 84 ], [ 89, 99 ] ] }, { "pmid": "15114505", "text": "These data suggest that the lavandulyl side chain and the position of the hydroxy group are important for high DGAT inhibitory activity.", "type": "CHEMICAL", "entities": [ "lavandulyl", "hydroxy" ], "offsets": [ [ 28, 38 ], [ 74, 81 ] ] }, { "pmid": "15114505", "text": "Compound 1 also inhibited de novo synthesis of triacylglycerol (TG) in Raji cells.", "type": "CHEMICAL", "entities": [ "triacylglycerol", "TG" ], "offsets": [ [ 47, 62 ], [ 64, 66 ] ] }, { "pmid": "17494951", "text": "IL-4", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "stimulates the expression of CXCL-8, E-selectin, VEGF, and inducible nitric oxide synthase mRNA by equine pulmonary artery endothelial cells.\n", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 69, 81 ] ] }, { "pmid": "17494951", "text": "Little is known concerning the possible contribution of T helper 2 (Th2)-type cytokines to the recruitment of neutrophils into the lung tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "In the present study, endothelial cells from equine pulmonary arteries were cultured in the presence of recombinant equine (re) IL-4 and reIL-5, and the cytokine mRNA expression of molecules implicated in the chemotaxis and migration of neutrophils was studied using real-time RT-PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "The functional response of reIL-4-induced endothelial cell stimulation on neutrophil migration was also studied using a chemotaxis chamber.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "ReIL-4 either increased the expression of CXCL-8, E-selectin, vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS), or potentiated the coeffects of lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) on CXCL-8.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 119, 131 ] ] }, { "pmid": "17494951", "text": "Supernatants collected from cultured endothelial cells stimulated with reIL-4 significantly promoted neutrophil migration in a dose-dependent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "Dexamethasone (DXM) decreased the expression of CXCL-8, VEGF, and iNOS induced by reIL-4, while 1400W dihydrochloride (1400W), a selective inhibitor of iNOS, decreased the expression of E-selectin, VEGF, and iNOS.", "type": "CHEMICAL", "entities": [ "1400W dihydrochloride", "1400W", "Dexamethasone", "DXM" ], "offsets": [ [ 96, 117 ], [ 119, 124 ], [ 0, 13 ], [ 15, 18 ] ] }, { "pmid": "17494951", "text": "DXM and 1400W attenuated the mRNA expression of E-selectin and iNOS induced by the costimulation of reIL-4, reTNF-alpha, and LPS.", "type": "CHEMICAL", "entities": [ "DXM", "1400W" ], "offsets": [ [ 0, 3 ], [ 8, 13 ] ] }, { "pmid": "17494951", "text": "Neither equine nor human recombinant IL-5 influenced the mRNA expression of CXCL-8, E-selectin, or VEGF.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "These findings suggest that Th2-type cytokines may contribute to pulmonary neutrophilia during allergic inflammation by the increased expression of neutrophil chemokines and adhesion molecules by endothelial cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17494951", "text": "DXM and the iNOS inhibitors may decrease pulmonary neutrophilia due, in part, to a direct inhibition of some of these factors.", "type": "CHEMICAL", "entities": [ "DXM" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23330847", "text": "Hydroxy-terminated conjugated polymer nanoparticles have near-unity bright fraction and reveal cholesterol-dependence of IGF1R nanodomains.\n", "type": "CHEMICAL", "entities": [ "Hydroxy", "cholesterol" ], "offsets": [ [ 0, 7 ], [ 95, 106 ] ] }, { "pmid": "23330847", "text": "Fluorescent nanoparticles have enabled many discoveries regarding how molecular machines function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "Quantum dots have been the dominant class of fluorescent nanoparticles but suffer from blinking and from a substantial dark fraction--particles where the fluorescence is never seen--complicating any analysis of biological function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "Nanoparticles composed of conjugated fluorescent polymers (Pdots) have recently been shown to have high brightness and no blinking.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "Here we develop a robust and efficient means to measure the dark fraction of Pdots, conjugating Atto dyes to the nanoparticles and testing fluorescence colocalization of dye and Pdot puncta.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "This established that the Pdots we generated had minimal dark fraction: ∼3%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "The application of nanoparticles in biological environments is highly sensitive to surface functionalization.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "For Pdots we found that passivation with uncharged hydroxy-terminated polyethylene glycol caused a dramatic reduction in nonspecific cell binding and aggregation compared to a charged coating.", "type": "CHEMICAL", "entities": [ "hydroxy", "polyethylene glycol" ], "offsets": [ [ 49, 56 ], [ 68, 87 ] ] }, { "pmid": "23330847", "text": "Using carbonyl di-imidazole the hydroxy-Pdots were functionalized efficiently with streptavidin for high stability targeting, allowing specific labeling of mammalian cells.", "type": "CHEMICAL", "entities": [ "carbonyl di-imidazole", "hydroxy" ], "offsets": [ [ 4, 25 ], [ 30, 37 ] ] }, { "pmid": "23330847", "text": "Type I insulin-like growth factor receptor (IGF1R) regulates cell survival and development, with roles in aging, heart disease, and cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23330847", "text": "We used hydroxy-Pdots to track the dynamics of IGF1R on a breast cancer cell-line, determining the diffusion characteristics and showing cholesterol-containing membrane nanodomains were important for receptor mobility at the plasma membrane.", "type": "CHEMICAL", "entities": [ "hydroxy", "cholesterol" ], "offsets": [ [ 6, 13 ], [ 135, 146 ] ] }, { "pmid": "23330847", "text": "The near-unity bright fraction and low nonspecific binding of hydroxy-Pdots, combined with Pdot photostability and lack of blinking, provides many advantages for investigations at the single molecule level.", "type": "CHEMICAL", "entities": [ "hydroxy" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "17000933", "text": "Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats.\n", "type": "CHEMICAL", "entities": [ "Medroxyprogesterone acetate", "aldosterone", "drospirenone", "17 beta-estradiol" ], "offsets": [ [ 0, 27 ], [ 105, 116 ], [ 36, 48 ], [ 84, 101 ] ] }, { "pmid": "17000933", "text": "Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction.", "type": "CHEMICAL", "entities": [ "progestins", "estrogens" ], "offsets": [ [ 113, 123 ], [ 99, 108 ] ] }, { "pmid": "17000933", "text": "To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity.", "type": "CHEMICAL", "entities": [ "progestins", "progesterone", "steroid", "aldosterone", "17beta-estradiol", "medroxyprogesterone acetate", "drospirenone", "progestogen" ], "offsets": [ [ 72, 82 ], [ 128, 140 ], [ 184, 191 ], [ 280, 291 ], [ 341, 357 ], [ 359, 386 ], [ 392, 404 ], [ 412, 423 ] ] }, { "pmid": "17000933", "text": "The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment.", "type": "CHEMICAL", "entities": [ "aldosterone", "17beta-estradiol" ], "offsets": [ [ 94, 105 ], [ 221, 237 ] ] }, { "pmid": "17000933", "text": "The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate.", "type": "CHEMICAL", "entities": [ "17beta-estradiol", "NO", "medroxyprogesterone acetate" ], "offsets": [ [ 23, 39 ], [ 149, 151 ], [ 246, 273 ] ] }, { "pmid": "17000933", "text": "In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation.", "type": "CHEMICAL", "entities": [ "drospirenone", "17beta-estradiol", "aldosterone" ], "offsets": [ [ 13, 25 ], [ 60, 76 ], [ 99, 110 ] ] }, { "pmid": "17000933", "text": "The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation.", "type": "CHEMICAL", "entities": [ "estrogen", "progesterone", "androgen" ], "offsets": [ [ 73, 81 ], [ 83, 95 ], [ 113, 121 ] ] }, { "pmid": "17000933", "text": "Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.", "type": "CHEMICAL", "entities": [ "progestins", "drospirenone", "medroxyprogesterone acetate", "aldosterone" ], "offsets": [ [ 6, 16 ], [ 26, 38 ], [ 78, 105 ], [ 120, 131 ] ] }, { "pmid": "23007555", "text": "Effect of ifenprodil on GluN1/GluN2B N-methyl-D-aspartate receptor gating.\n", "type": "CHEMICAL", "entities": [ "ifenprodil", "N-methyl-D-aspartate" ], "offsets": [ [ 10, 20 ], [ 37, 57 ] ] }, { "pmid": "23007555", "text": "Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors.", "type": "CHEMICAL", "entities": [ "Ifenprodil", "N-methyl-D-aspartate" ], "offsets": [ [ 0, 10 ], [ 54, 74 ] ] }, { "pmid": "23007555", "text": "Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23007555", "text": "Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism.", "type": "CHEMICAL", "entities": [ "ifenprodil,", "zinc", "amino" ], "offsets": [ [ 64, 75 ], [ 83, 87 ], [ 132, 137 ] ] }, { "pmid": "23007555", "text": "To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steady-state currents from cell-attached and outside-out patches.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23007555", "text": "At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time.", "type": "CHEMICAL", "entities": [ "ifenprodil" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "23007555", "text": "In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves.", "type": "CHEMICAL", "entities": [ "ifenprodil" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "23007555", "text": "Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state.", "type": "CHEMICAL", "entities": [ "ifenprodil" ], "offsets": [ [ 32, 42 ] ] }, { "pmid": "23007555", "text": "We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites.", "type": "CHEMICAL", "entities": [ "ifenprodil", "zinc" ], "offsets": [ [ 47, 57 ], [ 127, 131 ] ] }, { "pmid": "23007555", "text": "Our data also uncover the potential pH-dependent action of ifenprodil on gating.", "type": "CHEMICAL", "entities": [ "ifenprodil" ], "offsets": [ [ 59, 69 ] ] }, { "pmid": "23007555", "text": "At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.", "type": "CHEMICAL", "entities": [ "ifenprodil" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "23557706", "text": "mTOR Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23557706", "text": "Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23557706", "text": "Pharmacological doses of the mTOR inhibitor rapamycin reduce albuminura in diabetes.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 44, 53 ] ] }, { "pmid": "23557706", "text": "We explored the hypothesis that mTOR mediates podocyte injury in diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23557706", "text": "High glucose (HG) induces apoptosis of podocytes, inhibits AMPK activation, inactivates tuberin and activates mTOR.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 5, 12 ] ] }, { "pmid": "23557706", "text": "HG also increases the levels of Nox4 and Nox1 and NADPH oxidase activity.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 50, 55 ] ] }, { "pmid": "23557706", "text": "Inhibition of mTOR by low dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity and podocyte apoptosis.", "type": "CHEMICAL", "entities": [ "rapamycin", "NADPH" ], "offsets": [ [ 31, 40 ], [ 77, 82 ] ] }, { "pmid": "23557706", "text": "Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation indicating that mTOR is downstream of these signaling molecules.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23557706", "text": "In isolated glomeruli of OVE26 mice, there is similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 150, 155 ] ] }, { "pmid": "23557706", "text": "Inhibition of mTOR by small dose of rapamycin reduces podocyte apoptosis, attenuates glomerular injury and albuminuria.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "23557706", "text": "Our data provide evidence for a novel function of mTOR in Nox4-derived ROS generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23557706", "text": "Thus mTOR and or NADPH oxidase inhibition may represent a therapeutic modality of diabetic kidney disease.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 17, 22 ] ] }, { "pmid": "23641685", "text": "Cavity Ringdown Spectroscopy of the Hydroxy-Methyl-Peroxy Radical.\n", "type": "CHEMICAL", "entities": [ "Hydroxy-Methyl-Peroxy" ], "offsets": [ [ 36, 57 ] ] }, { "pmid": "23641685", "text": "We report vibrational and electronic spectra of the hydroxyl-methyl-peroxy radical (HOCH2OO, or HMP), the primary product of the reaction of the hydroperoxy radical, HO2, and formaldehyde, HCHO.", "type": "CHEMICAL", "entities": [ "hydroperoxy", "HO2", "formaldehyde", "HCHO", "hydroxyl-methyl-peroxy", "HOCH2OO", "HMP" ], "offsets": [ [ 145, 156 ], [ 166, 169 ], [ 175, 187 ], [ 189, 193 ], [ 52, 74 ], [ 84, 91 ], [ 96, 99 ] ] }, { "pmid": "23641685", "text": "The ν1 vibrational (OH stretch) spectrum and the Ã-X electronic spectrum of HMP were detected by Infrared Cavity Ringdown Spectroscopy (IR-CRDS), and assignments were verified with density functional calculations.", "type": "CHEMICAL", "entities": [ "OH", "HMP" ], "offsets": [ [ 20, 22 ], [ 76, 79 ] ] }, { "pmid": "23641685", "text": "The HMP radical was generated in reactions of HCHO with HO2.", "type": "CHEMICAL", "entities": [ "HMP", "HCHO", "HO2" ], "offsets": [ [ 2, 5 ], [ 44, 48 ], [ 54, 57 ] ] }, { "pmid": "23641685", "text": "Free radical reactions were initiated by pulsed laser photolysis (PLP) of Cl2 in the presence of HCHO and O2 in a flow reactor at 300-330 Torr and 295K. IR-CRDS spectra were measured in mid-IR and near-IR regions over the ranges 3525-3700 cm(-1) (ν1) and 7250-7800 cm(-1) (Ã-X) (respectively, at a delay time 100 µs after photolysis.", "type": "CHEMICAL", "entities": [ "Cl2", "HCHO", "O2" ], "offsets": [ [ 72, 75 ], [ 95, 99 ], [ 104, 106 ] ] }, { "pmid": "23641685", "text": "The ν1 spectrum had an origin at 3622 cm(-1) and exhibited partially resolved P- and R-branch contours and a small Q branch.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641685", "text": "At these short delay times, spectral interference from HOOH and HCOOH was minimal, and could be subtracted.", "type": "CHEMICAL", "entities": [ "HOOH", "HCOOH" ], "offsets": [ [ 49, 53 ], [ 58, 63 ] ] }, { "pmid": "23641685", "text": "From B3LYP/6-31G+(d,p) calculations, we found that the anharmonic vibrational frequency and band contour predicted for the lowest energy conformer, HMP-A, The calculated anharmonic vibrational frequency and band contour computed using B3LYP/63-1G(d,p) level were in good agreement with the observed spectrum.", "type": "CHEMICAL", "entities": [ "HMP" ], "offsets": [ [ 142, 145 ] ] }, { "pmid": "23641685", "text": "In the near-IR, we observed four well spaced vibronic bands, each with partially resolved rotational contours.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641685", "text": "We assigned the apparent origin of the electronic spectrum of HMP at 7392 cm(-1) and two bands to the blue to a progression in ν15', the lowest torsional mode of the state (ν15'= 171 cm(-1)).", "type": "CHEMICAL", "entities": [ "HMP" ], "offsets": [ [ 56, 59 ] ] }, { "pmid": "23641685", "text": "The band furthest to the red was assigned as a hot band in ν15\", leading to a ground state torsional frequency of (ν15\"= 122 cm(-1)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641685", "text": "We simulated the spectrum using second order vibrational perturbation theory (VPT2) with B3LYP/6-31+G(d,p) calculations at the minimum energy geometries of the HMP-A conformer on the X ̃ and A ̃ states.", "type": "CHEMICAL", "entities": [ "HMP" ], "offsets": [ [ 150, 153 ] ] }, { "pmid": "23641685", "text": "The predictions of the electronic origin frequency, torsional frequencies, anharmonicities and rotational band contours matched the observed spectrum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641685", "text": "We investigated the torsional modes more explicitly by computing potential energy surfaces of HMP as a function of the two dihedral angles τOCOH and τOOCO.", "type": "CHEMICAL", "entities": [ "HMP", "OCOH", "OOCO" ], "offsets": [ [ 82, 85 ], [ 128, 132 ], [ 138, 142 ] ] }, { "pmid": "23641685", "text": "Wave functions and energy levels were calculated based on this potential surface; these results were used to calculate the Franck-Condon factors, which reproduced the vibronic band intensities in the observed electronic spectrum.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641685", "text": "The transitions that we observed all involved states with wave functions localized on the minimum energy conformer, HMP-A. Our calculations indicated that the observed near-IR spectrum was that of the minimum energy conformer HMP-A, but that this conformer is not the lowest energy conformer in the state, which remains unobserved.", "type": "CHEMICAL", "entities": [ "HMP", "HMP" ], "offsets": [ [ 102, 105 ], [ 212, 215 ] ] }, { "pmid": "23641685", "text": "We estimated that the energy of this lowest conformer (HMP-B) of the à state to be T0 (Ã) ≈ 7200 cm(-1), based on the energy difference E0(HMP-B) - E0(HMP-A) on the à state computed at the B3LYP/6-31+G(d,p) level.", "type": "CHEMICAL", "entities": [ "HMP", "HMP", "HMP" ], "offsets": [ [ 41, 44 ], [ 125, 128 ], [ 137, 140 ] ] }, { "pmid": "16432501", "text": "Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses.\n", "type": "CHEMICAL", "entities": [ "formoterol", "salmeterol" ], "offsets": [ [ 56, 66 ], [ 71, 81 ] ] }, { "pmid": "16432501", "text": "beta(2)-Adrenoceptor agonists provide a potential therapy for muscle wasting and weakness, but their use may be limited by adverse effects on the heart, mediated in part, by beta(1)-adrenoceptor activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16432501", "text": "Two beta(2)-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater beta(2)-adrenoceptor selectivity.", "type": "CHEMICAL", "entities": [ "formoterol", "salmeterol" ], "offsets": [ [ 22, 32 ], [ 37, 47 ] ] }, { "pmid": "16432501", "text": "The pharmacological profiles of formoterol and salmeterol and their effects on skeletal and cardiac muscle mass were investigated in 12-week-old, male F344 rats.", "type": "CHEMICAL", "entities": [ "formoterol", "salmeterol" ], "offsets": [ [ 32, 42 ], [ 47, 57 ] ] }, { "pmid": "16432501", "text": "Formoterol and salmeterol were each administered via daily i.p. injection at one of seven doses (ranging from 1 to 2,000 microg kg(-1) day(-1)), for 4 weeks.", "type": "CHEMICAL", "entities": [ "Formoterol", "salmeterol" ], "offsets": [ [ 0, 10 ], [ 15, 25 ] ] }, { "pmid": "16432501", "text": "Rats were anaesthetised and the EDL and soleus muscles and the heart were excised and weighed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16432501", "text": "Dose-response curves were constructed based on skeletal and cardiac muscle hypertrophy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16432501", "text": "Formoterol was more potent than salmeterol, with a significantly lower ED(50) in EDL muscles (1 and 130 microg kg(-1) day(-1), P <0.05), whereas salmeterol had greater intrinsic activity than formoterol in both EDL and soleus muscles (12% greater hypertrophy than formoterol).", "type": "CHEMICAL", "entities": [ "salmeterol", "formoterol", "formoterol", "Formoterol", "salmeterol" ], "offsets": [ [ 145, 155 ], [ 192, 202 ], [ 264, 274 ], [ 0, 10 ], [ 32, 42 ] ] }, { "pmid": "16432501", "text": "The drugs had similar potency and intrinsic activity in the heart, with a smaller leftward shift for formoterol than seen in skeletal muscle.", "type": "CHEMICAL", "entities": [ "formoterol" ], "offsets": [ [ 101, 111 ] ] }, { "pmid": "16432501", "text": "A dose of 25 microg kg(-1) day(-1) of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar beta-adrenoceptor downregulation.", "type": "CHEMICAL", "entities": [ "formoterol", "salmeterol" ], "offsets": [ [ 38, 48 ], [ 98, 108 ] ] }, { "pmid": "16432501", "text": "These results show that doses as low as 1 microg kg(-1) day(-1) of formoterol can elicit significant muscle hypertrophy with minimal cardiac hypertrophy and provide important information regarding the potential therapeutic use of formoterol and salmeterol for muscle wasting.", "type": "CHEMICAL", "entities": [ "formoterol", "formoterol", "salmeterol" ], "offsets": [ [ 67, 77 ], [ 230, 240 ], [ 245, 255 ] ] }, { "pmid": "19275550", "text": "Clinical utility of acarbose, an alpha-glucosidase inhibitor in cardiometabolic disorders.\n", "type": "CHEMICAL", "entities": [ "acarbose" ], "offsets": [ [ 20, 28 ] ] }, { "pmid": "19275550", "text": "Diabetes is associated with an increase risk for cardiovascular disease (CVD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19275550", "text": "Recently, macrovascular complications of diabetes have been shown to start before the development of diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19275550", "text": "Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "19275550", "text": "Since postprandial hyperglycemia and insulin resistance are thought to play a central role in the development and progression of CVD in patients with IGT, amelioration of postprandial hyperglycemia as well as insulin resistance is a therapeutic target for the prevention of CVD in these high-risk patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19275550", "text": "Acarbose, an alpha-glucosidase inhibitor, delays the absorption of carbohydrate from the small intestine, thereby reducing postprandial hyperglycemia.", "type": "CHEMICAL", "entities": [ "Acarbose", "carbohydrate" ], "offsets": [ [ 0, 8 ], [ 67, 79 ] ] }, { "pmid": "19275550", "text": "Further, recently, acarbose has been shown to improve insulin resistance in vivo.", "type": "CHEMICAL", "entities": [ "acarbose", "acarbose has been shown to improve insulin resistance in vivo" ], "offsets": [ [ 19, 27 ], [ 19, 80 ] ] }, { "pmid": "19275550", "text": "These findings suggest that acarbose is a promising metabolic modifier that could reduce the risk of CVD in patients with the metabolic syndrome.", "type": "CHEMICAL", "entities": [ "acarbose" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "19275550", "text": "In this paper, we review the clinical utility of acarbose in various cardiometabolic disorders.", "type": "CHEMICAL", "entities": [ "acarbose" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "23402841", "text": "Hematologic and hepatic responses of the freshwater fish Hoplias malabaricus after saxitoxin exposure.\n", "type": "CHEMICAL", "entities": [ "saxitoxin" ], "offsets": [ [ 83, 92 ] ] }, { "pmid": "23402841", "text": "The bioaccumulation of saxitoxins (STX) in the trophic chain, mainly in freshwater, are not completely known.", "type": "CHEMICAL", "entities": [ "saxitoxins", "STX" ], "offsets": [ [ 23, 33 ], [ 35, 38 ] ] }, { "pmid": "23402841", "text": "This work aimed to elucidate the effects of STX on Hoplias malabaricus through trophic bioassay.", "type": "CHEMICAL", "entities": [ "STX" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "23402841", "text": "The fish were fed once every five days with Astyanax sp.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23402841", "text": "before being subjected to an intraperitoneal inoculation with the lysate of Cylindrospermopsis raciborskii culture containing 97% STX and 3% by neosaxitoxin and gonyautoxin during 20 days.", "type": "CHEMICAL", "entities": [ "STX", "neosaxitoxin", "gonyautoxin" ], "offsets": [ [ 130, 133 ], [ 144, 156 ], [ 161, 172 ] ] }, { "pmid": "23402841", "text": "The animal's liver was assessed using biomarkers as activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx), and concentrations of reduced glutathione (GSH) and lipoperoxidation (LPO) and protein carbonylation (PCO).", "type": "CHEMICAL", "entities": [ "superoxide", "glutathione", "glutathione", "reduced glutathione", "GSH" ], "offsets": [ [ 66, 76 ], [ 110, 121 ], [ 147, 158 ], [ 199, 218 ], [ 220, 223 ] ] }, { "pmid": "23402841", "text": "In the blood was analyzed the genotoxic and hematological parameters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23402841", "text": "The hepatosomatic index and the relative condition factor did not show a significant difference between the exposed and control groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23402841", "text": "The values of mean corpuscular hemoglobin concentration and mean corpuscular hemoglobin increased in the STX group.", "type": "CHEMICAL", "entities": [ "STX" ], "offsets": [ [ 105, 108 ] ] }, { "pmid": "23402841", "text": "The hepatic tissue from both groups exhibited a typical pattern that have been already described for most teleost fish.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23402841", "text": "The results suggested the generation of reactive oxygen species, with increased activity of GPx and concentrations of LPO and GSH; whereas the specific activity of SOD decreased.", "type": "CHEMICAL", "entities": [ "oxygen", "GSH" ], "offsets": [ [ 49, 55 ], [ 126, 129 ] ] }, { "pmid": "23402841", "text": "However, no changes were observed in the CAT, PCO, and DNA damage.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23402841", "text": "Although the STX effects are known as neurotoxic, this cyanotoxin caused liver biochemical alterations that can be considered ecologically relevant.", "type": "CHEMICAL", "entities": [ "STX" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23531536", "text": "The Protective Effects of α-Lipoic Acid on Kidneys in Type 2 Diabetic Goto-Kakisaki Rats via Reducing Oxidative Stress.\n", "type": "CHEMICAL", "entities": [ "α-Lipoic Acid" ], "offsets": [ [ 26, 39 ] ] }, { "pmid": "23531536", "text": "To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg-1 intraperitoneal injections.", "type": "CHEMICAL", "entities": [ "lipoic acid", "α-lipoic acid", "α-lipoic acid" ], "offsets": [ [ 182, 193 ], [ 222, 235 ], [ 37, 50 ] ] }, { "pmid": "23531536", "text": "Four healthy Wistar rats served as normal controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531536", "text": "Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured.", "type": "CHEMICAL", "entities": [ "MDA", "ascorbic acid", "vitamin C", "vitamin E", "glutathione", "GSH", "superoxide" ], "offsets": [ [ 11, 14 ], [ 17, 30 ], [ 32, 41 ], [ 44, 53 ], [ 55, 66 ], [ 68, 71 ], [ 77, 87 ] ] }, { "pmid": "23531536", "text": "The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 30, 35 ] ] }, { "pmid": "23531536", "text": "Pathological changes in renal tissue were evaluated by light and electron microscopy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531536", "text": "There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group.", "type": "CHEMICAL", "entities": [ "MDA", "GSH", "vitamin C", "vitamin E" ], "offsets": [ [ 56, 59 ], [ 154, 157 ], [ 164, 173 ], [ 178, 187 ] ] }, { "pmid": "23531536", "text": "Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531536", "text": "All the parameters above were improved in the α-lipoic acid-treated diabetic group.", "type": "CHEMICAL", "entities": [ "α-lipoic acid" ], "offsets": [ [ 40, 53 ] ] }, { "pmid": "23531536", "text": "Oxidative stress is increased in the kidney of type 2 diabetic GK rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531536", "text": "It is associated with the progression of diabetic nephropathy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23531536", "text": "α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23287538", "text": "Alcohol intoxications during adolescence increase motivation for alcohol in adult rats and induce neuroadaptations in the nucleus accumbens.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23287538", "text": "Adolescent alcohol binge drinking constitutes a major vulnerability factor to develop alcoholism.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23287538", "text": "However, mechanisms underlying this susceptibility remain unknown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23287538", "text": "We evaluated the effect of adolescent binge-like ethanol intoxication on vulnerability to alcohol abuse in Sprague-Dawley rats.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "23287538", "text": "To model binge-like ethanol intoxication, every 2 days, rats received an ethanol injection (3.0 g/kg) for 2 consecutive days across 14 days either from postnatal day 30 (PND30) to 43 (early adolescence) or from PND 45 to PND 58 (late adolescence).", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 20, 27 ], [ 73, 80 ] ] }, { "pmid": "23287538", "text": "In young adult animals, we measured free ethanol consumption in the two-bottle choice paradigm, motivation for ethanol in the operant self-administration task and both ethanol's rewarding and aversive properties in the conditioned place preference (CPP) and taste aversion (CTA) paradigms.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "ethanol" ], "offsets": [ [ 40, 47 ], [ 110, 117 ], [ 167, 174 ] ] }, { "pmid": "23287538", "text": "While intermittent ethanol intoxications (IEI) during late adolescence had no effect on free-choice 10% ethanol consumption, we found that IEI during early adolescence promoted free-choice 10% ethanol consumption, enhanced motivation for ethanol in the self-administration paradigm and induced a loss of both ethanol-induced CPP and CTA in young adults.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "ethanol", "ethanol", "ethanol" ], "offsets": [ [ 192, 199 ], [ 237, 244 ], [ 308, 315 ], [ 18, 25 ], [ 103, 110 ] ] }, { "pmid": "23287538", "text": "No modification in either sucrose self-administration or amphetamine-induced CPP was observed.", "type": "CHEMICAL", "entities": [ "sucrose", "amphetamine" ], "offsets": [ [ 25, 32 ], [ 56, 67 ] ] }, { "pmid": "23287538", "text": "As the nucleus accumbens (Nac) is particularly involved in addictive behavior, we analyzed IEI-induced long-term neuroadaptations in the Nac using c-Fos immunohistochemistry and an array of neurotransmission-related genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23287538", "text": "This vulnerability to ethanol abuse was associated with a lower c-Fos immunoreactivity in the Nac and enduring alterations of the expression of Penk and Slc6a4, 2 neurotransmission-related genes that have been shown to play critical roles in the behavioral effects of ethanol and alcoholism.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 21, 28 ], [ 267, 274 ] ] }, { "pmid": "23160530", "text": "Gliotransmission and brain glucose sensing: critical role of endozepines.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 27, 34 ] ] }, { "pmid": "23160530", "text": "Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 13, 20 ], [ 91, 98 ] ] }, { "pmid": "23160530", "text": "Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor.", "type": "CHEMICAL", "entities": [ "Diazepam" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23160530", "text": "Therefore, we investigated the involvement of endozepines in brain glucose sensing.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "23160530", "text": "First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 64, 71 ] ] }, { "pmid": "23160530", "text": "We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 26, 33 ] ] }, { "pmid": "23160530", "text": "Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 87, 94 ] ] }, { "pmid": "23160530", "text": "Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23160530", "text": "The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 149, 156 ], [ 47, 54 ] ] }, { "pmid": "23160530", "text": "Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 56, 63 ], [ 143, 150 ] ] }, { "pmid": "23160530", "text": "Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "10411647", "text": "Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection.\n", "type": "CHEMICAL", "entities": [ "Tyrosine", "tetrahydrobiopterin" ], "offsets": [ [ 0, 8 ], [ 27, 46 ] ] }, { "pmid": "10411647", "text": "Kinetic studies of tetrameric recombinant human tyrosine hydroxylase isoform 1 (hTH1) have revealed properties so far not reported for this enzyme.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 48, 56 ] ] }, { "pmid": "10411647", "text": "Firstly, with the natural cofactor (6R)-Lerythro-5,6,7, 8-tetrahydrobiopterin (H4biopterin) a time-dependent change (burst) in enzyme activity was observed, with a half-time of about 20 s for the kinetic transient.", "type": "CHEMICAL", "entities": [ "(6R)-Lerythro-5,6,7, 8-tetrahydrobiopterin", "H4biopterin" ], "offsets": [ [ 35, 77 ], [ 79, 90 ] ] }, { "pmid": "10411647", "text": "Secondly, nonhyperbolic saturation behaviour was found for H4biopterin with a pronounced negative cooperativity (0.39 < h < 0.58; [S]0.5 = 24 +/- 4 microM).", "type": "CHEMICAL", "entities": [ "H4biopterin" ], "offsets": [ [ 59, 70 ] ] }, { "pmid": "10411647", "text": "On phosphorylation of Ser40 by protein kinase A, the affinity for H4biopterin increased ([S]0.5 = 11 +/- 2 microM) and the negative cooperativity was amplified (h = 0.27 +/- 0.03).", "type": "CHEMICAL", "entities": [ "Ser40", "H4biopterin" ], "offsets": [ [ 22, 27 ], [ 66, 77 ] ] }, { "pmid": "10411647", "text": "The dimeric C-terminal deletion mutant (Delta473-528) of hTH1 also showed negative cooperativity of H4biopterin binding (h = 0.4).", "type": "CHEMICAL", "entities": [ "C", "H4biopterin" ], "offsets": [ [ 12, 13 ], [ 100, 111 ] ] }, { "pmid": "10411647", "text": "Cooperativity was not observed with the cofactor analogues 6-methyl-5,6,7,8-tetrahydropterin (h = 0.9 +/- 0.1; Km = 62.7 +/- 5.7 microM) and 3-methyl-5,6,7, 8-tetrahydropterin (H43-methyl-pterin)(h = 1.0 +/- 0.1;", "type": "CHEMICAL", "entities": [ "H43-methyl-pterin", "6-methyl-5,6,7,8-tetrahydropterin", "3-methyl-5,6,7, 8-tetrahydropterin" ], "offsets": [ [ 177, 194 ], [ 59, 92 ], [ 141, 175 ] ] }, { "pmid": "10411647", "text": "Km = 687 +/- 50 microM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10411647", "text": "In the presence of 1 mM H43-methyl-pterin, used as a competitive cofactor analogue to BH4, hyperbolic saturation curves were also found for H4biopterin (h = 1.0), thus confirming the genuine nature of the kinetic negative cooperativity.", "type": "CHEMICAL", "entities": [ "H43-methyl-pterin", "H4biopterin" ], "offsets": [ [ 24, 41 ], [ 140, 151 ] ] }, { "pmid": "10411647", "text": "This cooperativity was confirmed by real-time biospecific interaction analysis by surface plasmon resonance detection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10411647", "text": "The equilibrium binding of H4biopterin to the immobilized iron-free apoenzyme results in a saturable positive resonance unit (DeltaRU) response with negative cooperativity (h = 0.52-0.56).", "type": "CHEMICAL", "entities": [ "H4biopterin" ], "offsets": [ [ 27, 38 ] ] }, { "pmid": "10411647", "text": "Infrared spectroscopic studies revealed a reduced thermal stability both of the apo-and the holo-hTH1 on binding of H4biopterin and Lerythro-dihydrobiopterin (H2biopterin).", "type": "CHEMICAL", "entities": [ "H4biopterin", "Lerythro-dihydrobiopterin", "H2biopterin" ], "offsets": [ [ 116, 127 ], [ 132, 157 ], [ 159, 170 ] ] }, { "pmid": "10411647", "text": "Moreover, the ligand-bound forms of the enzyme also showed a decreased resistance to limited tryptic proteolysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10411647", "text": "These findings indicate that the binding of H4biopterin at the active site induces a destabilizing conformational change in the enzyme which could be related to the observed negative cooperativity.", "type": "CHEMICAL", "entities": [ "H4biopterin" ], "offsets": [ [ 44, 55 ] ] }, { "pmid": "10411647", "text": "Thus, our studies provide new insight into the regulation of TH by the concentration of H4biopterin which may have significant implications for the physiological regulation of catecholamine biosynthesis in neuroendocrine cells.", "type": "CHEMICAL", "entities": [ "H4biopterin", "catecholamine" ], "offsets": [ [ 88, 99 ], [ 176, 189 ] ] }, { "pmid": "12167567", "text": "Disposition of a specific cyclooxygenase-2 inhibitor, valdecoxib, in human.\n", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "12167567", "text": "Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain.", "type": "CHEMICAL", "entities": [ "Valdecoxib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12167567", "text": "Eight male human subjects each received a single 50-mg oral dose of [(14)C]valdecoxib.", "type": "CHEMICAL", "entities": [ "[(14)C]valdecoxib" ], "offsets": [ [ 68, 85 ] ] }, { "pmid": "12167567", "text": "Urine, feces, and blood samples were collected after administration of the radioactive dose.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12167567", "text": "Most of the radioactivity in plasma was associated with valdecoxib and the hydroxylated metabolite of valdecoxib (M1).", "type": "CHEMICAL", "entities": [ "valdecoxib", "valdecoxib" ], "offsets": [ [ 56, 66 ], [ 102, 112 ] ] }, { "pmid": "12167567", "text": "The estimated terminal half-life for valdecoxib was about 7 h. About 76.1% of the radioactive dose was recovered in urine and 18% of the radioactive dose was recovered in feces.", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "12167567", "text": "Valdecoxib was extensively metabolized in human, and nine phase I metabolites were identified.", "type": "CHEMICAL", "entities": [ "Valdecoxib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12167567", "text": "The primary oxidative metabolic pathways of valdecoxib involved hydroxylation at either the methyl group to form M1 or N-hydroxylation at the sulfonamide moiety to form M2.", "type": "CHEMICAL", "entities": [ "valdecoxib", "methyl", "N", "sulfonamide" ], "offsets": [ [ 44, 54 ], [ 92, 98 ], [ 119, 120 ], [ 142, 153 ] ] }, { "pmid": "12167567", "text": "Further oxidation of M1 led to the formation of several other phase I metabolites.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12167567", "text": "Oxidative breakdown of the N-hydroxy sulfonamide function group in M2 led to the formation of corresponding sulfinic acid and sulfonic acid metabolites.", "type": "CHEMICAL", "entities": [ "N-hydroxy sulfonamide", "sulfinic acid", "sulfonic acid" ], "offsets": [ [ 27, 48 ], [ 108, 121 ], [ 126, 139 ] ] }, { "pmid": "12167567", "text": "The O-glucuronide conjugate of M1 and N-glucuronide conjugate of valdecoxib were the major urinary metabolites, which accounted for 23.3 and 19.5% of the total administered dose, respectively.", "type": "CHEMICAL", "entities": [ "O-glucuronide", "N-glucuronide", "valdecoxib" ], "offsets": [ [ 4, 17 ], [ 38, 51 ], [ 65, 75 ] ] }, { "pmid": "12167567", "text": "The remaining urinary metabolites were glucuronide conjugates of other phase I metabolites.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12167567", "text": "Only 3% of the administered dose was recovered in urine as unchanged parent, suggesting that renal clearance is insignificant for valdecoxib.", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 130, 140 ] ] }, { "pmid": "12167567", "text": "Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <", "type": "CHEMICAL", "entities": [ "valdecoxib", "valdecoxib" ], "offsets": [ [ 14, 24 ], [ 71, 81 ] ] }, { "pmid": "12167567", "text": "1% of the administered dose.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "Hepatitis B virus (HBV) is implicated in liver cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBV-positive and HBV-negative human hepatocellular carcinoma (HCC) cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23444429", "text": "However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair.", "type": "CHEMICAL", "entities": [ "poly(ADP-ribose)" ], "offsets": [ [ 82, 98 ] ] }, { "pmid": "23444429", "text": "These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment.-Chung, Y.-L. Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "Effects of labor and delivery on fibrinolysis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "Because timing of sampling is crucial in an investigation of the effects of labor and delivery on fibrinolysis we conducted a study of fibrinolytic markers in plasma of 10 healthy multiparous women in whom labor was induced, which allowed standardization of sampling times in relation to the course of labor and delivery.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "Blood samples were taken 5 min before the start of oxytocin infusion, at full cervical dilatation, and within 5 min after delivery of the placenta.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "7958159", "text": "A sample of mixed free flowing cord blood was obtained after delivery with the placenta in situ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "Variables determined were tissue-type plasminogen-activator (t-PA) and the plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "The only significant change between the beginning of the induction of labor and the end of the first stage of labor was a rise in t-PA antigen (P = 0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "All variables, except PAI-2 antigen, changed significantly after delivery of the placenta: t-PA antigen and activity showed a rise (P < 0.05), accompanied by a fall in PAI-1 antigen and activity (P < 0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "T-PA activity in cord plasma was higher (P < 0.01) in comparison with maternal plasma concentrations at the end of the first stage of labor, t-PA antigen levels were similar, and PAI-1 antigen and activity and PAI-2 antigen were lower in cord plasma (P < 0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7958159", "text": "Our study shows that activation of the maternal fibrinolytic system can already be detected during labor, with a marked further increase in fibrinolytic potential after placental separation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Toxicity and toxicokinetics of binary combinations of petroleum hydrocarbon distillates with the earthworm Eisenia andrei.\n", "type": "CHEMICAL", "entities": [ "petroleum hydrocarbon" ], "offsets": [ [ 54, 75 ] ] }, { "pmid": "23401139", "text": "Petroleum hydrocarbons (PHCs) act via narcosis and are expected to have additive toxicity.", "type": "CHEMICAL", "entities": [ "Petroleum hydrocarbons", "PHCs" ], "offsets": [ [ 0, 22 ], [ 24, 28 ] ] }, { "pmid": "23401139", "text": "However, previous work has demonstrated less-than-additive toxicity with PHC distillates and earthworms.", "type": "CHEMICAL", "entities": [ "PHC" ], "offsets": [ [ 73, 76 ] ] }, { "pmid": "23401139", "text": "A study was initiated to investigate this through toxicity and toxicokinetic studies with the earthworm Eisenia andrei.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Three petroleum distillate fractions, F2 (>C10-C16), F3a (>C16-C23), and F3b (>C23-C34), were used in two binary combinations, F2F3a and F3aF3b.", "type": "CHEMICAL", "entities": [ "C10-C16", "C16-C23", "C23-C34" ], "offsets": [ [ 43, 50 ], [ 59, 66 ], [ 79, 86 ] ] }, { "pmid": "23401139", "text": "In the toxicity study, clean soil was spiked with equitoxic combinations of the two distillates ranging from 0.5 to 2.5 toxic units.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "In the toxicokinetic study, a binary combination consisting of one concentration of each distillate was used.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "On a soil concentration basis, the toxicity of the binary combinations of distillates was less than additive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Accumulation of the individual distillates, however, was generally reduced when a second distillate was present, resulting in lower body burden.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "This is thought to be due to the presence of a nonaqueous-phase liquid at the soil concentrations used.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "On a tissue concentration basis, toxicity was closer to additive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "The results demonstrate that tissue concentrations are the preferred metric for toxicity for earthworms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "They also demonstrate that the Canada-wide soil standards based on individual distillates are likely protective.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Environ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Toxicol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "Chem.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "2013;32:1016-1026.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23401139", "text": "© 2013 SETAC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23381951", "text": "Pharmacogenetics of Allopurinol-Making an Old Drug Safer.\n", "type": "CHEMICAL", "entities": [ "Allopurinol" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "23381951", "text": "Allopurinol is a drug that has been used for decades to lower serum urate levels in patients with gout or chronic renal failure and in cancer patients undergoing chemotherapy at risk of tumor lysis syndrome.", "type": "CHEMICAL", "entities": [ "Allopurinol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23381951", "text": "Patients may develop cutaneous hypersensitivity reactions, ranging from mild rashes to potentially fatal severe cutaneous adverse reactions (SCARs) namely drug hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23381951", "text": "Recent studies have demonstrated the association between human leukocyte antigen (HLA) B*58:01 allele and allopurinol-induced SCARs, which might explain ethnic differences in their incidences.", "type": "CHEMICAL", "entities": [ "allopurinol" ], "offsets": [ [ 106, 117 ] ] }, { "pmid": "23381951", "text": "Genotyping is now required before starting abacavir and carbamazepine so as to identify individuals susceptible to SJS.", "type": "CHEMICAL", "entities": [ "abacavir", "carbamazepine" ], "offsets": [ [ 43, 51 ], [ 56, 69 ] ] }, { "pmid": "23381951", "text": "However, no genetic screening is advocated before commencement of allopurinol.", "type": "CHEMICAL", "entities": [ "allopurinol" ], "offsets": [ [ 66, 77 ] ] }, { "pmid": "23381951", "text": "The lack of availability of a rapid and inexpensive screening test for the HLA-B*58:01 allele is one of the obstacles to such screening.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23381951", "text": "Development of a test that is quick, accurate, and cost-effective is warranted.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22619007", "text": "Silibinin triggers apoptosis and cell-cycle arrest of SGC7901 cells.\n", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22619007", "text": "Silibinin, a flavonoid compound, has shown to be of chemopreventive potential against many cancers.", "type": "CHEMICAL", "entities": [ "Silibinin", "flavonoid" ], "offsets": [ [ 0, 9 ], [ 13, 22 ] ] }, { "pmid": "22619007", "text": "However, its efficacy against gastric cancer has not been well elucidated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22619007", "text": "Here, we assessed the activity of Silibinin on apoptosis and cell-cycle arrest in human gastric cells culture system using SGC-7901 as the model.", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "22619007", "text": "Silibinin treatment could inhibit the cell growth and cause a prominent G2 phase arrest and apoptosis in dose- and time-dependent manner.", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22619007", "text": "In mechanistic studies, Silibinin decreased the protein level of p34cdc2, which might be the possible molecular mechanism of Silibinin efficacy on the growth inhibition in SGC-7901 cells.", "type": "CHEMICAL", "entities": [ "Silibinin", "Silibinin" ], "offsets": [ [ 24, 33 ], [ 125, 134 ] ] }, { "pmid": "22619007", "text": "In addition, Silibinin caused an increase in p53 and p21 protein level as well as mRNA levels.", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "22619007", "text": "Interestingly, Silibinin-induced apoptosis in SGC-7901 cells was independent of caspases activation.", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "22619007", "text": "These results indicated that Silibinin is a cell-cycle regulator and apoptosis inducer in human gastric carcinoma SGC-7901 cells and might be used as a candidate chemopreventive agent for gastric carcinoma prevention and intervention.", "type": "CHEMICAL", "entities": [ "Silibinin" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "22619007", "text": "Copyright © 2012 John Wiley & Sons, Ltd.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23246732", "text": "Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus.\n", "type": "CHEMICAL", "entities": [ "methyl cytosine" ], "offsets": [ [ 85, 100 ] ] }, { "pmid": "23246732", "text": "Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood.", "type": "CHEMICAL", "entities": [ "Pb" ], "offsets": [ [ 32, 34 ] ] }, { "pmid": "23246732", "text": "Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23246732", "text": "Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine-binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus.", "type": "CHEMICAL", "entities": [ "methyl cytosine", "Pb" ], "offsets": [ [ 65, 80 ], [ 153, 155 ] ] }, { "pmid": "23246732", "text": "Long Evans dams were fed chow with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and remained on the same diet through weaning (perinatal exposure group).", "type": "CHEMICAL", "entities": [ "Pb acetate" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "23246732", "text": "Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group).", "type": "CHEMICAL", "entities": [ "Pb" ], "offsets": [ [ 48, 50 ] ] }, { "pmid": "23246732", "text": "All animals were euthanized on day 55 and hippocampi were removed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23246732", "text": "Western blot analyses showed significant effects of Pb exposure on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and modified by sex and developmental window of Pb exposure.", "type": "CHEMICAL", "entities": [ "Pb", "Pb" ], "offsets": [ [ 52, 54 ], [ 208, 210 ] ] }, { "pmid": "23246732", "text": "These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases.", "type": "CHEMICAL", "entities": [ "Pb" ], "offsets": [ [ 65, 67 ] ] }, { "pmid": "18633030", "text": "Synergy between pairs of competitive antagonists at adult human muscle acetylcholine receptors.\n", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 71, 84 ] ] }, { "pmid": "18633030", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "Synergistic neuromuscular blocking effects have been observed clinically with certain pairs of nicotinic acetylcholine receptor (nAChR) competitive antagonists.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 105, 118 ] ] }, { "pmid": "18633030", "text": "The mechanism for synergy has not been elucidated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We tested the hypothesis that synergy arises from a differential selectivity of antagonists for the two ligand binding sites on adult human nAChR. METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We expressed nAChR in BOSC23 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We applied ACh with or without antagonists to outside-out patches and measured macroscopic currents at room temperature.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We determined the IC(90) for (+)-tubocurarine, metocurine, pancuronium, vecuronium, cisatracurium, rocuronium, and atracurium.", "type": "CHEMICAL", "entities": [ "(+)-tubocurarine", "metocurine", "pancuronium", "vecuronium", "cisatracurium", "rocuronium", "atracurium" ], "offsets": [ [ 29, 45 ], [ 47, 57 ], [ 59, 70 ], [ 72, 82 ], [ 84, 97 ], [ 99, 109 ], [ 115, 125 ] ] }, { "pmid": "18633030", "text": "For 15 combinations of two antagonists, we determined the IC(90) for one antagonist in the presence of the IC(70) of a second antagonist.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We constructed isobolograms for 90% inhibition.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "For single antagonists, we measured inhibition of receptors containing mutations in the epsilon- and delta-subunits to determine site selectivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "Two pairs of antagonists, metocurine+cisatracurium and cisatracurium+ atracurium exhibited additive inhibition.", "type": "CHEMICAL", "entities": [ "metocurine", "cisatracurium", "cisatracurium", "atracurium" ], "offsets": [ [ 26, 36 ], [ 37, 50 ], [ 55, 68 ], [ 70, 80 ] ] }, { "pmid": "18633030", "text": "Ten combinations, including (+)-tubocurarine+ pancuronium and pancuronium+vecuronium, were highly synergistic such that the combination was two to three times more effective than expected for additivity.", "type": "CHEMICAL", "entities": [ "(+)-tubocurarine", "pancuronium", "pancuronium", "vecuronium" ], "offsets": [ [ 28, 44 ], [ 46, 57 ], [ 62, 73 ], [ 74, 84 ] ] }, { "pmid": "18633030", "text": "Three combinations were 1.5-1.6 times more effective than expected for additivity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "Inhibition by (+)-tubocurarine and metocurine was sensitive to mutations in the epsilon-subunit only.", "type": "CHEMICAL", "entities": [ "(+)-tubocurarine", "metocurine" ], "offsets": [ [ 14, 30 ], [ 35, 45 ] ] }, { "pmid": "18633030", "text": "Vecuronium was affected by the delta-subunit mutation only.", "type": "CHEMICAL", "entities": [ "Vecuronium" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18633030", "text": "Inhibition by other antagonists was decreased by mutations in either subunit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "CONCLUSIONS: Many combinations of antagonists exhibited synergistic effects on adult human nAChR. Synergy was observed with structurally similar and dissimilar antagonists.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "The degree of synergy did not always correlate well with site specificity assayed with mutants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "In some, but not all cases, the synergy at the receptor level correlated with clinical determinations of synergy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18633030", "text": "We conclude that the synergistic actions of muscle relaxants can be partially explained by direct interactions with adult human nAChR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22659088", "text": "The interaction between mGluR1 and the calcium channel Cav₂.₁ preserves coupling in the presence of long Homer proteins.\n", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 39, 46 ] ] }, { "pmid": "22659088", "text": "Group I metabotropic glutamate receptors (mGluR1 and 5) are G protein coupled receptors that regulate neuronal activity in a number of ways.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "22659088", "text": "Some of the most well studied functions of group I mGluRs, such as initiation of multiple forms of mGluR-dependent long-term depression, require receptor localization near the post-synaptic density (PSD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22659088", "text": "This localization is in turn dependent on the Homer family of scaffolding proteins which bind to a small motif on the distal C-termini of mGluR1 and 5, localize the receptors near the PSD, strengthen coupling to post-synaptic effectors and simultaneously uncouple the mGluRs from extra-synaptic effectors such as voltage dependent ion channels.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 121, 122 ] ] }, { "pmid": "22659088", "text": "Here the selectivity of this uncoupling process was examined by testing the ability of Homer-2b to uncouple mGluR1 from multiple voltage dependent calcium channels including Ca(V2.2) (N-type), Ca(V3.2) (T-type), and Ca(V2.1) (P/Q-type) expressed in rat sympathetic neurons from the superior cervical ganglion (SCG).", "type": "CHEMICAL", "entities": [ "calcium", "Ca", "Ca", "Ca" ], "offsets": [ [ 143, 150 ], [ 170, 172 ], [ 189, 191 ], [ 212, 214 ] ] }, { "pmid": "22659088", "text": "Of these, only the mGluR1-Ca(V2.1) modulatory pathway was insensitive to Homer-2b expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22659088", "text": "Uncoupling from this channel was achieved by co-expression of an mGluR1 C-terminal protein designed to disrupt a previously described direct interaction between these two proteins, suggesting that this interaction allows incorporation of Ca(V2.1) into the mGluR1/Homer signaling complex, thereby preserving modulation in the presence of scaffolding Homer proteins.", "type": "CHEMICAL", "entities": [ "C", "Ca" ], "offsets": [ [ 68, 69 ], [ 234, 236 ] ] }, { "pmid": "22659088", "text": "This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.", "type": "CHEMICAL", "entities": [ "Glutamate" ], "offsets": [ [ 59, 68 ] ] }, { "pmid": "17553661", "text": "Transfection of HepG2 cells with hGSTA4 provides protection against 4-hydroxynonenal-mediated oxidative injury.\n", "type": "CHEMICAL", "entities": [ "4-hydroxynonenal" ], "offsets": [ [ 68, 84 ] ] }, { "pmid": "17553661", "text": "4-Hydroxynonenal (4-HNE) is a mutagenic alpha,beta-unsaturated aldehyde produced during oxidative injury that is conjugated by several glutathione S-transferase (GST) isoforms.", "type": "CHEMICAL", "entities": [ "4-Hydroxynonenal", "glutathione", "S", "4-HNE", "alpha,beta-unsaturated aldehyde" ], "offsets": [ [ 0, 16 ], [ 135, 146 ], [ 147, 148 ], [ 18, 23 ], [ 40, 71 ] ] }, { "pmid": "17553661", "text": "The alpha class human GSTA4-4 enzyme (hGSTA4-4) has a particularly high catalytic efficiency toward 4-HNE conjugation.", "type": "CHEMICAL", "entities": [ "4-HNE" ], "offsets": [ [ 100, 105 ] ] }, { "pmid": "17553661", "text": "However, hGST4-4 expression is low in most human cells and there are other aldehyde metabolizing enzymes that detoxify 4-HNE.", "type": "CHEMICAL", "entities": [ "aldehyde", "4-HNE" ], "offsets": [ [ 75, 83 ], [ 119, 124 ] ] }, { "pmid": "17553661", "text": "In the current study, we determined the effect of over-expression of hGSTA4 mRNA on the sensitivity of HepG2 cells to 4-HNE injury.", "type": "CHEMICAL", "entities": [ "4-HNE" ], "offsets": [ [ 118, 123 ] ] }, { "pmid": "17553661", "text": "HepG2 cells transfected with an hGSTA4 vector construct exhibited high steady-state hGSTA4 mRNA, high GST-4-HNE catalytic activities, but lower basal glutathione (GSH) concentrations relative to insert-free vector (control) cells.", "type": "CHEMICAL", "entities": [ "4-HNE", "glutathione", "GSH" ], "offsets": [ [ 106, 111 ], [ 150, 161 ], [ 163, 166 ] ] }, { "pmid": "17553661", "text": "Exposure to 4-HNE elicited an increase in GSH concentrations in the control and hGSTA4 cells, although the dose-response of GSH induction differed among the two cell types.", "type": "CHEMICAL", "entities": [ "4-HNE", "GSH", "GSH" ], "offsets": [ [ 12, 17 ], [ 42, 45 ], [ 124, 127 ] ] }, { "pmid": "17553661", "text": "Specifically, hGSTA4 cells had significantly higher GSH concentrations when exposed to 5-15 microM 4-HNE, but not at 20 microM 4-HNE, suggesting extensive GSH utilization at high concentrations of 4-HNE.", "type": "CHEMICAL", "entities": [ "GSH", "4-HNE", "4-HNE", "GSH", "4-HNE" ], "offsets": [ [ 52, 55 ], [ 99, 104 ], [ 127, 132 ], [ 155, 158 ], [ 197, 202 ] ] }, { "pmid": "17553661", "text": "The hGSTA4 cells exhibited a significant growth advantage relative to control cells in the absence of 4-HNE, and a trend towards increased growth at low dose exposures to 4-HNE.", "type": "CHEMICAL", "entities": [ "4-HNE", "4-HNE" ], "offsets": [ [ 102, 107 ], [ 171, 176 ] ] }, { "pmid": "17553661", "text": "However, the hGSTA4 cells did not exhibit a growth advantage relative to control cells at higher 4-HNE exposures associated with increased GSH utilization.", "type": "CHEMICAL", "entities": [ "4-HNE", "GSH" ], "offsets": [ [ 97, 102 ], [ 139, 142 ] ] }, { "pmid": "17553661", "text": "As expected, the hGSTA4 cells showed resistance to 4-HNE stimulated lipid peroxidation at all 4-HNE doses.", "type": "CHEMICAL", "entities": [ "4-HNE", "4-HNE" ], "offsets": [ [ 51, 56 ], [ 94, 99 ] ] }, { "pmid": "17553661", "text": "In summary, our data indicates that over-expression of hGSTA4 at levels conferring high GST-4-HNE conjugating activity confers a partial growth advantage to HepG2 cells and protects against 4-HNE oxidative injury.", "type": "CHEMICAL", "entities": [ "4-HNE", "4-HNE" ], "offsets": [ [ 92, 97 ], [ 190, 195 ] ] }, { "pmid": "17553661", "text": "However, the loss of proliferative capacity of hGSTA4 cells challenged with levels of 4-HNE associated with severe oxidative stress indicates a role of other aldehyde metabolizing enzymes, and/or GSH-electrophile transporter proteins, in providing full cellular protection against 4-HNE toxicity.", "type": "CHEMICAL", "entities": [ "4-HNE", "aldehyde", "GSH", "4-HNE" ], "offsets": [ [ 86, 91 ], [ 158, 166 ], [ 196, 199 ], [ 281, 286 ] ] }, { "pmid": "12582227", "text": "DRF 2655: a unique molecule that reduces body weight and ameliorates metabolic abnormalities.\n", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12582227", "text": "OBJECTIVE: Preclinical evaluation of DRF 2655, a peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma agonist, as a body-weight lowering, hypolipidemic and euglycemic agent.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "12582227", "text": "RESEARCH METHODS AND PROCEDURES:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12582227", "text": "DRF 2655 was studied in different genetic, normal, and hyperlipidemic animal models.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12582227", "text": "HEK 293 cells were used to conduct the reporter-based transactivation of PPARalpha and PPARgamma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12582227", "text": "To understand the biochemical mechanism of lipid-, body-weight-, and glucose-lowering effects, activities of key beta-oxidation and lipid catabolism enzymes and gluconeogenic enzymes were studied in db/db mice treated with DRF 2655.", "type": "CHEMICAL", "entities": [ "glucose", "DRF 2655" ], "offsets": [ [ 69, 76 ], [ 223, 231 ] ] }, { "pmid": "12582227", "text": "3T3L1 cells were used for adipogenesis study, and HepG2 cells were used to study the effect of DRF 2655 on total cholesterol and triglyceride synthesis using [(14)C]acetate and", "type": "CHEMICAL", "entities": [ "DRF 2655", "cholesterol", "triglyceride", "[(14)C]acetate" ], "offsets": [ [ 95, 103 ], [ 113, 124 ], [ 129, 141 ], [ 158, 172 ] ] }, { "pmid": "12582227", "text": "[(3)H]glycerol.", "type": "CHEMICAL", "entities": [ "[(3)H]glycerol" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "12582227", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12582227", "text": "DRF 2655 showed concentration-dependent transactivation of PPARalpha and PPARgamma.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12582227", "text": "In the 3T3L1 cell-differentiation study, DRF 2655 and rosiglitazone showed 369% and 471% increases, respectively, in triglyceride accumulation.", "type": "CHEMICAL", "entities": [ "triglyceride", "DRF 2655", "rosiglitazone" ], "offsets": [ [ 117, 129 ], [ 41, 49 ], [ 54, 67 ] ] }, { "pmid": "12582227", "text": "DRF 2655 showed body-weight lowering and euglycemic and hypolipidemic effects in various animal models.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12582227", "text": "db/db mice treated with DRF 2655 showed 5- and 3.6-fold inhibition in phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity and 651% and 77% increases in the beta-oxidation enzymes carnitine palmitoyltransferase and carnitine acetyltransferase, respectively.", "type": "CHEMICAL", "entities": [ "DRF 2655", "phosphoenolpyruvate", "glucose", "carnitine", "carnitine" ], "offsets": [ [ 24, 32 ], [ 70, 89 ], [ 108, 115 ], [ 196, 205 ], [ 231, 240 ] ] }, { "pmid": "12582227", "text": "HepG2 cells treated with DRF 2655 showed significant reduction in lipid synthesis.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "12582227", "text": "DISCUSSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12582227", "text": "DRF 2655 showed excellent euglycemic and hypolipidemic activities in different animal models.", "type": "CHEMICAL", "entities": [ "DRF 2655" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12582227", "text": "An exciting finding is its body-weight lowering effect in these models, which might be mediated by the induction of target enzymes involved in hepatic lipid catabolism through PPARalpha activation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7832763", "text": "Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7832763", "text": "The enzyme cyclo-oxygenase catalyses the oxygenation of arachidonic acid, leading to the formation of prostaglandins.", "type": "CHEMICAL", "entities": [ "prostaglandins", "arachidonic acid" ], "offsets": [ [ 102, 116 ], [ 56, 72 ] ] }, { "pmid": "7832763", "text": "Recently two forms of cyclo-oxygenase have been described: a constitutive (COX-1) enzyme present in most cells and tissues, and an inducible (COX-2) isoenzyme observed in many cells in response to pro-inflammatory cytokines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7832763", "text": "Constitutive and inducible forms of human cyclo-oxygenase (hCOX-1 and hCOX-2) were cloned and expressed in insect cells, utilizing a baculovirus expression system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7832763", "text": "hCOX-1 had a specific activity of 18.8 mumol of O2/mg with a Km of 13.8 microM for arachidonate and Vmax. of 1500 nmol of O2/nmol of enzyme, whereas hCOX-2 had a specific activity of 12.2 mumol of O2/mg with a Km of 8.7 microM for arachidonate and a Vmax. of 1090 nmol of O2/nmol of enzyme.", "type": "CHEMICAL", "entities": [ "O2", "arachidonate", "O2", "arachidonate", "O2" ], "offsets": [ [ 48, 50 ], [ 83, 95 ], [ 197, 199 ], [ 231, 243 ], [ 272, 274 ] ] }, { "pmid": "7832763", "text": "Indomethacin inhibited both hCOX-1 and hCOX-2, whereas NS-398 and Dup-697 selectively inhibited hCOX-2.", "type": "CHEMICAL", "entities": [ "Indomethacin", "NS-398", "Dup-697" ], "offsets": [ [ 0, 12 ], [ 55, 61 ], [ 66, 73 ] ] }, { "pmid": "7832763", "text": "Both NS-398 and Dup-697 exhibited time-dependent inactivation of hCOX-2, as did indomethacin on both enzymes.", "type": "CHEMICAL", "entities": [ "NS-398", "Dup-697", "indomethacin" ], "offsets": [ [ 5, 11 ], [ 16, 23 ], [ 80, 92 ] ] }, { "pmid": "7832763", "text": "The competitive inhibitor of hCOX-1, mefenamic acid, also displayed competitive inhibition of hCOX-2.", "type": "CHEMICAL", "entities": [ "mefenamic acid" ], "offsets": [ [ 37, 51 ] ] }, { "pmid": "7832763", "text": "These results demonstrate the ability to generate selective non-steroidal anti-inflammatory drugs (NSAIDs), which could provide useful improvement therapeutically in the treatment of chronic inflammatory disease.", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "16395286", "text": "Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation.\n", "type": "CHEMICAL", "entities": [ "tetracyclines" ], "offsets": [ [ 24, 37 ] ] }, { "pmid": "16395286", "text": "Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16395286", "text": "Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16395286", "text": "Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF).", "type": "CHEMICAL", "entities": [ "Doxycycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16395286", "text": "In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain.", "type": "CHEMICAL", "entities": [ "doxycycline", "minocycline" ], "offsets": [ [ 65, 76 ], [ 81, 92 ] ] }, { "pmid": "16395286", "text": "Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week.", "type": "CHEMICAL", "entities": [ "doxycycline", "minocycline" ], "offsets": [ [ 23, 34 ], [ 38, 49 ] ] }, { "pmid": "16395286", "text": "Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02).", "type": "CHEMICAL", "entities": [ "doxycycline" ], "offsets": [ [ 96, 107 ] ] }, { "pmid": "16395286", "text": "Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day.", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16395286", "text": "At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02).", "type": "CHEMICAL", "entities": [ "minocycline", "doxycycline" ], "offsets": [ [ 112, 123 ], [ 33, 44 ] ] }, { "pmid": "16395286", "text": "The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16395286", "text": "We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines.", "type": "CHEMICAL", "entities": [ "tetracyclines" ], "offsets": [ [ 130, 143 ] ] }, { "pmid": "16395286", "text": "In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway.", "type": "CHEMICAL", "entities": [ "minocycline", "doxycycline" ], "offsets": [ [ 10, 21 ], [ 31, 42 ] ] }, { "pmid": "16395286", "text": "This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.", "type": "CHEMICAL", "entities": [ "tetracyclines" ], "offsets": [ [ 42, 55 ] ] }, { "pmid": "12668769", "text": "Investigating the regulation of one-carbon metabolism in Arabidopsis thaliana.\n", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "12668769", "text": "Serine (Ser) biosynthesis in C(3) plants can occur via several pathways.", "type": "CHEMICAL", "entities": [ "Serine", "Ser" ], "offsets": [ [ 0, 6 ], [ 8, 11 ] ] }, { "pmid": "12668769", "text": "One major route involves the tetrahydrofolate (THF)-dependent activities of the glycine decarboxylase complex (GDC, EC 2.1.1.10) and serine hydroxymethyltransferase (SHMT, EC 2.1.2.1) with glycine (Gly) as one-carbon (1-C) source.", "type": "CHEMICAL", "entities": [ "tetrahydrofolate", "THF", "glycine", "serine", "glycine", "Gly", "carbon", "1-C" ], "offsets": [ [ 29, 45 ], [ 47, 50 ], [ 80, 87 ], [ 133, 139 ], [ 189, 196 ], [ 198, 201 ], [ 210, 216 ], [ 218, 221 ] ] }, { "pmid": "12668769", "text": "An alternative THF-dependent pathway involves the C1-THF synthase/SHMT activities with formate as 1-C source.", "type": "CHEMICAL", "entities": [ "THF", "C1", "THF", "formate", "1-C" ], "offsets": [ [ 15, 18 ], [ 50, 52 ], [ 53, 56 ], [ 87, 94 ], [ 98, 101 ] ] }, { "pmid": "12668769", "text": "Here, we have investigated aspects of the regulation of these two folate-mediated pathways in Arabidopsis thaliana (L.) Heynh.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668769", "text": "Columbia using two approaches.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12668769", "text": "Firstly, transgenic plants overexpressing formate dehydrogenase (FDH, EC 1.2.1.2) were used to continue our previous studies on the function of FDH in formate metabolism.", "type": "CHEMICAL", "entities": [ "formate", "formate" ], "offsets": [ [ 42, 49 ], [ 151, 158 ] ] }, { "pmid": "12668769", "text": "The formate pool size was approximately 73 nmol (g FW)(-1) in wild type (WT) Arabidopsis plants; three independent transgenic lines had similar-sized pools of formate.", "type": "CHEMICAL", "entities": [ "formate", "formate" ], "offsets": [ [ 4, 11 ], [ 159, 166 ] ] }, { "pmid": "12668769", "text": "Transgenic plants produced more (13)CO(2) from supplied [(13)C]formate than did WT plants but were not significantly different from WT plants in their synthesis of Ser.", "type": "CHEMICAL", "entities": [ "Ser", "(13)CO(2)", "[(13)C]formate" ], "offsets": [ [ 164, 167 ], [ 32, 41 ], [ 56, 70 ] ] }, { "pmid": "12668769", "text": "We concluded that FDH has no direct role in the regulation of the above two pathways of Ser synthesis; the breakdown of formate to CO(2) by the FDH reaction is the primary and preferred fate of the organic acid in Arabidopsis.", "type": "CHEMICAL", "entities": [ "Ser", "formate", "CO(2)" ], "offsets": [ [ 88, 91 ], [ 120, 127 ], [ 131, 136 ] ] }, { "pmid": "12668769", "text": "The ratio between the GDC/SHMT and C1-THF synthase/SHMT pathways of Ser synthesis from [alpha-(13)C]Gly and [(13)C]formate, respectively, in Arabidopsis shoots was 21 : 1; in roots, 9 : 1.", "type": "CHEMICAL", "entities": [ "C1", "THF", "Ser", "[alpha-(13)C]Gly", "[(13)C]formate" ], "offsets": [ [ 35, 37 ], [ 38, 41 ], [ 68, 71 ], [ 87, 103 ], [ 108, 122 ] ] }, { "pmid": "12668769", "text": "In shoots, therefore, the pathway from formate plays only a small role in Ser synthesis; in the case of roots, results indicated that the 9 : 1 ratio was as a result of greater fluxes of (13)C through both pathways together with a relatively higher contribution from the C1-THF synthase/SHMT route than in shoots.", "type": "CHEMICAL", "entities": [ "formate", "Ser", "(13)C", "C1", "THF" ], "offsets": [ [ 39, 46 ], [ 74, 77 ], [ 187, 192 ], [ 271, 273 ], [ 274, 277 ] ] }, { "pmid": "12668769", "text": "We also examined the synthesis of Ser in a GDC-deficient mutant of Arabidopsis (glyD) where the GDC/SHMT pathway was impaired.", "type": "CHEMICAL", "entities": [ "Ser", "glyD" ], "offsets": [ [ 34, 37 ], [ 80, 84 ] ] }, { "pmid": "12668769", "text": "Compared with WT, glyD plants accumulated 5-fold more Gly than WT after supplying [alpha-(13)C]Gly for 24 h; the accumulation of Ser from [alpha-(13)C]Gly was reduced by 25% in the same time period.", "type": "CHEMICAL", "entities": [ "glyD", "Gly", "[alpha-(13)C]Gly", "Ser", "[alpha-(13)C]Gly" ], "offsets": [ [ 18, 22 ], [ 54, 57 ], [ 82, 98 ], [ 129, 132 ], [ 138, 154 ] ] }, { "pmid": "12668769", "text": "On the other hand, the accumulation of Ser through the C1-THF synthase/SHMT pathway in glyD plants was 2.5-fold greater than that in WT plants.", "type": "CHEMICAL", "entities": [ "Ser", "C1", "THF", "glyD" ], "offsets": [ [ 39, 42 ], [ 55, 57 ], [ 58, 61 ], [ 87, 91 ] ] }, { "pmid": "12668769", "text": "Our experiments confirmed that the GDC/SHMT and C1-THF synthase/SHMT pathways normally operate independently in Arabidopsis plants but that when the primary GDC/SHMT pathway is impaired the alternative C1-THF synthase/SHMT pathway can partially compensate for deficiencies in the synthesis of Ser.", "type": "CHEMICAL", "entities": [ "C1", "THF", "C1", "THF", "Ser" ], "offsets": [ [ 48, 50 ], [ 51, 54 ], [ 202, 204 ], [ 205, 208 ], [ 293, 296 ] ] }, { "pmid": "19244097", "text": "Studies of the biogenic amine transporters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19244097", "text": "13.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19244097", "text": "Identification of \"agonist\" and \"antagonist\" allosteric modulators of amphetamine-induced dopamine release.\n", "type": "CHEMICAL", "entities": [ "amphetamine", "dopamine" ], "offsets": [ [ 70, 81 ], [ 90, 98 ] ] }, { "pmid": "19244097", "text": "Recent studies identified novel allosteric modulators of the dopamine (DA) transporter (DAT).", "type": "CHEMICAL", "entities": [ "dopamine", "DA" ], "offsets": [ [ 61, 69 ], [ 71, 73 ] ] }, { "pmid": "19244097", "text": "N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine (SoRI-9804), N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine (SoRI-20040), and N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine (SoRI-20041) partially inhibited [(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [(125)I]RTI-55 from the DAT, and partially inhibited [(3)H]dopamine uptake.", "type": "CHEMICAL", "entities": [ "SoRI-9804", "N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine", "SoRI-20040", "N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine", "SoRI-20041", "[(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester", "RTI-55", "[(125)I]RTI-55", "[(3)H]dopamine", "N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine" ], "offsets": [ [ 47, 56 ], [ 59, 107 ], [ 109, 119 ], [ 126, 175 ], [ 177, 187 ], [ 209, 279 ], [ 281, 287 ], [ 330, 344 ], [ 383, 397 ], [ 0, 45 ] ] }, { "pmid": "19244097", "text": "In the present study, we report that SoRI-9804 and SoRI-20040, at doses that do not alter release, partially inhibited d-amphetamine-induced DAT-mediated release of [(3)H]1-methyl-4-phenylpyridinium (MPP(+))or[(3)H]dopamine from striatal synaptosomes (\"DAT-mediated DA release\") in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "SoRI-9804", "SoRI-20040", "d-amphetamine", "[(3)H]1-methyl-4-phenylpyridinium", "MPP(+)", "[(3)H]dopamine", "DA" ], "offsets": [ [ 37, 46 ], [ 51, 61 ], [ 119, 132 ], [ 165, 198 ], [ 200, 206 ], [ 209, 223 ], [ 266, 268 ] ] }, { "pmid": "19244097", "text": "SoRI-20041, which does not alter DAT-mediated DA release measured with [(3)H]DA, reversed the effect of SoRI-20040.", "type": "CHEMICAL", "entities": [ "SoRI-20041", "DA", "[(3)H]DA", "SoRI-20040" ], "offsets": [ [ 0, 10 ], [ 46, 48 ], [ 71, 79 ], [ 104, 114 ] ] }, { "pmid": "19244097", "text": "SoRI-20040 and SoRI-9804 also partially inhibited DAT-mediated DA release induced by DA or (+/-)-3,4-methylenedioxyamphetamine, demonstrating that the observed partial inhibition is not specific for a particular DAT substrate.", "type": "CHEMICAL", "entities": [ "DA", "(+/-)-3,4-methylenedioxyamphetamine", "SoRI-20040", "SoRI-9804", "DA" ], "offsets": [ [ 85, 87 ], [ 91, 126 ], [ 0, 10 ], [ 15, 24 ], [ 63, 65 ] ] }, { "pmid": "19244097", "text": "SoRI-9804 and SoRI-20040 did not attenuate D-amphetamine-induced release of [(3)H]5-hydroxytryptamine from serotonergic, or [(3)H]MPP(+) from noradrenergic, nerve terminals.", "type": "CHEMICAL", "entities": [ "SoRI-9804", "SoRI-20040", "D-amphetamine", "[(3)H]5-hydroxytryptamine", "[(3)H]MPP(+)" ], "offsets": [ [ 0, 9 ], [ 14, 24 ], [ 43, 56 ], [ 76, 101 ], [ 124, 136 ] ] }, { "pmid": "19244097", "text": "Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of [(3)H]MPP(+) from dopaminergic nerve terminals without altering the apparent rate constants.", "type": "CHEMICAL", "entities": [ "SoRI-9804", "cocaine", "D-amphetamine", "[(3)H]MPP(+)" ], "offsets": [ [ 38, 47 ], [ 64, 71 ], [ 80, 93 ], [ 113, 125 ] ] }, { "pmid": "19244097", "text": "The two major findings of this study are 1) the identification of both \"agonist\" (SoRI-9804 and SoRI-20040) and \"antagonist\" (SoRI-20041) allosteric modulators of D-amphetamine-induced DAT-mediated DA release and 2)", "type": "CHEMICAL", "entities": [ "SoRI-9804", "SoRI-20040", "SoRI-20041", "D-amphetamine", "DA" ], "offsets": [ [ 82, 91 ], [ 96, 106 ], [ 126, 136 ], [ 163, 176 ], [ 198, 200 ] ] }, { "pmid": "19244097", "text": "[(3)H]DA uptake and d-amphetamine-induced DAT-mediated efflux can be separately modulated.", "type": "CHEMICAL", "entities": [ "[(3)H]DA", "d-amphetamine" ], "offsets": [ [ 0, 8 ], [ 20, 33 ] ] }, { "pmid": "19244097", "text": "Such agents may have therapeutic potential for the treatment of stimulant addiction, Parkinson's disease, and other psychiatric disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "Enhanced beta2-adrenergic receptor (beta2AR) signaling by adeno-associated viral (AAV)-mediated gene transfer.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "BACKGROUND: Beta2-adrenergic receptors (beta2AR) play important regulatory roles in a variety of cells and organ systems and are important therapeutic targets in the treatment of airway and cardiovascular disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "Prolonged use of beta-agonists results in tolerance secondary to receptor down-regulation resulting in reduced therapeutic efficiency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "The purpose of this work is to evaluate the signaling capabilities of the beta2AR expressed by a recombinant adeno-associated viral (AAV) vector that also included an enhanced green fluorescent protein (EGFP) gene (AAV-beta2AR/EGFP).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "By epifluorescence microscopy, approximately 40% of infected HEK 293 cells demonstrated EGFP expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "beta2AR density measured with [3H]dihydroalprenolol ([3H]DHA) increased either 13- or 77-fold in infected cells compared to mock infected controls depending on the culture conditions used.", "type": "CHEMICAL", "entities": [ "[3H]dihydroalprenolol", "[3H]DHA" ], "offsets": [ [ 30, 51 ], [ 53, 60 ] ] }, { "pmid": "14656380", "text": "The [3H]DHA binding was to a single receptor population with a dissociation constant of 0.42 nM, as would be expected for wild-type beta2AR.", "type": "CHEMICAL", "entities": [ "[3H]DHA" ], "offsets": [ [ 4, 11 ] ] }, { "pmid": "14656380", "text": "Agonist competition assays with [3H]DHA showed the following rank order of potency: isoproterenol>epinephrine> norepinephrine, consistent with beta2AR interaction.", "type": "CHEMICAL", "entities": [ "[3H]DHA", "isoproterenol", "epinephrine", "norepinephrine" ], "offsets": [ [ 32, 39 ], [ 84, 97 ], [ 98, 109 ], [ 111, 125 ] ] }, { "pmid": "14656380", "text": "Isoproterenol-stimulated cyclic AMP levels were 5-fold higher in infected cells compared to controls (314 +/- 43 vs. 63.4 +/- 9.6 nmol/dish;", "type": "CHEMICAL", "entities": [ "Isoproterenol", "cyclic AMP" ], "offsets": [ [ 0, 13 ], [ 25, 35 ] ] }, { "pmid": "14656380", "text": "n = 3).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "Receptor trafficking demonstrated surface expression of beta2AR with vehicle treatment and internalization following isoproterenol treatment.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 117, 130 ] ] }, { "pmid": "14656380", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "We conclude that HEK 293 cells infected with AAV-beta2AR/EGFP effectively express beta2AR and that increased expression of these receptors results in enhanced beta2AR signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14656380", "text": "This method of gene transfer may provide an important means to enhance function in in vivo systems.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Update on rivastigmine.\n", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 10, 22 ] ] }, { "pmid": "14587496", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Rivastigmine is a carbamate drug designed to inhibit both acetylcholinesterase and butyrylcholinesterase by reversibly covalently bonding to these enzymes.", "type": "CHEMICAL", "entities": [ "Rivastigmine", "carbamate" ], "offsets": [ [ 0, 12 ], [ 18, 27 ] ] }, { "pmid": "14587496", "text": "Butyrylcholinesterase in-creases as Alzheimer disease progresses, so its inhibition may become more important as the disease worsens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Metabolism of rivastigmine occurs at the synapse rather than at the liver and previous studies have demonstrated no drug-drug interactions.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "14587496", "text": "Rivastigmine has a half-life at the synapse of 9 hours allowing for bid dosing.", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14587496", "text": "REVIEW SUMMARY: Effective therapy requires up-titration from initial dosage of 3 mg/d to 6 mg/d with additional increases to 9 mg or 12 mg/d giving additional benefits in some patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Beneficial effects with rivastigmine therapy in the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild to moderate Alzheimer disease in 4 large double-blind, placebo-controlled multicenter clinical trials.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 24, 36 ] ] }, { "pmid": "14587496", "text": "Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Rivastigmine also was proven effective in decreasing psychiatric symptoms and cognitive deficits in a large double-blind, placebo-controlled trial in patients with diffuse Lewy body disease.", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14587496", "text": "Other studies have suggested that rivastigmine improves symptoms in nursing home patients with more severe stage Alzheimer disease, Parkinson dementia, and subcortical dementia.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "14587496", "text": "Follow-up studies have suggested that rivastigmine may delay disease progression and, in patients discontinuing the drug, no withdrawal effects were seen.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 38, 50 ] ] }, { "pmid": "14587496", "text": "CONCLUSION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14587496", "text": "Rivastigmine is an effective therapeutic agent for treating cognitive and behavioral symptoms in Alzheimer disease and diffuse Lewy body disease and may also have beneficial effects in vascular and Parkinson dementias.", "type": "CHEMICAL", "entities": [ "Rivastigmine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23409763", "text": "The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs.\n", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "23409763", "text": "G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409763", "text": "Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409763", "text": "One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409763", "text": "As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409763", "text": "Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23409763", "text": "The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 226, 236 ] ] }, { "pmid": "23262028", "text": "Chemokine expression is upregulated in chondrocytes in diabetic fracture healing.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "Chemokines are thought to play an important role in several aspects of bone metabolism including the recruitment of leukocytes and the formation of osteoclasts.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "We investigated the impact of diabetes on chemokine expression in normal and diabetic fracture healing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "Fracture of the femur was performed in streptozotocin-induced diabetic and matched normoglycemic control mice.", "type": "CHEMICAL", "entities": [ "streptozotocin" ], "offsets": [ [ 39, 53 ] ] }, { "pmid": "23262028", "text": "Microarray analysis was carried out and chemokine mRNA levels in vivo were assessed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "CCL4 were examined in fracture calluses by immunohistochemistry and the role of TNF in diabetes-enhanced expression was investigated by treatment of animals with the TNF-specific inhibitor, pegsunercept.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "In vitro studies were conducted with ATDC5 chondrocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "Diabetes significantly upregulated mRNA levels of several chemokines in vivo including CCL4, CCL8, CCL6, CCL11, CCL20, CCL24, CXCL2, CXCL5 and chemokine receptors CCR5 and CXCR4.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "Chondrocytes were identified as a significant source of CCL4 and its expression in diabetic fractures was dependent on TNF (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "TNF-α significantly increased mRNA levels of several chemokines in vitro which were knocked down with FOXO1 siRNA (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "CCL4 expression at the mRNA and proteins levels was induced by FOXO1 over-expression and reduced by FOXO1 knockdown.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "The current studies point to the importance of TNF-α as a mechanism for diabetes enhanced chemokine expression by chondrocytes, which may contribute to the accelerated loss of cartilage observed in diabetic fracture healing.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23262028", "text": "Moreover, in vitro results point to FOXO1 as a potentially important transcription factor in mediating this effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22288603", "text": "Allelopathic activity studies of Mikania scandens.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22288603", "text": "Preliminary investigation of a number of plant extracts for allelopathic activity using seed germination inhibition bioassay showed a promising activity of the water extract of the aerial parts of Mikania scandens.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22288603", "text": "Activity-guided fractionation of the M. scandens extract led to the isolation of the highly allelopathic active compound mikanolide, with minimum inhibitory concentration of 0.083 µM mL(-1).", "type": "CHEMICAL", "entities": [ "mikanolide" ], "offsets": [ [ 121, 131 ] ] }, { "pmid": "22288603", "text": "As M. scandens is a highly abundant invasive plant in Sri Lanka and other South Asian countries, this plant could be developed as an environment friendly natural herbicide, either in crude form as shredded plant material or as pure mikanolide, which is the major constituent (∼0.02%) in the plant.", "type": "CHEMICAL", "entities": [ "mikanolide" ], "offsets": [ [ 227, 237 ] ] }, { "pmid": "11166732", "text": "Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage.\n", "type": "CHEMICAL", "entities": [ "topotecan", "topotecan" ], "offsets": [ [ 27, 36 ], [ 58, 67 ] ] }, { "pmid": "11166732", "text": "Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma.", "type": "CHEMICAL", "entities": [ "Topotecan" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11166732", "text": "Here, we analysed the effects of topotecan on 12 human malignant glioma cell lines in vitro.", "type": "CHEMICAL", "entities": [ "topotecan" ], "offsets": [ [ 33, 42 ] ] }, { "pmid": "11166732", "text": "All cell lines expressed topoisomerase I mRNA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11166732", "text": "High p53 protein levels, but not genetic or functional p53 status, were associated with increased topotecan-induced DNA/topoisomerase I complex formation.", "type": "CHEMICAL", "entities": [ "topotecan" ], "offsets": [ [ 98, 107 ] ] }, { "pmid": "11166732", "text": "Neither functional p53 status, nor p53 protein levels, nor complex formation predicted topotecan-induced growth inhibition.", "type": "CHEMICAL", "entities": [ "topotecan" ], "offsets": [ [ 87, 96 ] ] }, { "pmid": "11166732", "text": "We thus confirm a possible role for p53 protein in modulating topoisomerase I activity but conclude that the major molecular determinants of topotecan sensitivity in glioma cells await identification.", "type": "CHEMICAL", "entities": [ "topotecan" ], "offsets": [ [ 141, 150 ] ] }, { "pmid": "11562773", "text": "Binding site of amiloride to urokinase plasminogen activator depends on species.\n", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "11562773", "text": "A novel drug candidate is checked on its potency on animal models before it can advance to human phase of the research.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Usually negative results on animal phase disqualify it.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Targeting specific enzymes by small chemicals raises the question about the appropriateness of this approach.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "As an example, the urokinase (uPA) is recognized as an important enzyme responsible for cancer metastasis and angiogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "It is therefore important to ask the question if a small chemical will inhibit uPA of different species with the same or different potency.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Using DNA sequence and known structure of uPA we have modeled 3D structures of uPAs for several different species.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "By theoretical calculations we have determined most probable structure of amiloride/uPAs complexes.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "11562773", "text": "Catalytic triad (B57, B102, B195) and specificity pocket (B187-B197, B212-B229) are highly conserved in all cases, and are the regions responsible for proteolytic activity and recognition of the substrate.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Significant differences were observed in a different region (loop B93-B101), that we identified as binding site of amiloride to the tissue plasminogen activator (tPA).", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 115, 124 ] ] }, { "pmid": "11562773", "text": "Although tPA shares the same function of activating plasminogen and it is structurally similar to uPA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Amiloride is a specific inhibitor of uPA but does not inhibit tPA.", "type": "CHEMICAL", "entities": [ "Amiloride" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11562773", "text": "Our study shows that predicted position of amiloride depends on species and in some cases was located, as expected, in the specificity pocket, but in the other cases close to the loop B93-B101.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "11562773", "text": "This location could weaken affinity of binding or prevent inhibition of uPA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "11562773", "text": "Therefore, drug screening and elimination process based solely on animal study, without careful structural analysis, could lead to the elimination of potential drugs for humans.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10522750", "text": "Threshold concentrations of endothelin-1: the effects on contractions induced by 5-hydroxytryptamine in isolated rat cerebral and mesenteric arteries.\n", "type": "CHEMICAL", "entities": [ "5-hydroxytryptamine" ], "offsets": [ [ 81, 100 ] ] }, { "pmid": "10522750", "text": "This study compares the effects of threshold concentrations of endothelin-1 in isolated rat basilar arteries with those in mesenteric arterial branches and investigates the mechanisms of inhibitory and potentiating endothelin-1-effects.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10522750", "text": "In basilar arteries, endothelin-1 reduces the contractions induced by 5-hydroxytryptamine (5-HT), by the thromboxane A2 agonist U46619, and by vasopressin.", "type": "CHEMICAL", "entities": [ "5-hydroxytryptamine", "5-HT", "thromboxane A2", "U46619", "vasopressin" ], "offsets": [ [ 70, 89 ], [ 91, 95 ], [ 105, 119 ], [ 128, 134 ], [ 143, 154 ] ] }, { "pmid": "10522750", "text": "The inhibitory effect of endothelin-1 on the contraction induced by 5-HT is abolished by deendothelialization, by the endothelin ET(B) receptor antagonist RES 701-1, by indomethacin, or by glibenclamide.", "type": "CHEMICAL", "entities": [ "5-HT", "RES 701-1", "indomethacin", "glibenclamide" ], "offsets": [ [ 68, 72 ], [ 155, 164 ], [ 169, 181 ], [ 189, 202 ] ] }, { "pmid": "10522750", "text": "In mesenteric arteries, endothelin-1 potentiates the contractile effects of 5-HT, U46619, and vasopressin.", "type": "CHEMICAL", "entities": [ "5-HT", "U46619", "vasopressin" ], "offsets": [ [ 76, 80 ], [ 82, 88 ], [ 94, 105 ] ] }, { "pmid": "10522750", "text": "The potentiation of the contractile effect induced by 5-HT is only somewhat modified by deendothelialization, but abolished by the thromboxane A2 receptor antagonists GR32191 and ridogrel.", "type": "CHEMICAL", "entities": [ "5-HT", "thromboxane A2", "GR32191", "ridogrel" ], "offsets": [ [ 54, 58 ], [ 131, 145 ], [ 167, 174 ], [ 179, 187 ] ] }, { "pmid": "10522750", "text": "U46619 potentiates the 5-HT-effect in mesenteric arteries.", "type": "CHEMICAL", "entities": [ "U46619", "5-HT" ], "offsets": [ [ 0, 6 ], [ 23, 27 ] ] }, { "pmid": "10522750", "text": "Thus, though the contractile endothelin ET(A) receptors were not blocked, threshold concentrations of endothelin-1 inhibited contractile effects in the rat basilar artery via activation of endothelial ET(B) receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10522750", "text": "Prostaglandins and ATP-sensitive K+ channels are involved in this inhibitory action.", "type": "CHEMICAL", "entities": [ "Prostaglandins", "ATP", "K+" ], "offsets": [ [ 0, 14 ], [ 19, 22 ], [ 33, 35 ] ] }, { "pmid": "10522750", "text": "In contrast, endothelin-1 potentiates contractile actions in mesenteric arteries via the release of endogeneous thromboxane A2 from non-endothelial cells.", "type": "CHEMICAL", "entities": [ "thromboxane A2" ], "offsets": [ [ 112, 126 ] ] }, { "pmid": "10522750", "text": "The study points out the completely different role of the endothelium in combined effects of endothelin-1 between cerebral and mesenteric arteries.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "ABCA1 single nucleotide polymorphisms on high-density lipoprotein-cholesterol and overweight: the D.E.S.I.R. study.\n", "type": "CHEMICAL", "entities": [ "nucleotide", "cholesterol" ], "offsets": [ [ 13, 23 ], [ 66, 77 ] ] }, { "pmid": "17135600", "text": "The adenosine triphosphate-binding cassette A1 (ABCA1) gene plays a key role in reverse cholesterol transport.", "type": "CHEMICAL", "entities": [ "adenosine triphosphate", "cholesterol" ], "offsets": [ [ 4, 26 ], [ 88, 99 ] ] }, { "pmid": "17135600", "text": "Some ABCA1 gene polymorphisms have been associated with high-density lipoprotein-cholesterol (HDL-C) concentrations.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 81, 92 ] ] }, { "pmid": "17135600", "text": "The aim of this study was to assess the effect of three polymorphisms, C69T, G378C, and G1051A (R219K), on HDL-C levels and their interaction with BMI in more than 5000 French whites from the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "The T allele of the C69T single nucleotide polymorphism (SNP) was associated with higher HDL-C levels in normal-weight men (BMI <25 kg/m(2)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "The C allele of the G378C SNP was associated with lower HDL-C in overweight subjects (BMI > or =25 kg/m(2)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "For the G1051A SNP, in the normal-weight group, the minor A allele was significantly associated with higher HDL-C levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "In contrast, in overweight people, the minor allele was associated with lower HDL-C levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "After accounting for multiple testing, empiric p values remained significant for the associations between G378C SNP and HDL-C in the overweight group and between G1051A SNP and HDL-C in the normal-weight group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17135600", "text": "This study suggests that ABCA1 gene polymorphisms modulate HDL-C concentrations, in interaction with BMI, and, thus, they might influence cardiovascular risk in the general population.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "Metformin and Sulfonylureas in Relation to Cancer Risk in Type II Diabetes Patients: A Meta-analysis using primary data of published studies.\n", "type": "CHEMICAL", "entities": [ "Metformin", "Sulfonylureas" ], "offsets": [ [ 0, 9 ], [ 14, 27 ] ] }, { "pmid": "23419783", "text": "INTRODUCTION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "Accumulating evidence suggests that patients with type 2 diabetes mellitus (T2DM) and hyperinsulinemia are at increased risk for developing malignancies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "It remains to be fully elucidated whether use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affect cancer incidence in subjects with T2DM.", "type": "CHEMICAL", "entities": [ "metformin", "sulfonylureas" ], "offsets": [ [ 49, 58 ], [ 90, 103 ] ] }, { "pmid": "23419783", "text": "MATERIAL & METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "We performed a meta-analysis using PubMed, of randomized control trials (RCTs), cohorts, and case-control studies published through July 2012 that assess effects of metformin and/or sulfonylurea sulfonylureas on cancer risk at any site, in subjects with T2DM.", "type": "CHEMICAL", "entities": [ "metformin", "sulfonylurea", "sulfonylureas" ], "offsets": [ [ 165, 174 ], [ 182, 194 ], [ 195, 208 ] ] }, { "pmid": "23419783", "text": "Fixed and random effects meta-analysis models were used, and the effect size was summarized as relative risk (RR) for RCTs/cohorts and as odds ratio (OR) for the case-control studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "Analysis of 24 metformin studies in subjects with T2DM showed that metformin use is associated with reduced risk for the development of cancer, in both cohort (RR=0.70 [95% CI=0.67-0.73]) and case-control studies (OR=0.90 [95% CI=0.84-0.98]), but this finding was not supported by RCTs (RR=1.01[95% CI=0.81-1.26]).", "type": "CHEMICAL", "entities": [ "metformin", "metformin" ], "offsets": [ [ 15, 24 ], [ 67, 76 ] ] }, { "pmid": "23419783", "text": "Data from 18 sulfonylurea studies in subjects with T2DM showed that sulfonylurea use is associated with an increase in all-cancer risk, in cohort studies (RR=1.55 [95% CI=1.48 -1.63]), though data from RCTs (RR=1.17 [95% CI=0.95-1.45]) and case-control studies (OR=1.02 [95% CI=0.93-1.13]) failed to demonstrate a statistically significant effect.", "type": "CHEMICAL", "entities": [ "sulfonylurea", "sulfonylurea" ], "offsets": [ [ 13, 25 ], [ 68, 80 ] ] }, { "pmid": "23419783", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23419783", "text": "This analysis using pooled primary data demonstrates that metformin use reduces, while sulfonylurea use may be associated with an increased cancer risk in subjects with T2DM.", "type": "CHEMICAL", "entities": [ "metformin", "sulfonylurea" ], "offsets": [ [ 58, 67 ], [ 87, 99 ] ] }, { "pmid": "23419783", "text": "These findings need to be confirmed in large-scale RCTs before they are translated into clinical practice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375228", "text": "Discovery and structure-activity relationships of small molecules that block the human immunoglobulin G-human neonatal Fc receptor (hIgG-hFcRn) protein-protein interaction.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375228", "text": "The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375228", "text": "Small molecules that block the protein-protein interactions of human IgG-human FcRn may lower pathogenic autoantibodies and provide effective treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23375228", "text": "A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein-protein interaction through optimization of a hit derived from a virtual ligand-based screen.", "type": "CHEMICAL", "entities": [ "quinoxalines" ], "offsets": [ [ 17, 29 ] ] }, { "pmid": "23265474", "text": "Comparative formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in creatinine/phenylalanine and creatinine/phenylalanine/4-oxo-2-nonenal reaction mixtures.\n", "type": "CHEMICAL", "entities": [ "creatinine", "phenylalanine", "4-oxo-2-nonenal", "2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine", "PhIP", "creatinine", "phenylalanine" ], "offsets": [ [ 112, 122 ], [ 123, 136 ], [ 137, 152 ], [ 25, 72 ], [ 74, 78 ], [ 83, 93 ], [ 94, 107 ] ] }, { "pmid": "23265474", "text": "The comparative formation of the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in both creatinine/phenylalanine (CRN/Phe) and creatinine/phenylalanine/4-oxo-2-nonenal (CRN/Phe/ON) systems was studied to analyse the ability of lipid-derived reactive carbonyls to promote PhIP formation.", "type": "CHEMICAL", "entities": [ "PhIP", "creatinine", "phenylalanine", "CRN", "Phe", "creatinine", "phenylalanine", "4-oxo-2-nonenal", "CRN", "Phe", "carbonyls", "PhIP", "2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine" ], "offsets": [ [ 110, 114 ], [ 124, 134 ], [ 135, 148 ], [ 150, 153 ], [ 154, 157 ], [ 163, 173 ], [ 174, 187 ], [ 188, 203 ], [ 205, 208 ], [ 209, 212 ], [ 286, 295 ], [ 307, 311 ], [ 61, 108 ] ] }, { "pmid": "23265474", "text": "Although PhIP was produced to some extent in the CRN/Phe system, the presence of the oxidized lipid increased considerably the amount of PhIP produced.", "type": "CHEMICAL", "entities": [ "PhIP", "CRN", "Phe", "PhIP" ], "offsets": [ [ 9, 13 ], [ 49, 52 ], [ 53, 56 ], [ 137, 141 ] ] }, { "pmid": "23265474", "text": "This increase seemed to be a consequence of the decrease in the E(a) of the reaction when the lipid was present, which diminished from 112.9 to 80.9 kJ/mol.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23265474", "text": "On the other hand, the addition of the lipid did not seem to produce PhIP by an alternative mechanism because PhIP was formed analogously in both CRN/Phe and CRN/Phe/ON systems as a function of pH, creatinine concentration, phenylalanine concentration, time, temperature, oxygen concentration in the reaction atmosphere, and the addition of different amounts of ammonia.", "type": "CHEMICAL", "entities": [ "PhIP", "PhIP", "CRN", "Phe", "CRN", "Phe", "creatinine", "phenylalanine", "oxygen", "ammonia" ], "offsets": [ [ 69, 73 ], [ 110, 114 ], [ 146, 149 ], [ 150, 153 ], [ 158, 161 ], [ 162, 165 ], [ 198, 208 ], [ 224, 237 ], [ 272, 278 ], [ 362, 369 ] ] }, { "pmid": "23265474", "text": "All these results suggest that the ability of lipid oxidation products to produce PhIP is related to their capacity to induce the Strecker degradation of phenylalanine to phenylacetaldehyde.", "type": "CHEMICAL", "entities": [ "PhIP", "phenylalanine", "phenylacetaldehyde" ], "offsets": [ [ 82, 86 ], [ 154, 167 ], [ 171, 189 ] ] }, { "pmid": "23265474", "text": "Therefore, any other reactive carbonyl compound that can produce the Strecker degradation of phenylalanine should also be considered as a potential inducer of PhIP formation under appropriate conditions.", "type": "CHEMICAL", "entities": [ "carbonyl", "phenylalanine", "PhIP" ], "offsets": [ [ 30, 38 ], [ 93, 106 ], [ 159, 163 ] ] }, { "pmid": "7906055", "text": "Agmatine: an endogenous clonidine-displacing substance in the brain.\n", "type": "CHEMICAL", "entities": [ "Agmatine", "clonidine" ], "offsets": [ [ 0, 8 ], [ 24, 33 ] ] }, { "pmid": "7906055", "text": "Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors.", "type": "CHEMICAL", "entities": [ "Clonidine", "imidazoline" ], "offsets": [ [ 0, 9 ], [ 69, 80 ] ] }, { "pmid": "7906055", "text": "The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain.", "type": "CHEMICAL", "entities": [ "imidazoline", "clonidine" ], "offsets": [ [ 26, 37 ], [ 57, 66 ] ] }, { "pmid": "7906055", "text": "This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain.", "type": "CHEMICAL", "entities": [ "clonidine", "agmatine", "decarboxylated arginine" ], "offsets": [ [ 5, 14 ], [ 91, 99 ], [ 101, 124 ] ] }, { "pmid": "7906055", "text": "Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells.", "type": "CHEMICAL", "entities": [ "Agmatine", "imidazoline", "catecholamines" ], "offsets": [ [ 0, 8 ], [ 41, 52 ], [ 89, 103 ] ] }, { "pmid": "7906055", "text": "Its biosynthetic enzyme, arginine decarboxylase, is present in brain.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "7906055", "text": "Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.", "type": "CHEMICAL", "entities": [ "Agmatine", "imidazoline", "noncatecholamine" ], "offsets": [ [ 0, 8 ], [ 59, 70 ], [ 84, 100 ] ] }, { "pmid": "23537574", "text": "Amino acids as co-amorphous stabilizers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement.\n", "type": "CHEMICAL", "entities": [ "Amino acids" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23537574", "text": "Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug (crystallization).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 126, 137 ] ] }, { "pmid": "23537574", "text": "The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs.", "type": "CHEMICAL", "entities": [ "carbamazepine", "indomethacin", "amino acids" ], "offsets": [ [ 35, 48 ], [ 53, 65 ], [ 85, 96 ] ] }, { "pmid": "23537574", "text": "Mixtures of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepared by vibrational ball milling.", "type": "CHEMICAL", "entities": [ "amino acids", "arginine", "phenylalanine", "tryptophan", "tyrosine" ], "offsets": [ [ 25, 36 ], [ 37, 45 ], [ 47, 60 ], [ 62, 72 ], [ 77, 85 ] ] }, { "pmid": "23537574", "text": "Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepared as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temperature (Tg) in the DSC measurements.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "In addition, the Tgs of the co-amorphous mixtures were significantly increased over those of the individual drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "The drugs remained chemically stable during the milling process and the co-amorphous formulations were generally physically stable over at least 6months at 40°C under dry conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23537574", "text": "The dissolution rate of all co-amorphous drug-amino acid mixtures was significantly increased over that of the respective crystalline and amorphous pure drugs.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 45, 55 ] ] }, { "pmid": "23537574", "text": "Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissolution of amorphous drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439661", "text": "Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic.\n", "type": "CHEMICAL", "entities": [ "GSK2251052", "Boron" ], "offsets": [ [ 30, 40 ], [ 60, 65 ] ] }, { "pmid": "23439661", "text": "(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections.", "type": "CHEMICAL", "entities": [ "(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole", "boron", "leucyl", "GSK2251052" ], "offsets": [ [ 0, 80 ], [ 105, 110 ], [ 157, 163 ], [ 82, 92 ] ] }, { "pmid": "23439661", "text": "In this study, six healthy adult male subjects received a single i.v. dose of [(14)C]GSK2251052, 1500 mg infused over 1 hour.", "type": "CHEMICAL", "entities": [ "[(14)C]GSK2251052" ], "offsets": [ [ 78, 95 ] ] }, { "pmid": "23439661", "text": "Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439661", "text": "An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439661", "text": "Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues.", "type": "CHEMICAL", "entities": [ "GSK2251052" ], "offsets": [ [ 137, 147 ] ] }, { "pmid": "23439661", "text": "The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439661", "text": "GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively.", "type": "CHEMICAL", "entities": [ "GSK2251052", "propanol", "carboxylic acid" ], "offsets": [ [ 0, 10 ], [ 77, 85 ], [ 118, 133 ] ] }, { "pmid": "23439661", "text": "Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23439661", "text": "A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.", "type": "CHEMICAL", "entities": [ "4-methylpyrazole", "alcohol", "aldehyde" ], "offsets": [ [ 107, 123 ], [ 154, 161 ], [ 209, 217 ] ] }, { "pmid": "17325243", "text": "Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1: contribution to hypertension and endothelial dysfunction.\n", "type": "CHEMICAL", "entities": [ "L-arginine" ], "offsets": [ [ 59, 69 ] ] }, { "pmid": "17325243", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 43, 55 ] ] }, { "pmid": "17325243", "text": "We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 139, 147 ] ] }, { "pmid": "17325243", "text": "METHODS AND RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "We have identified a novel C/T polymorphism in the 3'UTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 gene (SLC7A1).", "type": "CHEMICAL", "entities": [ "arginine", "cationic amino acid" ], "offsets": [ [ 74, 82 ], [ 121, 140 ] ] }, { "pmid": "17325243", "text": "The minor T allele significantly attenuates reporter gene expression (P<0.01) and is impaired in its capacity to form DNA-protein complexes (P<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects (P<0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives (P<0.001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing L-arginine transporter SLC7A1.", "type": "CHEMICAL", "entities": [ "L-arginine" ], "offsets": [ [ 98, 108 ] ] }, { "pmid": "17325243", "text": "The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (-log EC50 for wild-type versus Slc7A1 transgenic: 6.87+/-0.10 versus 7.56+/-0.13; P<0.001).", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 111, 124 ] ] }, { "pmid": "17325243", "text": "This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 47, 59 ] ] }, { "pmid": "17325243", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "The present study identifies a key, functionally active polymorphism in the 3'UTR of SLC7A1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325243", "text": "As such, this polymorphism may account for the apparent link between altered endothelial function, L-arginine, and nitric oxide metabolism and predisposition to essential hypertension.", "type": "CHEMICAL", "entities": [ "L-arginine", "nitric oxide" ], "offsets": [ [ 99, 109 ], [ 115, 127 ] ] }, { "pmid": "23632081", "text": "Identification of an Allosteric Modulator of Serotonin Transporter with Novel Mechanism of Action.\n", "type": "CHEMICAL", "entities": [ "Serotonin" ], "offsets": [ [ 45, 54 ] ] }, { "pmid": "23632081", "text": "Serotonin transporters (SERT) play an essential role in the termination and regulation of serotonin signaling in the brain.", "type": "CHEMICAL", "entities": [ "Serotonin", "serotonin" ], "offsets": [ [ 0, 9 ], [ 90, 99 ] ] }, { "pmid": "23632081", "text": "SERT is also the target of antidepressants and psychostimulants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632081", "text": "Molecules with novel activities and modes of interaction with regard to SERT function are of great scientific and clinical interest.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632081", "text": "We explored structural regions outside the putative serotonin translocation pathway to identify potential binding sites for allosteric transporter modulators (ATMs).", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 52, 61 ] ] }, { "pmid": "23632081", "text": "Mutational studies revealed a pocket of amino acids outside the orthosteric substrate binding sites located in the interface between extracellular loops 1 and 3 that when mutated affect transporter function.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 40, 51 ] ] }, { "pmid": "23632081", "text": "Using the structure of the bacterial transporter homologue leucine transporter as a template, we developed a structural model of SERT.", "type": "CHEMICAL", "entities": [ "leucine" ], "offsets": [ [ 59, 66 ] ] }, { "pmid": "23632081", "text": "We performed molecular dynamics simulations to further characterize the allosteric pocket that was identified by site-directed mutagenesis studies and employed this pocket in a virtual screen for small-molecule modulators of SERT function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632081", "text": "In functional transport assays, we found that one of the identified molecules, ATM7, increased the reuptake of serotonin, possibly by facilitating the interaction of serotonin with transport-ready conformations of SERT when concentrations of serotonin were low and rate limiting.", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin", "serotonin" ], "offsets": [ [ 111, 120 ], [ 166, 175 ], [ 242, 251 ] ] }, { "pmid": "23632081", "text": "In addition, ATM7 potentiates 3,4-methylenedioxy-N-methylamphetamine (MDMA, \"Ecstasy\")-induced reversed transport by SERT.", "type": "CHEMICAL", "entities": [ "3,4-methylenedioxy-N-methylamphetamine", "MDMA" ], "offsets": [ [ 30, 68 ], [ 70, 74 ] ] }, { "pmid": "23632081", "text": "Taking advantage of a conformationally sensitive residue in transmembrane domain 6, we demonstrate that ATM7 mechanistically stabilizes an outward-facing conformation of SERT.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23632081", "text": "Taken together these observations demonstrate that ATM7 acts through a novel mechanism that involves allosteric modulation of SERT function.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22349823", "text": "Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22349823", "text": "The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 226, 234 ] ] }, { "pmid": "22349823", "text": "The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22349823", "text": "They display sensitivity to TK inhibitors, including gefitinib and erlotinib.", "type": "CHEMICAL", "entities": [ "gefitinib", "erlotinib" ], "offsets": [ [ 53, 62 ], [ 67, 76 ] ] }, { "pmid": "22349823", "text": "In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22349823", "text": "In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant.", "type": "CHEMICAL", "entities": [ "gefitinib" ], "offsets": [ [ 101, 110 ] ] }, { "pmid": "22349823", "text": "The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity.", "type": "CHEMICAL", "entities": [ "gefitinib" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "22349823", "text": "The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 33, 36 ] ] }, { "pmid": "22349823", "text": "Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22349823", "text": "The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands.", "type": "CHEMICAL", "entities": [ "Met", "gefitinib" ], "offsets": [ [ 4, 7 ], [ 76, 85 ] ] }, { "pmid": "22349823", "text": "In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop.", "type": "CHEMICAL", "entities": [ "Phe" ], "offsets": [ [ 89, 92 ] ] }, { "pmid": "22349823", "text": "Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity.", "type": "CHEMICAL", "entities": [ "gefitinib", "gefitinib" ], "offsets": [ [ 69, 78 ], [ 212, 221 ] ] }, { "pmid": "22349823", "text": "Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells.\n", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "23335025", "text": "Excessive level of estrogen is considered as a main cause of breast cancer, therefore, many studies have focused on estrogen receptor (ER)-positive breast cancer, even though ER-negative cancer has a poor prognosis than ER-positive breast cancer.", "type": "CHEMICAL", "entities": [ "estrogen", "estrogen" ], "offsets": [ [ 116, 124 ], [ 19, 27 ] ] }, { "pmid": "23335025", "text": "We evaluated the anti-cancer effects of Ginkgo biloba extract (GBE) in estrogen-independent breast cancer.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "23335025", "text": "GBE has been traditionally used as a platelet activating factor, a circulatory stimulant, a tonic, and anti-asthmatic drug, and anti-cancer agent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": " ", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "However, anti-cancer effects of GBE on ER-negative breast cancer have not been proved yet.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "In this study, we tested chemotherapeutic potential of GBE in the MDA-MB-231 (ER-negative) human breast cancer cell line.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "Our results showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1,000 μg/ml).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "Caspase-3 was significantly activated and mRNA levels of apoptosis-related genes (Bcl-2 and Bax) were altered.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "These results indicate that GBE induces apoptosis in MDA-MB-231 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23335025", "text": "It is presumed that GBE has chemopreventive effects in ER-independent breast cancer through anti-proliferation and apoptosis-inducing activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12196163", "text": "Biosynthesis of iron-sulphur clusters is a complex and highly conserved process.\n", "type": "CHEMICAL", "entities": [ "iron", "sulphur" ], "offsets": [ [ 16, 20 ], [ 21, 28 ] ] }, { "pmid": "12196163", "text": "Iron-sulphur ([Fe-S]) clusters are simple inorganic prosthetic groups that are contained in a variety of proteins having functions related to electron transfer, gene regulation, environmental sensing and substrate activation.", "type": "CHEMICAL", "entities": [ "Iron", "Fe-S", "sulphur" ], "offsets": [ [ 0, 4 ], [ 15, 19 ], [ 5, 12 ] ] }, { "pmid": "12196163", "text": "In spite of their simple structures, biological [Fe-S] clusters are not formed spontaneously.", "type": "CHEMICAL", "entities": [ "Fe-S" ], "offsets": [ [ 49, 53 ] ] }, { "pmid": "12196163", "text": "Rather, a consortium of highly conserved proteins is required for both the formation of [Fe-S] clusters and their insertion into various protein partners.", "type": "CHEMICAL", "entities": [ "Fe-S" ], "offsets": [ [ 89, 93 ] ] }, { "pmid": "12196163", "text": "Among the [Fe-S] cluster biosynthetic proteins are included a pyridoxal phosphate-dependent enzyme (NifS) that is involved in the activation of sulphur from l-cysteine, and a molecular scaffold protein (NifU) upon which [Fe-S] cluster precursors are formed.", "type": "CHEMICAL", "entities": [ "Fe-S", "pyridoxal phosphate", "sulphur", "l-cysteine", "Fe-S" ], "offsets": [ [ 11, 15 ], [ 62, 81 ], [ 144, 151 ], [ 157, 167 ], [ 221, 225 ] ] }, { "pmid": "12196163", "text": "The formation or transfer of [Fe-S] clusters appears to require an electron-transfer step.", "type": "CHEMICAL", "entities": [ "Fe-S" ], "offsets": [ [ 30, 34 ] ] }, { "pmid": "12196163", "text": "Another complexity is that molecular chaperones homologous to DnaJ and DnaK are involved in some aspect of the maturation of [Fe-S]-cluster-containing proteins.", "type": "CHEMICAL", "entities": [ "Fe-S" ], "offsets": [ [ 126, 130 ] ] }, { "pmid": "12196163", "text": "It appears that the basic biochemical features of [Fe-S] cluster formation are strongly conserved in Nature, since organisms from all three life Kingdoms contain the same consortium of homologous proteins required for [Fe-S] cluster formation that were discovered in the eubacteria.", "type": "CHEMICAL", "entities": [ "Fe-S", "Fe-S" ], "offsets": [ [ 51, 55 ], [ 219, 223 ] ] }, { "pmid": "23641914", "text": "Copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate, a well-defined and efficient process for achieving functionalized polyesters for covalent binding of bioactive molecules.\n", "type": "CHEMICAL", "entities": [ "polyesters", "2-methylene-1,3-dioxepane", "glycidyl methacrylate" ], "offsets": [ [ 139, 149 ], [ 20, 45 ], [ 50, 71 ] ] }, { "pmid": "23641914", "text": "The understanding of cell-material interactions is important for creating personalized implants for tissue engineering.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "This has resulted in an interest in developing polymers with functional groups with the possibility of controlling the macromolecular surface.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "We have in a one-pot reaction synthesized a series of amorphous and degradable polyester-based copolymers with active functional groups by copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate.", "type": "CHEMICAL", "entities": [ "polyester", "2-methylene-1,3-dioxepane", "glycidyl methacrylate" ], "offsets": [ [ 79, 88 ], [ 159, 184 ], [ 189, 210 ] ] }, { "pmid": "23641914", "text": "The properties of the final polymers were varied by varying the feed ratios of the monomers and it was seen that it was possible to control the amount of active functional groups.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "The resulting epoxy-functionalized polyester was further modified by covalent immobilization of heparin.", "type": "CHEMICAL", "entities": [ "epoxy-functionalized polyester" ], "offsets": [ [ 14, 44 ] ] }, { "pmid": "23641914", "text": "The heparinization was done in order, in a future aspect, to enhance the osteogenic differentiation of mesenchymal stem cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "Heparin binds directly with the growth factor bone morphogenetic protein-2 and helps to retain its activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "The molecular structure of the copolymers was characterized by nuclear magnetic resonance, size exclusion chromatography, and fourier transform infrared spectroscopy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "Differential scanning calorimetry and tensile testing showed that the monomer feed ratio had a great influence on the properties of the final polymer and that it thus was possible to control the mechanical properties to suit an intended application.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23641914", "text": "The presence of heparin was verified by toluidine blue staining and all the films tested showed positive signals for heparin.", "type": "CHEMICAL", "entities": [ "toluidine blue" ], "offsets": [ [ 40, 54 ] ] }, { "pmid": "23219161", "text": "DNA polymerase POLQ and cellular defense against DNA damage.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "In mammalian cells, POLQ (pol θ) is an unusual specialized DNA polymerase whose in vivo function is under active investigation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "POLQ has been implicated by different experiments to play a role in resistance to ionizing radiation and defense against genomic instability, in base excision repair, and in immunological diversification.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "The protein is formed by an N-terminal helicase-like domain, a C-terminal DNA polymerase domain, and a large central domain that spans between the two.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 27, 28 ], [ 62, 63 ] ] }, { "pmid": "23219161", "text": "This arrangement is also found in the Drosophila Mus308 protein, which functions in resistance to DNA interstrand crosslinking agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "Homologs of POLQ and Mus308 are found in multicellular eukaryotes, including plants, but a comparison of phenotypes suggests that not all of these genes are functional orthologs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "Flies defective in Mus308 are sensitive to DNA interstrand crosslinking agents, while mammalian cells defective in POLQ are primarily sensitive to DNA double-strand breaking agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "Cells from Polq(-/-) mice are hypersensitive to radiation and peripheral blood cells display increased spontaneous and ionizing radiation-induced levels of micronuclei (a hallmark of gross chromosomal aberrations), though mice apparently develop normally.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "Loss of POLQ in human and mouse cells causes sensitivity to ionizing radiation and other double strand breaking agents and increased DNA damage signaling.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "Retrospective studies of clinical samples show that higher levels of POLQ gene expression in breast and colorectal cancer are correlated with poorer outcomes for patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23219161", "text": "A clear understanding of the mechanism of action and physiologic function of POLQ in the cell is likely to bear clinical relevance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "Impaired in vivo binding of MeCP2 to chromatin in the absence of its DNA methyl-binding domain.\n", "type": "CHEMICAL", "entities": [ "methyl" ], "offsets": [ [ 73, 79 ] ] }, { "pmid": "23558747", "text": "MeCP2 is a methyl-CpG-binding protein that is a main component of brain chromatin in vertebrates.", "type": "CHEMICAL", "entities": [ "methyl" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "23558747", "text": "In vitro studies have determined that in addition to its specific methyl-CpG-binding domain (MBD) MeCP2 also has several chromatin association domains.", "type": "CHEMICAL", "entities": [ "methyl" ], "offsets": [ [ 66, 72 ] ] }, { "pmid": "23558747", "text": "However, the specific interactions of MeCP2 with methylated or non-methylated chromatin regions and the structural characteristics of the resulting DNA associations in vivo remain poorly understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "We analysed the role of the MBD in MeCP2-chromatin associations in vivo using an MeCP2 mutant Rett syndrome mouse model (Mecp2(tm)(1)(.)(1)(Jae)) in which exon 3 deletion results in an N-terminal truncation of the protein, including most of the MBD.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 185, 186 ] ] }, { "pmid": "23558747", "text": "Our results show that in mutant mice, the truncated form of MeCP2 (ΔMeCP2) is expressed in different regions of the brain and liver, albeit at 50% of its wild-type (wt) counterpart.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "In contrast to the punctate nuclear distribution characteristic of wt MeCP2, ΔMeCP2 exhibits both diffuse nuclear localization and a substantial retention in the cytoplasm, suggesting a dysfunction of nuclear transport.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "In mutant brain tissue, neuronal nuclei are smaller, and ΔMeCP2 chromatin is digested faster by nucleases, producing a characteristic nuclease-resistant dinucleosome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "Although a fraction of ΔMeCP2 is found associated with nucleosomes, its interaction with chromatin is transient and weak.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23558747", "text": "Thus, our results unequivocally demonstrate that in vivo the MBD of MeCP2 together with its adjacent region in the N-terminal domain are critical for the proper interaction of the protein with chromatin, which cannot be replaced by any other of its protein domains.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15547682", "text": "Pseudohypoaldosteronism type 1 and the genes encoding prostasin, alpha-spectrin, and Nedd4.\nPseudohypoaldosteronism type 1 (PHA1), a rare disorder of infancy, presents with potential life-threatening salt wasting and failure to thrive.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15547682", "text": "Thus far, PHA1 has been attributed to mutations affecting the mineralocorticoid receptor or any of the three subunits assembling the amiloride-sensitive epithelial sodium channel (ENaC).", "type": "CHEMICAL", "entities": [ "amiloride", "sodium" ], "offsets": [ [ 133, 142 ], [ 164, 170 ] ] }, { "pmid": "15547682", "text": "However, a lot of patients with a phenotype resembling PHA1, show no defects in these proteins, making it likely that further genes are involved in the aetiology of this disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15547682", "text": "Recent studies have elucidated additional participants (alpha-spectrin and members of the families of transmembrane serine proteases, ubiquitin-protein ligases, and serum- and glucocorticoid-regulated kinases, respectively) regulating and/or interacting in the complex pathway of sodium retention in the amiloride-sensitive distal nephron.", "type": "CHEMICAL", "entities": [ "serine", "sodium", "amiloride" ], "offsets": [ [ 116, 122 ], [ 280, 286 ], [ 304, 313 ] ] }, { "pmid": "15547682", "text": "This led us to investigate whether PHA1 can also be associated with mutations in some of these genes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "15547682", "text": "Our data suggest that at least the prostasin gene might be excluded as a causative locus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291240", "text": "Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 27, 38 ] ] }, { "pmid": "23291240", "text": "The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 24, 35 ] ] }, { "pmid": "23291240", "text": "These putative relationships and their underlying mechanisms are not well understood.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291240", "text": "The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 94, 105 ] ] }, { "pmid": "23291240", "text": "We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "lanosterol", "lathosterol", "desmosterol", "cholesterol", "24S-hydroxycholesterol", "27-hydroxycholesterol" ], "offsets": [ [ 102, 113 ], [ 119, 130 ], [ 142, 152 ], [ 154, 165 ], [ 170, 181 ], [ 191, 202 ], [ 224, 246 ], [ 251, 272 ] ] }, { "pmid": "23291240", "text": "CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels.", "type": "CHEMICAL", "entities": [ "desmosterol", "cholesterol", "24S-hydroxycholesterol", "24S-hydroxycholesterol" ], "offsets": [ [ 3, 14 ], [ 16, 27 ], [ 32, 54 ], [ 80, 102 ] ] }, { "pmid": "23291240", "text": "Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23291240", "text": "In multivariate regression tests including age, gender, albumin ratio, number of the APOEɛ4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations.", "type": "CHEMICAL", "entities": [ "desmosterol", "cholesterol", "24S-hydroxycholesterol" ], "offsets": [ [ 162, 173 ], [ 175, 186 ], [ 191, 213 ] ] }, { "pmid": "23291240", "text": "The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group.", "type": "CHEMICAL", "entities": [ "cholesterol", "24S-hydroxycholesterol" ], "offsets": [ [ 43, 54 ], [ 59, 81 ] ] }, { "pmid": "23291240", "text": "The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "23074021", "text": "In vivo genotoxicity of methyleugenol in gpt delta transgenic rats following medium-term exposure.\n", "type": "CHEMICAL", "entities": [ "methyleugenol" ], "offsets": [ [ 24, 37 ] ] }, { "pmid": "23074021", "text": "Methyleugenol (MEG), which is commonly used as a fragrance and flavoring agent, has been shown to induce hepatocellular tumors in rodents.", "type": "CHEMICAL", "entities": [ "Methyleugenol", "MEG" ], "offsets": [ [ 0, 13 ], [ 15, 18 ] ] }, { "pmid": "23074021", "text": "However, the role of genotoxicity as a possible mechanism of action is not fully understood even though the DNA-reactive metabolite of MEG has been identified.", "type": "CHEMICAL", "entities": [ "MEG" ], "offsets": [ [ 135, 138 ] ] }, { "pmid": "23074021", "text": "In this study, a gpt delta transgenic rat model was used to clarify whether genotoxic mechanisms are involved in MEG-induced hepatocarcinogenesis following medium-term exposure.", "type": "CHEMICAL", "entities": [ "MEG" ], "offsets": [ [ 113, 116 ] ] }, { "pmid": "23074021", "text": "F344 gpt delta rats were subjected to repeated oral administration of MEG at dosages of 0, 10, 30, or 100mg/kg (a carcinogenic dose) for 13 weeks.", "type": "CHEMICAL", "entities": [ "MEG" ], "offsets": [ [ 70, 73 ] ] }, { "pmid": "23074021", "text": "The relative weight of the liver of the male and female rats that were administered 100mg/kg MEG and the absolute weight of the liver of the male rats that were administered 100mg/kg MEG were significantly increased.", "type": "CHEMICAL", "entities": [ "MEG", "MEG" ], "offsets": [ [ 93, 96 ], [ 183, 186 ] ] }, { "pmid": "23074021", "text": "In addition, the number and area of glutathione S-transferase placental form (GST-P) positive foci and proliferating cell nuclear antigen (PCNA) positive cell ratios in the hepatocytes were significantly increased in the male and female rats that were administered 100mg/kg MEG compared with the control animals.", "type": "CHEMICAL", "entities": [ "MEG", "glutathione", "S" ], "offsets": [ [ 274, 277 ], [ 36, 47 ], [ 48, 49 ] ] }, { "pmid": "23074021", "text": "In the in vivo mutation assays, a significant increase in the gpt and Spi(-) mutant frequencies was observed in both sexes at the carcinogenic dose.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23074021", "text": "These results suggest the possible participation of genotoxic mechanisms in MEG-induced hepatocarcinogenesis.", "type": "CHEMICAL", "entities": [ "MEG" ], "offsets": [ [ 76, 79 ] ] }, { "pmid": "23451797", "text": "Structural Investigation and Biological Activity of Sesquiterpene Lactones from the Traditional Chinese Herb Inula racemosa.\n", "type": "CHEMICAL", "entities": [ "Sesquiterpene Lactones" ], "offsets": [ [ 52, 74 ] ] }, { "pmid": "23451797", "text": "Five new sesquiterpene lactones, racemosalactones A-E (1-5), along with 19 known sesquiterpene latones (6-24), were isolated from the roots of Inula racemosa.", "type": "CHEMICAL", "entities": [ "racemosalactones A-E", "sesquiterpene latones", "sesquiterpene lactones" ], "offsets": [ [ 33, 53 ], [ 81, 102 ], [ 9, 31 ] ] }, { "pmid": "23451797", "text": "Their structures were elucidated by extensive spectroscopic analysis, and the absolute configuration of 2 was deduced from X-ray diffraction analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23451797", "text": "Compounds 1, 6, 8, 10, 12, 14, and 17 exhibited antiproliferative activities with IC50 values ranging from 0.38 to 4.19 μg/mL against human non-small-cell lung cancer A549, hepatocellular carcinoma HepG2, and human fibrosarcoma HT1080 cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23451797", "text": "Compounds 6 and 8 exhibited antiproliferative activities against endothelial cells with IC50 values of 2.4 and 2.5 μg/mL, respectively.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23451797", "text": "Furthermore, compounds 6 and 8 both inhibited endothelial cell tube formation at 1.0 μg/mL. A method for the rapid and straightforward preparative-scale isolation of compound 6 from alantolides is described.", "type": "CHEMICAL", "entities": [ "alantolides" ], "offsets": [ [ 180, 191 ] ] }, { "pmid": "23416143", "text": "Narirutin fraction from citrus peels attenuates alcoholic liver disease in mice.\n", "type": "CHEMICAL", "entities": [ "Narirutin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23416143", "text": "This study aimed to demonstrate protective activities of the narirutin fraction from peels of Citrus unshiu against ethanol-induced hepatic damage through an animal study.", "type": "CHEMICAL", "entities": [ "ethanol", "narirutin" ], "offsets": [ [ 116, 123 ], [ 61, 70 ] ] }, { "pmid": "23416143", "text": "Citrus narirutin fraction (CNF), contained 75% of narirutin, was obtained by an ultra-sonicated extraction and further purification.", "type": "CHEMICAL", "entities": [ "narirutin", "narirutin" ], "offsets": [ [ 7, 16 ], [ 50, 59 ] ] }, { "pmid": "23416143", "text": "ICR mice were divided into four groups; normaldiet control, ethanol control (6.5g ethanol/kg), low-CNF (ethanol+150mg CNF/kg) and high-CNF (ethanol+300mg CNF/kg) groups.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "ethanol", "ethanol" ], "offsets": [ [ 60, 67 ], [ 82, 89 ], [ 104, 111 ], [ 140, 147 ] ] }, { "pmid": "23416143", "text": "Consumption of alcohol for 8weeks induced severe liver damage with increases in prognostic indicators such as aspartate transaminase, alanine transaminase in serum whereas co-administration of CNF suppressed their increases.", "type": "CHEMICAL", "entities": [ "alcohol", "aspartate" ], "offsets": [ [ 15, 22 ], [ 110, 119 ] ] }, { "pmid": "23416143", "text": "Excessive accumulations in liver TG and TC in ethanol control group were also suppressed by co-administration of CNF.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23416143", "text": "Co-administration of CNF maintained SOD activity, GSH and malondialdehyde levels close to those of the normal diet group.", "type": "CHEMICAL", "entities": [ "GSH", "malondialdehyde" ], "offsets": [ [ 50, 53 ], [ 58, 73 ] ] }, { "pmid": "23416143", "text": "Chronic consumption of alcohol also stimulated abrupt increases in pro-inflammatory cytokines such as nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in liver otherwise co-administration of CNF effectively suppressed production of these cytokines dose-dependently.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 23, 30 ] ] }, { "pmid": "23416143", "text": "These results indicate that co-administration of CNF with alcohol can alleviate alcohol induced liver damage through preventing lipid formation, protecting antioxidant system and suppressing productions of pro-inflammatory cytokines.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 55, 62 ], [ 77, 84 ] ] }, { "pmid": "23349501", "text": "Impaired local production of pro-resolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation.\n", "type": "CHEMICAL", "entities": [ "17-HDHA" ], "offsets": [ [ 74, 81 ] ] }, { "pmid": "23349501", "text": "Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration including insulin resistance and type 2 diabetes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349501", "text": "Chronic inflammation may be a consequence of a failure to actively resolve inflammation,and could result from a lack of local specialized pro-resolving lipid mediators (SPM) such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).", "type": "CHEMICAL", "entities": [ "resolvins", "polyunsaturated fatty acids", "eicosapentaenoic acid", "EPA", "docosahexaenoic acid", "DHA" ], "offsets": [ [ 182, 191 ], [ 234, 261 ], [ 262, 283 ], [ 285, 288 ], [ 294, 314 ], [ 316, 319 ] ] }, { "pmid": "23349501", "text": "We assessed obesity-induced changes of n-3-derived SPM in adipose tissue and effects of dietary EPA/DHA thereon.", "type": "CHEMICAL", "entities": [ "EPA", "DHA" ], "offsets": [ [ 96, 99 ], [ 100, 103 ] ] }, { "pmid": "23349501", "text": "Moreover, we treated obese mice with SPM precursors and investigated effects on inflammation and metabolic dysregulation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23349501", "text": "Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 levels in murine adipose tissue.", "type": "CHEMICAL", "entities": [ "DHA", "17-hydroxydocosahexaenoic acid", "17-HDHA", "resolvin D1", "protectin D1" ], "offsets": [ [ 32, 35 ], [ 44, 74 ], [ 76, 83 ], [ 85, 96 ], [ 112, 124 ] ] }, { "pmid": "23349501", "text": "Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3 derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity.", "type": "CHEMICAL", "entities": [ "EPA", "DHA" ], "offsets": [ [ 8, 11 ], [ 12, 15 ] ] }, { "pmid": "23349501", "text": "Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression and improved glucose tolerance parallel to insulin sensitivity in obese mice.", "type": "CHEMICAL", "entities": [ "17-HDHA", "glucose" ], "offsets": [ [ 9, 16 ], [ 134, 141 ] ] }, { "pmid": "23349501", "text": "These findings indicate that impaired biosynthesis of certain SPM and SPM precursors including 17-HDHA and protectin D1 contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications.", "type": "CHEMICAL", "entities": [ "17-HDHA", "protectin D1", "17-HDHA" ], "offsets": [ [ 95, 102 ], [ 107, 119 ], [ 186, 193 ] ] }, { "pmid": "23164673", "text": "The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells.\n", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 78, 89 ] ] }, { "pmid": "23164673", "text": "Cinobufagin, a major component of cinobufacini (huachansu), is an important cardenolidal steroid.", "type": "CHEMICAL", "entities": [ "cardenolidal steroid" ], "offsets": [ [ 75, 95 ] ] }, { "pmid": "23164673", "text": "Several studies have suggested that cinobufagin has potent anti-cancer effects.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "23164673", "text": "The present study examines the apoptosis-inducing activity and the underlying mechanism of action of cinobufagin in osteosarcoma (OS) cells.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 100, 111 ] ] }, { "pmid": "23164673", "text": "Our results showed that cinobufagin potently inhibited the proliferation of U2OS, MG63 and SaOS-2 cells.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "23164673", "text": "Significant increases in G2/M cell-cycle arrest and apoptosis in OS cells were also observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164673", "text": "The expression levels of several apoptotic proteins were assessed after cinobufagin treatment in U2OS cells.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 71, 82 ] ] }, { "pmid": "23164673", "text": "Among them, xIAP, cIAP-1, survivin and Bcl-2 levels decreased remarkably, while the levels of Bax and cleaved-PARP increased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23164673", "text": "Furthermore, we validated the inhibition of GSK-3β/NF-κB signaling following cinobufagin treatment.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 76, 87 ] ] }, { "pmid": "23164673", "text": "Western blots showed a decrease in nuclear p65 protein expression after exposure to different concentrations of cinobufagin, while the phosphorylation of GSK-3β was simultaneously increased.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 109, 120 ] ] }, { "pmid": "23164673", "text": "Transduction with constitutively active forms of GSK-3β could protect against the downregulation of p65 and upregulation of cleaved-PARP that are induced by cinobufagin treatment.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 153, 164 ] ] }, { "pmid": "23164673", "text": "However, combined treatment with cinobufagin and SB216367 resulted in a significant reduction in p65 and an increase in cleaved-PARP in U2OS cells.", "type": "CHEMICAL", "entities": [ "cinobufagin", "SB216367" ], "offsets": [ [ 28, 39 ], [ 44, 52 ] ] }, { "pmid": "23164673", "text": "Altogether, these results show that cinobufagin is a promising agent for the treatment of OS.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "23164673", "text": "These studies are the first to reveal the involvement of the GSK-3β/NF-κB pathway in cinobufagin-induced apoptosis.", "type": "CHEMICAL", "entities": [ "cinobufagin" ], "offsets": [ [ 80, 91 ] ] }, { "pmid": "23152186", "text": "Arsenic activates endothelin-1 Gi protein-coupled receptor signaling to inhibit stem cell differentiation in adipogenesis.\n", "type": "CHEMICAL", "entities": [ "Arsenic" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23152186", "text": "Dysfunctional lipid and glucose metabolism contribute to metabolic syndrome-a major public health concern that enhances cardiovascular disease risk.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23152186", "text": "Arsenic (As(III)) exposure may increase metabolic syndrome and cardiovascular disease risk by impairing adipose tissue differentiation, function, and insulin sensitivity through pathogenic mechanisms that remain unclear.", "type": "CHEMICAL", "entities": [ "Arsenic", "As(III)" ], "offsets": [ [ 0, 7 ], [ 9, 16 ] ] }, { "pmid": "23152186", "text": "We hypothesized that As(III) signals through the Pertussis toxin (Ptx) sensitive, Gi protein-coupled receptor (GPCR) to impair adipogenesis, as previously demonstrated for its stimulation of vascular oxidant generation, angiogenesis, and remodeling.", "type": "CHEMICAL", "entities": [ "As(III)" ], "offsets": [ [ 21, 28 ] ] }, { "pmid": "23152186", "text": "Because both As(III) and GPCR ligands inhibit progenitor cell differentiation into adipocytes, we investigated the hypothesis in a model of low-passage human mesenchymal stem cells (hMSC).", "type": "CHEMICAL", "entities": [ "As(III)" ], "offsets": [ [ 13, 20 ] ] }, { "pmid": "23152186", "text": "As(III)", "type": "CHEMICAL", "entities": [ "As(III)" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23152186", "text": "(0.1-1.0 µM) suppressed dexamethasone/insulin-induced hMSC adipogenesis, as indicated by decreased transcriptional promoters of differentiation, decreased fat droplet formation, and decreased expression of differentiated adipocyte markers, such as adiponectin and perilipin.", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 24, 37 ] ] }, { "pmid": "23152186", "text": "Preincubating hMSC with Ptx prevented 90% of the suppressive effect of As(III).", "type": "CHEMICAL", "entities": [ "As(III)" ], "offsets": [ [ 70, 77 ] ] }, { "pmid": "23152186", "text": "Selective competitive antagonists of Gi-coupled endothelin-1 type A and B receptors were ~60% effective in blocking As(III) inhibition and combination of antagonists to both receptors were 85% effective.", "type": "CHEMICAL", "entities": [ "As(III)" ], "offsets": [ [ 115, 122 ] ] }, { "pmid": "23152186", "text": "In contrast, antagonists to the sphingosine-1-phosphate type 1 receptor (previously shown to mediate As(III) vascular effects) or the angiotensin II type 1 receptor were ineffective in blocking As(III) effects.", "type": "CHEMICAL", "entities": [ "sphingosine-1-phosphate", "As(III)", "As(III)" ], "offsets": [ [ 31, 54 ], [ 100, 107 ], [ 193, 200 ] ] }, { "pmid": "23152186", "text": "These studies suggest a majority of arsenic-inhibited adipocyte differentiation, and metabolism requires endothelin-1 GPCRs and that As(III) effects on GPCR signaling are tissue and context specific.", "type": "CHEMICAL", "entities": [ "arsenic", "As(III)" ], "offsets": [ [ 35, 42 ], [ 132, 139 ] ] }, { "pmid": "23152186", "text": "This may represent a significant mechanism for the contribution of arsenic exposure to increased metabolic and cardiovascular diseases.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 66, 73 ] ] }, { "pmid": "9079657", "text": "Activation-dependent exposure of the inter-EGF sequence Leu83-Leu88 in factor Xa mediates ligand binding to effector cell protease receptor-1.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "Binding of factor Xa to human umbilical vein endothelial cells (HUVEC) is contributed by effector cell protease receptor-1 (EPR-1).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "The structural requirements of this recognition were investigated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "Factor Xa or catalytically inactive 5-dimethylaminonaphthalene-1sulfonyl (dansyl) Glu-Gly-Arg-(DEGR)-chloromethylketone-factor Xa bound indistinguishably to HUVEC and EPR-1 transfectants, and inhibited equally well the binding of 125I-factor Xa to these cells.", "type": "CHEMICAL", "entities": [ "5-dimethylaminonaphthalene-1sulfonyl (dansyl) Glu-Gly-Arg-(DEGR)-chloromethylketone" ], "offsets": [ [ 36, 119 ] ] }, { "pmid": "9079657", "text": "Similarly, factor Xa active site inhibitors TAP or NAP5 did not reduce ligand binding to EPR-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "A factor X peptide duplicating the inter-EGF sequence Leu83-Phe84-Thr85-Arg86-Lys87-Leu88- (Gly) inhibited factor V/Va-independent prothrombin activation by HUVEC and blocked binding of 125I-factor Xa to these cells in a dose-dependent manner", "type": "CHEMICAL", "entities": [ "Gly", "125I" ], "offsets": [ [ 92, 95 ], [ 186, 190 ] ] }, { "pmid": "9079657", "text": "(IC50 approximately 20-40 microM).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "In contrast, none of the other factor X peptides tested or a control peptide with the inter-EGF sequence in scrambled order was effective.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "A recombinant chimeric molecule expressing the factor X sequence Leu83-Leu88 within a factor IX backbone inhibited binding of 125I-factor Xa to HUVEC and EPR-1 transfectants in a dose-dependent fashion, while recombinant factor IX or plasma IXa had no effect.", "type": "CHEMICAL", "entities": [ "125I" ], "offsets": [ [ 126, 130 ] ] }, { "pmid": "9079657", "text": "An antibody generated against the factor X peptide 83-88, and designated JC15, inhibited 125I-factor Xa binding to HUVEC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "The JC15 antibody bound to factor Xa and the recombinant IX/X83-88 chimera in a concentration dependent manner, while no specific reactivity with factors X or IXa was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "Furthermore, binding of 125I-factor Xa to immobilized JC15 was inhibited by molar excess of unlabeled factor Xa, but not by comparable concentrations of factors X or IXa.", "type": "CHEMICAL", "entities": [ "125I" ], "offsets": [ [ 24, 28 ] ] }, { "pmid": "9079657", "text": "These findings identify the inter-EGF sequence Leu83-Leu88 in factor Xa as a novel recognition site for EPR-1, and suggest its potential role as a protease activation-dependent neo-epitope.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9079657", "text": "This interacting motif may help elucidate the contribution of factor Xa to cellular assembly of coagulation and vascular injury.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23479389", "text": "[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease.\n", "type": "CHEMICAL", "entities": [ "[6]-gingerol" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23479389", "text": "Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23479389", "text": "A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23479389", "text": "[6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23479389", "text": "The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23479389", "text": "The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.", "type": "CHEMICAL", "entities": [ "[6]-gingerol" ], "offsets": [ [ 29, 41 ] ] }, { "pmid": "23541928", "text": "Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541928", "text": "Biodegradable oligo(poly(ethylene glycol) fumarate) (OPF) composite hydrogels have been investigated for the delivery of growth factors (GFs) with the aid of gelatin microparticles (GMPs) and stem cell populations for osteochondral tissue regeneration.", "type": "CHEMICAL", "entities": [ "oligo(poly(ethylene glycol) fumarate)", "OPF" ], "offsets": [ [ 14, 51 ], [ 53, 56 ] ] }, { "pmid": "23541928", "text": "In this study, a bilayered OPF composite hydrogel that mimics the distinctive hierarchical structure of native osteochondral tissue was utilized to investigate the effect of transforming growth factor-β3 (TGF-β3) with varying release kinetics and/or insulin-like growth factor-1 (IGF-1) on osteochondral tissue regeneration in a rabbit full-thickness osteochondral defect model.", "type": "CHEMICAL", "entities": [ "OPF" ], "offsets": [ [ 27, 30 ] ] }, { "pmid": "23541928", "text": "The four groups investigated included (i) a blank control (no GFs), (ii) GMP-loaded IGF-1 alone, (iii) GMP-loaded IGF-1 and gel-loaded TGF-β3, and (iv) GMP-loaded IGF-1 and GMP-loaded TGF-β3 in OPF composite hydrogels.", "type": "CHEMICAL", "entities": [ "OPF" ], "offsets": [ [ 192, 195 ] ] }, { "pmid": "23541928", "text": "The results of an in vitro release study demonstrated that TGF-β3 release kinetics could be modulated by the GF incorporation method.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541928", "text": "At 12weeks post-implantation, the quality of tissue repair in both chondral and subchondral layers was analyzed based on quantitative histological scoring.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541928", "text": "All groups incorporating GFs resulted in a significant improvement in cartilage morphology compared to the control.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541928", "text": "Single delivery of IGF-1 showed higher scores in subchondral bone morphology as well as chondrocyte and glycosaminoglycan amount in adjacent cartilage tissue when compared to a dual delivery of IGF-1 and TGF-β3, independent of the TGF-β3 release kinetics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23541928", "text": "The results suggest that although the dual delivery of TGF-β3 and IGF-1 may not synergistically enhance the quality of engineered tissue, the delivery of IGF-1 alone from bilayered composite hydrogels positively affects osteochondral tissue repair and holds promise for osteochondral tissue engineering applications.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23494186", "text": "LDL Cholesterol Goals in High-Risk Patients: How Low Do We Go and How Do We Get There?\n", "type": "CHEMICAL", "entities": [ "Cholesterol" ], "offsets": [ [ 4, 15 ] ] }, { "pmid": "23494186", "text": "It is widely recognised that low-density lipoprotein cholesterol (LDL-C) is one of the most important and modifiable risk factors for cardiovascular disease (CVD).", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "23494186", "text": "Statins (HMG-CoA reductase inhibitors) have consistently been shown to decrease both LDL-C and CVD risk in almost all patient categories, with the exception of heart and kidney failure as well as advanced aortic stenosis.", "type": "CHEMICAL", "entities": [ "HMG-CoA" ], "offsets": [ [ 9, 16 ] ] }, { "pmid": "23494186", "text": "As a consequence, statins have become the cornerstone in current prevention guidelines.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23494186", "text": "In patients who do not reach the LDL-C target, combination therapy with additional LDL-C lowering drugs (e.g. ezetimibe, bile acid sequestrants or fibrates) should be considered.", "type": "CHEMICAL", "entities": [ "ezetimibe", "bile acid", "fibrates" ], "offsets": [ [ 110, 119 ], [ 121, 130 ], [ 147, 155 ] ] }, { "pmid": "23494186", "text": "Guidelines provide different LDL-C levels to strive for, depending on the CVD risk.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23494186", "text": "In this review, we describe the rationale for these LDL-C targets and how these goals might be reached by current and future therapies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10839989", "text": "Contrasting effects of N5-substituted tetrahydrobiopterin derivatives on phenylalanine hydroxylase, dihydropteridine reductase and nitric oxide synthase.\n", "type": "CHEMICAL", "entities": [ "dihydropteridine", "nitric oxide", "N5-substituted tetrahydrobiopterin", "phenylalanine" ], "offsets": [ [ 100, 116 ], [ 131, 143 ], [ 23, 57 ], [ 73, 86 ] ] }, { "pmid": "10839989", "text": "Tetrahydrobiopterin [(6R)-5,6,7,8-tetrahydro-L-biopterin, H(4)biopterin] is one of several cofactors of nitric oxide synthases (EC 1.14.13.39).", "type": "CHEMICAL", "entities": [ "Tetrahydrobiopterin", "nitric oxide", "(6R)-5,6,7,8-tetrahydro-L-biopterin", "H(4)biopterin" ], "offsets": [ [ 0, 19 ], [ 104, 116 ], [ 21, 56 ], [ 58, 71 ] ] }, { "pmid": "10839989", "text": "Here we compared the action of N(5)-substituted derivatives on recombinant rat neuronal nitric oxide synthase with their effects on dihydropteridine reductase (EC 1.6.99.7) and phenylalanine hydroxylase (EC 1.14.16.1),the well-studied classical H(4)biopterin-dependent reactions.", "type": "CHEMICAL", "entities": [ "N(5)", "nitric oxide", "dihydropteridine", "phenylalanine", "H(4)biopterin" ], "offsets": [ [ 31, 35 ], [ 88, 100 ], [ 132, 148 ], [ 177, 190 ], [ 245, 258 ] ] }, { "pmid": "10839989", "text": "H(4)biopterin substituted at N(5) with methyl, hydroxymethyl, formyl and acetyl groups were used.", "type": "CHEMICAL", "entities": [ "H(4)biopterin", "N(5)", "methyl", "hydroxymethyl", "formyl", "acetyl" ], "offsets": [ [ 0, 13 ], [ 29, 33 ], [ 39, 45 ], [ 47, 60 ], [ 62, 68 ], [ 73, 79 ] ] }, { "pmid": "10839989", "text": "Substitution at N(5) occurs at a position critical to the redox cycle of the cofactor in phenylalanine hydroxylase/dihydropteridine reductase.", "type": "CHEMICAL", "entities": [ "N(5)", "phenylalanine", "dihydropteridine" ], "offsets": [ [ 16, 20 ], [ 89, 102 ], [ 115, 131 ] ] }, { "pmid": "10839989", "text": "We also included N(2)'-methyl H(4)biopterin, a derivative substituted at a position not directly involved in redox cycling, as a control.", "type": "CHEMICAL", "entities": [ "N(2)'-methyl H(4)biopterin" ], "offsets": [ [ 17, 43 ] ] }, { "pmid": "10839989", "text": "As compared with N(5)-methyl H(4)biopterin, N(5)-formyl H(4)biopterin bound with twice the capacity but stimulated nitric oxide synthase to a lesser extent.", "type": "CHEMICAL", "entities": [ "N(5)-methyl H(4)biopterin", "N(5)-formyl H(4)biopterin", "nitric oxide" ], "offsets": [ [ 17, 42 ], [ 44, 69 ], [ 115, 127 ] ] }, { "pmid": "10839989", "text": "Depending on the substituent used, N(5)-substituted derivatives were redox-active: N(5)-methyl- and N(5)-hydroxyl methyl H(4)biopterin, but not N(5)-formyl- and N(5)-acetyl H(4)biopterin, reduced 2,6-dichlorophenol indophenol.", "type": "CHEMICAL", "entities": [ "N(5)-methyl", "N(5)-hydroxyl methyl H(4)biopterin", "N(5)-formyl", "N(5)-acetyl H(4)biopterin", "2,6-dichlorophenol indophenol", "N(5)" ], "offsets": [ [ 83, 94 ], [ 100, 134 ], [ 144, 155 ], [ 161, 186 ], [ 196, 225 ], [ 35, 39 ] ] }, { "pmid": "10839989", "text": "N(5)-Substituted H(4)biopterin derivatives were not oxidized to products serving as substrates for dihydropteridine reductase and,depending on the substituent, were competitive inhibitors of phenylalanine hydroxylase: N(5)-methyl- and N(5)-hydroxymethyl H(4)biopterin inhibited phenylalanine hydroxylase, whereas N(5)-formyl- and N(5)-acetyl H(4)biopterin had no effect.", "type": "CHEMICAL", "entities": [ "N(5)-Substituted H(4)biopterin", "dihydropteridine", "phenylalanine", "N(5)-methyl", "N(5)-hydroxymethyl H(4)biopterin", "phenylalanine", "N(5)-formyl", "N(5)-acetyl H(4)biopterin" ], "offsets": [ [ 0, 30 ], [ 99, 115 ], [ 191, 204 ], [ 218, 229 ], [ 235, 267 ], [ 278, 291 ], [ 313, 324 ], [ 330, 355 ] ] }, { "pmid": "10839989", "text": "Our data demonstrate differences in the mechanism of stimulation of phenylalanine hydroxylase and nitric oxide synthase by H(4)biopterin.", "type": "CHEMICAL", "entities": [ "phenylalanine", "nitric oxide", "H(4)biopterin" ], "offsets": [ [ 68, 81 ], [ 98, 110 ], [ 123, 136 ] ] }, { "pmid": "10839989", "text": "They are compatible with a novel, non-classical, redox-active contribution of H(4)biopterin to the catalysis of the nitric oxide synthase reaction.", "type": "CHEMICAL", "entities": [ "H(4)biopterin", "nitric oxide" ], "offsets": [ [ 78, 91 ], [ 116, 128 ] ] }, { "pmid": "21712771", "text": "Vesicular monoamine transporter-1 (VMAT-1) mRNA", "type": "CHEMICAL", "entities": [ "monoamine" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "21712771", "text": "and immunoreactive proteins in mouse brain.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "OBJECTIVE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "Vesicular monoamine transporter 1 (VMAT-1) mRNA and protein were examined (1) to determine whether adult mouse brain expresses full-length VMAT-1 mRNA", "type": "CHEMICAL", "entities": [ "monoamine" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "21712771", "text": "that can be translated to functional transporter protein and (2) to compare immunoreactive VMAT-1 proteins in brain and adrenal.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "VMAT-1 mRNA was detected in mouse brain with RT-PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "The cDNA was sequenced, cloned into an expression vector, transfected into COS-1 cells, and cell protein was assayed for VMAT-1 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "Immunoreactive proteins were examined on western blots probed with four different antibodies to VMAT-1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "Sequencing confirmed identity of the entire coding sequences of VMAT-1 cDNA from mouse medulla oblongata/pons and adrenal to a Gen-Bank reference sequence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "Transfection of the brain cDNA into COS-1 cells resulted in transporter activity that was blocked by the VMAT inhibitor reserpine and a proton ionophore, but not by tetrabenazine, which has a high affinity for VMAT-2.", "type": "CHEMICAL", "entities": [ "reserpine", "tetrabenazine" ], "offsets": [ [ 120, 129 ], [ 165, 178 ] ] }, { "pmid": "21712771", "text": "Antibodies to either the C- or N- terminus of VMAT-1 detected two proteins (73 and 55 kD) in transfected COS-1 cells.", "type": "CHEMICAL", "entities": [ "C", "N" ], "offsets": [ [ 25, 26 ], [ 31, 32 ] ] }, { "pmid": "21712771", "text": "The C-terminal antibodies detected both proteins in extracts of mouse medulla/pons, cortex, hypothalamus, and cerebellum but only the 73 kD protein and higher molecular weight immunoreactive proteins in mouse adrenal and rat PC12 cells, which are positive controls for rodent VMAT-1.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 4, 5 ] ] }, { "pmid": "21712771", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "21712771", "text": "These findings demonstrate that a functional VMAT-1 mRNA coding sequence is expressed in mouse brain and suggest processing of VMAT-1 protein differs in mouse adrenal and brain.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10561751", "text": "Chloride channels in renal disease.\n", "type": "CHEMICAL", "entities": [ "Chloride" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "10561751", "text": "Recent studies of hereditary renal tubular disorders have facilitated the identification and roles of chloride channels and cotransporters in the regulation of the most abundant anion, Cl-, in the ECF.", "type": "CHEMICAL", "entities": [ "chloride", "Cl-" ], "offsets": [ [ 102, 110 ], [ 185, 188 ] ] }, { "pmid": "10561751", "text": "Thus, mutations that result in a loss of function of the voltage-gated chloride channel, CLC-5, are associated with Dent's disease, which is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure.", "type": "CHEMICAL", "entities": [ "chloride" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "10561751", "text": "Mutations of another voltage-gated chloride channel, CLC-Kb, are associated with a form of Bartter's syndrome, whereas other forms of Bartter's syndrome are caused by mutations in the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC2) and the potassium channel, ROMK.", "type": "CHEMICAL", "entities": [ "chloride", "bumetanide", "sodium-potassium-chloride", "potassium" ], "offsets": [ [ 35, 43 ], [ 184, 194 ], [ 205, 230 ], [ 261, 270 ] ] }, { "pmid": "10561751", "text": "Finally, mutations of the thiazide-sensitive sodium-chloride cotransporter (NCCT) are associated with Gitelman's syndrome.", "type": "CHEMICAL", "entities": [ "thiazide", "sodium-chloride" ], "offsets": [ [ 26, 34 ], [ 45, 60 ] ] }, { "pmid": "10561751", "text": "These studies have helped to elucidate some of the renal tubular mechanisms regulating mineral homeostasis and the role of chloride channels.", "type": "CHEMICAL", "entities": [ "chloride" ], "offsets": [ [ 123, 131 ] ] }, { "pmid": "16801455", "text": "Mitochondrial arginase II modulates nitric-oxide synthesis through nonfreely exchangeable L-arginine pools in human endothelial cells.\n", "type": "CHEMICAL", "entities": [ "nitric-oxide", "L-arginine" ], "offsets": [ [ 36, 48 ], [ 90, 100 ] ] }, { "pmid": "16801455", "text": "Reduced synthesis of nitric oxide (NO) contributes to the endothelial dysfunction and may be related to limited availability of L-arginine, the common substrate of constitutive nitric-oxide synthase (NOS) and cytosolic arginase I and mitochondrial arginase II.", "type": "CHEMICAL", "entities": [ "L-arginine", "nitric-oxide", "nitric oxide", "NO" ], "offsets": [ [ 128, 138 ], [ 177, 189 ], [ 21, 33 ], [ 35, 37 ] ] }, { "pmid": "16801455", "text": "To determine whether arginases modulate the endothelial NO synthesis, we investigated the effects of the competitive arginase inhibitor N(omega)-hydroxy-nor-L-arginine (Nor-NOHA) on the activity of NOS, arginases, and L-arginine transporter and on NO release at surface of human umbilical vein endothelial cells (HUVECs).", "type": "CHEMICAL", "entities": [ "NO", "N(omega)-hydroxy-nor-L-arginine", "Nor-NOHA", "L-arginine", "NO" ], "offsets": [ [ 56, 58 ], [ 136, 167 ], [ 169, 177 ], [ 218, 228 ], [ 248, 250 ] ] }, { "pmid": "16801455", "text": "In unstimulated cells, Nor-NOHA dose-dependently reduced the arginase activity with maximal inhibition at 20 microM. When HUVECs were stimulated by thrombin without extracellular L-arginine, Nor-NOHA dose-dependently increased the NOS activity and the NO release with maximal effects at 20 microM. Extracellular L-arginine also dose-dependently increased NO release and arginase activity.", "type": "CHEMICAL", "entities": [ "Nor-NOHA", "L-arginine", "Nor-NOHA", "NO", "L-arginine", "NO" ], "offsets": [ [ 23, 31 ], [ 179, 189 ], [ 191, 199 ], [ 252, 254 ], [ 312, 322 ], [ 355, 357 ] ] }, { "pmid": "16801455", "text": "When HUVECs were stimulated by thrombin in the presence of 100 microM L-arginine, NOS activity and NO release were similar in untreated and Nor-NOHA-treated cells.", "type": "CHEMICAL", "entities": [ "L-arginine", "NO", "Nor-NOHA" ], "offsets": [ [ 70, 80 ], [ 99, 101 ], [ 140, 148 ] ] }, { "pmid": "16801455", "text": "However, despite activation of L-arginine uptake, the inhibition of arginase activity by Nor-NOHA was still significant.", "type": "CHEMICAL", "entities": [ "L-arginine", "Nor-NOHA" ], "offsets": [ [ 31, 41 ], [ 89, 97 ] ] }, { "pmid": "16801455", "text": "The depletion of freely exchangeable L-arginine pools with extracellular L-lysine did not prevent Nor-NOHA from increasing the NO release.", "type": "CHEMICAL", "entities": [ "L-arginine", "L-lysine", "Nor-NOHA", "NO" ], "offsets": [ [ 37, 47 ], [ 73, 81 ], [ 98, 106 ], [ 127, 129 ] ] }, { "pmid": "16801455", "text": "This indicates the presence of pools, which are accessible to NOS and arginase, but not exchangeable.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16801455", "text": "Interestingly, the mitochondrial arginase II was constitutively expressed, whereas the cytosolic arginase I was barely detectable in HUVECs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16801455", "text": "These data suggest that endothelial NO synthesis depends on the activity of arginase II in mitochondria and l-arginine carriers in cell membrane.", "type": "CHEMICAL", "entities": [ "NO", "l-arginine" ], "offsets": [ [ 36, 38 ], [ 108, 118 ] ] }, { "pmid": "16686685", "text": "The role of late I and antiarrhythmic drugs in EAD formation and termination in Purkinje fibers.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16686685", "text": "Multiple components of cardiac Na current play a role in determining electrical excitation in the heart.", "type": "CHEMICAL", "entities": [ "Na" ], "offsets": [ [ 31, 33 ] ] }, { "pmid": "16686685", "text": "Recently, the role of nonequilibrium components in controlling cardiac action potential plateau duration, and their importance in regulating the occurrence of afterdepolarizations and arrhythmias have garnered more attention.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16686685", "text": "In particular, late Na current (late I(Na)) has been shown to be important in LQT2 and LQT3 arrhythmias.", "type": "CHEMICAL", "entities": [ "Na", "Na" ], "offsets": [ [ 20, 22 ], [ 39, 41 ] ] }, { "pmid": "16686685", "text": "Class III agents like dofetilide, clofilium, and sotalol, which can all cause a drug-induced form of LQT2, significantly lengthen action potential duration at 50% and 90% repolarization in isolated rabbit Purkinje fibers, and can initiate the formation of early afterdepolarizations, and extra beats.", "type": "CHEMICAL", "entities": [ "dofetilide", "clofilium", "sotalol" ], "offsets": [ [ 22, 32 ], [ 34, 43 ], [ 49, 56 ] ] }, { "pmid": "16686685", "text": "These actions can lead to the development of a serious ventricular tachycardia, torsades de pointes, in animal models and patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16686685", "text": "However, pretreatment with agents that block late I(Na), like lidocaine, mexiletine, and RSD1235, a novel mixed ion channel blocker for the rapid pharmacologic conversion of atrial fibrillation, significantly attenuates the prolonging effects of Class III agents or those induced by ATX-II, a specific toxin that delays Na channel inactivation and amplifies late I(Na) greatly, mimicking LQT3.", "type": "CHEMICAL", "entities": [ "Na", "Na", "Na", "lidocaine", "mexiletine", "RSD1235" ], "offsets": [ [ 320, 322 ], [ 365, 367 ], [ 52, 54 ], [ 62, 71 ], [ 73, 83 ], [ 89, 96 ] ] }, { "pmid": "16686685", "text": "The Na channel block caused by lidocaine and RSD1235 can be through the open or inactivated states of the channel, but both equivalently inhibit a late component of Na current (I(Na)), recorded at 22 degrees C using whole-cell patch clamp of Nav 1.5 expressed in HEK cells.", "type": "CHEMICAL", "entities": [ "Na", "lidocaine", "RSD1235", "Na", "Na" ], "offsets": [ [ 4, 6 ], [ 31, 40 ], [ 45, 52 ], [ 165, 167 ], [ 179, 181 ] ] }, { "pmid": "16686685", "text": "These protective actions of lidocaine, mexiletine, and RSD1235 may result, at least in part, from their ability to inhibit late I(Na) during action potential repolarization, and inhibition of the inward currents contributing to EAD and arrhythmia formation.", "type": "CHEMICAL", "entities": [ "lidocaine", "mexiletine", "RSD1235", "Na" ], "offsets": [ [ 28, 37 ], [ 39, 49 ], [ 55, 62 ], [ 130, 132 ] ] }, { "pmid": "10712236", "text": "Polyamine depletion delays apoptosis of rat intestinal epithelial cells.\n", "type": "CHEMICAL", "entities": [ "Polyamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10712236", "text": "The polyamines spermidine, spermine, and their precursor putrescine are essential for cell growth and the regulation of the cell cycle.", "type": "CHEMICAL", "entities": [ "spermidine", "spermine", "polyamines", "putrescine" ], "offsets": [ [ 15, 25 ], [ 27, 35 ], [ 4, 14 ], [ 57, 67 ] ] }, { "pmid": "10712236", "text": "Recent studies suggest that excessive accumulation of polyamines favors either malignant transformation or apoptosis, depending on the cell type and the stimulus.", "type": "CHEMICAL", "entities": [ "polyamines" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "10712236", "text": "This study examines the involvement of polyamines in the induction of apoptosis by the DNA topoisomerase I inhibitor, camptothecin.", "type": "CHEMICAL", "entities": [ "polyamines" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "10712236", "text": "In IEC-6 cells, camptothecin induced apoptosis within 6 h, accompanied by detachment of cells.", "type": "CHEMICAL", "entities": [ "camptothecin" ], "offsets": [ [ 16, 28 ] ] }, { "pmid": "10712236", "text": "Detached cells showed DNA laddering and caspase 3 induction, characteristic features of apoptosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10712236", "text": "Depletion of putrescine, spermidine, and spermine by DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC) that is the first rate-limiting enzyme for polyamine biosynthesis, decreased the apoptotic index.", "type": "CHEMICAL", "entities": [ "putrescine", "spermidine", "spermine", "DL-alpha-difluoromethylornithine", "DFMO", "ornithine", "polyamine" ], "offsets": [ [ 13, 23 ], [ 25, 35 ], [ 41, 49 ], [ 53, 85 ], [ 87, 91 ], [ 118, 127 ], [ 191, 200 ] ] }, { "pmid": "10712236", "text": "Delayed apoptosis was accompanied by a decrease in caspase 3 activity in polyamine-depleted cells.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 73, 82 ] ] }, { "pmid": "10712236", "text": "Addition of putrescine restored the induction of apoptosis as indicated by an increase in the number of detached cells and caspase 3 activity.", "type": "CHEMICAL", "entities": [ "putrescine" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "10712236", "text": "Polyamine depletion did not change the level of caspase 3 protein.", "type": "CHEMICAL", "entities": [ "Polyamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10712236", "text": "Inhibition of S-adenosylmethionine decarboxylase by a specific inhibitor [diethylglyoxal bis-(guanylhydrazone); DEGBG] led to depletion of spermidine and spermine with a significant accumulation of putrescine and induction of ODC.", "type": "CHEMICAL", "entities": [ "S-adenosylmethionine", "diethylglyoxal bis-(guanylhydrazone)", "DEGBG", "spermidine", "spermine", "putrescine" ], "offsets": [ [ 14, 34 ], [ 74, 110 ], [ 112, 117 ], [ 139, 149 ], [ 154, 162 ], [ 198, 208 ] ] }, { "pmid": "10712236", "text": "The DEGBG-treated cells showed an increase in apoptosis, suggesting the importance of putrescine in the apoptotic process.", "type": "CHEMICAL", "entities": [ "DEGBG", "putrescine" ], "offsets": [ [ 4, 9 ], [ 86, 96 ] ] }, { "pmid": "10712236", "text": "Addition of putrescine to DFMO-treated cell extracts did not increase caspase 3 activity.", "type": "CHEMICAL", "entities": [ "putrescine", "DFMO" ], "offsets": [ [ 12, 22 ], [ 26, 30 ] ] }, { "pmid": "10712236", "text": "The above results indicate that polyamine depletion delays the onset of apoptosis in IEC-6 cells and confers protection against DNA damaging agents, suggesting that polyamines might be involved in the caspase activating signal cascade.", "type": "CHEMICAL", "entities": [ "polyamine", "polyamines" ], "offsets": [ [ 32, 41 ], [ 165, 175 ] ] }, { "pmid": "23620660", "text": "Profile of certolizumab and its potential in the treatment of psoriatic arthritis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-alpha) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab' fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-alpha.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-alpha agents tested for the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA.", "type": "CHEMICAL", "entities": [ "PEG" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "23620660", "text": "In contrast to other anti-TNF-alpha agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-alpha efficacy in Crohn's disease.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23620660", "text": "This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313633", "text": "Predictive modeling of insulin release profile from cross-linked chitosan microspheres.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313633", "text": "Insulin-loaded microspheres composed of chitosan 3% (w/v), and loading 120 IU insulin were produced by emulsion cross-linking method.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313633", "text": "Cross-linking time was 5 h and glutaraldehyde 3.5% (v/v) was used as cross-linker.", "type": "CHEMICAL", "entities": [ "glutaraldehyde" ], "offsets": [ [ 31, 45 ] ] }, { "pmid": "23313633", "text": "Swelling ratio studies were evaluated to predict release of insulin from chitosan microspheres.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313633", "text": "Bacitracin and sodium taurocholate were incorporated in the formulations as proteolytic enzyme inhibitor and absorption enhancer, respectively.", "type": "CHEMICAL", "entities": [ "Bacitracin", "sodium taurocholate" ], "offsets": [ [ 0, 10 ], [ 15, 34 ] ] }, { "pmid": "23313633", "text": "In vitro insulin release studies were performed in phosphate buffer pH 7.4 and also in HCl pH 2 with and without trypsin.", "type": "CHEMICAL", "entities": [ "phosphate", "HCl" ], "offsets": [ [ 51, 60 ], [ 87, 90 ] ] }, { "pmid": "23313633", "text": "Activity of bacitracin was also evaluated.", "type": "CHEMICAL", "entities": [ "bacitracin" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "23313633", "text": "In vitro release showed a controlled profile up to 12 h and the formulation containing 0.15% (w/v) of bacitracin revealed a maximum biological activity of about 49.1 ± 4.1%.", "type": "CHEMICAL", "entities": [ "bacitracin" ], "offsets": [ [ 102, 112 ] ] }, { "pmid": "23313633", "text": "Mathematical modeling using Higuchi and Korsmeyer-Peppas suggested a non-Fickian diffusion as the mechanism of insulin release.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313633", "text": "Insulin-loaded chitosan microspheres for oral delivery showed to be an innovative and reliable delivery system to overcome conventional insulin therapy.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14692707", "text": "Serum carvedilol concentration and its relation to change in plasma brain natriuretic peptide level in the treatment of heart failure: a preliminary study.\n", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 6, 16 ] ] }, { "pmid": "14692707", "text": "OBJECTIVE: To examine the influence of carvedilol dose and concentration in serum on plasma brain natriuretic peptide (BNP), a measure of heart failure progression.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "14692707", "text": "METHODS: 12 patients with New York Heart Association (NYHA) functional class II-III chronic heart failure were enrolled in the study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14692707", "text": "They received carvedilol at daily doses of 1-20 mg with a 1-2 weekly adjustment.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "14692707", "text": "Serum carvedilol trough concentrations were measured in steady-state using a specific fluorescence HPLC method.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 6, 16 ] ] }, { "pmid": "14692707", "text": "The degree of improvement in heart failure was assessed from the ratio of change in the plasma BNP concentration, 2 weeks, 1 month and 3 months after the commencement of carvedilol administration.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 170, 180 ] ] }, { "pmid": "14692707", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14692707", "text": "From the pharmacokinetic aspect, there was no valid correlation between the trough serum carvedilol concentration (Cmin) and daily dose per body weight (Dd/BW), indicating that there was a wide difference in the carvedilol elimination capacity among individuals.", "type": "CHEMICAL", "entities": [ "carvedilol", "carvedilol" ], "offsets": [ [ 89, 99 ], [ 212, 222 ] ] }, { "pmid": "14692707", "text": "A significant decrease in the BNP was observed at the 3rd month in patients treated with the high dose (> 750 mg/3 months).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "14692707", "text": "On the other hand, in patients with a mean serum carvedilol level (Cmin) of less than 2.5 nmol/l up to 2 weeks after the start ofcarvedilol therapy, the degree of reduction in the BNP value after the 3rd month was significantly larger, relative to the patient group with Cmin over 2.5 nmol/l. CONCLUSIONS:", "type": "CHEMICAL", "entities": [ "carvedilol", "carvedilol" ], "offsets": [ [ 49, 59 ], [ 129, 139 ] ] }, { "pmid": "14692707", "text": "The total carvedilol dose was confirmed to be one of the determinants for improvement in heart failure, and it was suggested that the initial serum level also plays an important role in therapeutic outcome.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "14692707", "text": "Therefore, it may be important to monitor the serum carvedilol level at the introductory period to determine the daily dose requirements because of the wide inter-individual variability in its metabolic clearance.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "9666414", "text": "Mechanism of action of leflunomide in rheumatoid arthritis.\n", "type": "CHEMICAL", "entities": [ "leflunomide" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "9666414", "text": "Leflunomide, a novel drug with proven efficacy in rheumatoid arthritis, is an isoxazol derivative structurally unrelated to other immunomodulatory drugs.", "type": "CHEMICAL", "entities": [ "Leflunomide", "isoxazol" ], "offsets": [ [ 0, 11 ], [ 78, 86 ] ] }, { "pmid": "9666414", "text": "Leflunomide is rapidly metabolized to its active form, A77 1726.", "type": "CHEMICAL", "entities": [ "Leflunomide", "A77 1726" ], "offsets": [ [ 0, 11 ], [ 55, 63 ] ] }, { "pmid": "9666414", "text": "Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases.", "type": "CHEMICAL", "entities": [ "A77 1726", "dihydroorotate", "tyrosine" ], "offsets": [ [ 50, 58 ], [ 74, 88 ], [ 129, 137 ] ] }, { "pmid": "9666414", "text": "DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action.", "type": "CHEMICAL", "entities": [ "A77 1726", "tyrosine" ], "offsets": [ [ 51, 59 ], [ 73, 81 ] ] }, { "pmid": "9666414", "text": "Stimulated lymphocytes must increase ribonucleotide levels from 8 to 16-fold before proceeding from the G1 into the S phase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9666414", "text": "Increased levels of ribonucleotides can only be met by de novo ribonucleotide synthesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9666414", "text": "At low levels of ribonucleotides, p53, a \"sensor\" molecule, gets activated and prevents progression through the cell cycle.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9666414", "text": "Therefore, an inhibitor of de novo uridine monophosphate synthesis would predictably arrest stimulated cells at the G1 phase.", "type": "CHEMICAL", "entities": [ "uridine monophosphate" ], "offsets": [ [ 35, 56 ] ] }, { "pmid": "9666414", "text": "In support of this mechanism of action, in vitro mitogen stimulated human peripheral blood lymphocytes treated with A77 1726 undergo arrest at the G1 phase; this inhibition is reversed by uridine.", "type": "CHEMICAL", "entities": [ "A77 1726", "uridine" ], "offsets": [ [ 116, 124 ], [ 188, 195 ] ] }, { "pmid": "12513997", "text": "L-proline accumulation", "type": "CHEMICAL", "entities": [ "L-proline" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "12513997", "text": "and", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12513997", "text": "freeze tolerance of Saccharomyces cerevisiae are caused by a mutation in the PRO1 gene encoding gamma-glutamyl kinase.\n", "type": "CHEMICAL", "entities": [ "gamma-glutamyl" ], "offsets": [ [ 96, 110 ] ] }, { "pmid": "12513997", "text": "We previously isolated a mutant which showed a high tolerance to freezing that correlated with higher levels of intracellular L-proline derived from L-proline analogue-resistant mutants.", "type": "CHEMICAL", "entities": [ "L-proline", "L-proline" ], "offsets": [ [ 126, 135 ], [ 149, 158 ] ] }, { "pmid": "12513997", "text": "The mutation responsible for the analogue resistance and L-proline accumulation was a single nuclear dominant mutation.", "type": "CHEMICAL", "entities": [ "L-proline" ], "offsets": [ [ 57, 66 ] ] }, { "pmid": "12513997", "text": "By introducing the mutant-derived genomic library into a non-L-proline-utilizing strain, the mutant was found to carry an allele of the wild-type PRO1 gene encoding gamma-glutamyl kinase, which resulted in a single amino acid replacement; Asp (GAC) at position 154 was replaced by Asn (AAC).", "type": "CHEMICAL", "entities": [ "L-proline", "gamma-glutamyl", "amino acid", "Asp", "Asn" ], "offsets": [ [ 61, 70 ], [ 165, 179 ], [ 215, 225 ], [ 239, 242 ], [ 281, 284 ] ] }, { "pmid": "12513997", "text": "Interestingly, the allele of PRO1 was shown to enhance the activities of gamma-glutamyl kinase and gamma-glutamyl phosphate reductase, both of which catalyze the first two steps of L-proline synthesis from L-glutamate and which together may form a complex in vivo.", "type": "CHEMICAL", "entities": [ "gamma-glutamyl", "gamma-glutamyl phosphate", "L-proline", "L-glutamate" ], "offsets": [ [ 73, 87 ], [ 99, 123 ], [ 181, 190 ], [ 206, 217 ] ] }, { "pmid": "12513997", "text": "When cultured in liquid minimal medium, yeast cells expressing the mutated gamma-glutamyl kinase were found to accumulate intracellular L-proline and showed a prominent increase in cell viability after freezing at -20 degrees C compared to the viability of cells harboring the wild-type PRO1 gene.", "type": "CHEMICAL", "entities": [ "L-proline", "gamma-glutamyl" ], "offsets": [ [ 136, 145 ], [ 75, 89 ] ] }, { "pmid": "12513997", "text": "These results suggest that the altered gamma-glutamyl kinase results in stabilization of the complex or has an indirect effect on gamma-glutamyl phosphate reductase activity, which leads to an increase in L-proline production in Saccharomyces cerevisiae.", "type": "CHEMICAL", "entities": [ "gamma-glutamyl", "gamma-glutamyl phosphate", "L-proline" ], "offsets": [ [ 39, 53 ], [ 130, 154 ], [ 205, 214 ] ] }, { "pmid": "12513997", "text": "The approach described in this paper could be a practical method for breeding novel freeze-tolerant yeast strains.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23145773", "text": "Structural optimization of 2,5-thiophene amides as highly potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis.\n", "type": "CHEMICAL", "entities": [ "2,5-thiophene amides", "17β-hydroxysteroid" ], "offsets": [ [ 27, 47 ], [ 79, 97 ] ] }, { "pmid": "23145773", "text": "Inhibition of 17β-HSD2 is an attractive mechanism for the treatment of osteoporosis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23145773", "text": "We report here the optimization of human 17β-HSD2 inhibitors in the 2,5-thiophene amide class by varying the size of the linker (n equals 0 and 2) between the amide moiety and the phenyl group.", "type": "CHEMICAL", "entities": [ "2,5-thiophene amide", "amide", "phenyl" ], "offsets": [ [ 66, 85 ], [ 157, 162 ], [ 178, 184 ] ] }, { "pmid": "23145773", "text": "While none of the phenethylamides (n = 2) were active, most of the anilides (n = 0) turned out to moderately or strongly inhibit 17β-HSD2.", "type": "CHEMICAL", "entities": [ "phenethylamides", "anilides" ], "offsets": [ [ 15, 30 ], [ 64, 72 ] ] }, { "pmid": "23145773", "text": "The four most active compounds showed an IC₅₀ of around 60 nM and a very good selectivity toward 17β-HSD1, 17β-HSD4, 17β-HSD5, 11β-HSD1, 11β-HSD2 and the estrogen receptors α and β.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 150, 158 ] ] }, { "pmid": "23145773", "text": "The investigated compounds inhibited monkey 17β-HSD2 moderately, and one of them showed good inhibitory activity on mouse 17β-HSD2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23145773", "text": "SAR studies allowed a first characterization of the human 17β-HSD2 active site, which is predicted to be considerably larger than that of 17β-HSD1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16651698", "text": "Changes in submaxillary gland gene expression in F344 rats by multiple dosing of theophylline.\n", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 81, 93 ] ] }, { "pmid": "16651698", "text": "Multiple exposure to theophylline, a phosphodiesterase (PDE) inhibitor, induces acinar hypertrophy in the salivary gland.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 21, 33 ] ] }, { "pmid": "16651698", "text": "This study examined the effect of theophylline on the gene expression of secretory proteins and phosphodiesterases in the submaxillary gland.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "16651698", "text": "Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally for 4 days.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "16651698", "text": "The gene expressions for the secretory protein, cystatin S (CysS), and PDE subfamilies 3A and 4D in the submaxillary gland were quantified using RT-PCR.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 57, 58 ] ] }, { "pmid": "16651698", "text": "Theophylline exposure resulted in a sustained increase in mRNA expression for CysS and PDE3A, but PDE4D gene expression was unchanged.", "type": "CHEMICAL", "entities": [ "Theophylline" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "16651698", "text": "Our results suggest that submaxillary hypertrophy is primarily caused by the enhanced transcription of CysS, and that the transcription of each PDE subfamily gene is regulated differently.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "eIF4F suppression in breast cancer affects maintenance and progression.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "22484424", "text": "Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, eIF4E and eIF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "22484424", "text": "Targeting this pathway may be of therapeutic benefit.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10434156", "text": "[Psychopharmacological profile of venlafaxine].\n", "type": "CHEMICAL", "entities": [ "venlafaxine" ], "offsets": [ [ 34, 45 ] ] }, { "pmid": "10434156", "text": "Venlafaxine is an antidepressant which blocks reuptake of noradrenaline and serotonin and, to a lesser extent, dopamine.", "type": "CHEMICAL", "entities": [ "Venlafaxine", "dopamine", "noradrenaline", "serotonin" ], "offsets": [ [ 0, 11 ], [ 111, 119 ], [ 58, 71 ], [ 76, 85 ] ] }, { "pmid": "10434156", "text": "These data have been confirmed by behavioral tests.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10434156", "text": "It has been shown that by decreasing the overall cerebral quantity of 5-HT and NA, venlafaxine continued to have an antidepressant action in animal models.", "type": "CHEMICAL", "entities": [ "5-HT", "NA", "venlafaxine" ], "offsets": [ [ 70, 74 ], [ 79, 81 ], [ 83, 94 ] ] }, { "pmid": "10434156", "text": "In addition, the drug has been shown to act preferentially on 5-HT1A and 5-HT1B receptors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23358194", "text": "Transcriptome alterations following developmental atrazine exposure in zebrafish are associated with disruption of neuroendocrine and reproductive system function, cell cycle, and carcinogenesis.\n", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23358194", "text": "Atrazine, a herbicide commonly applied to agricultural areas and a common contaminant of potable water supplies, is implicated as an endocrine-disrupting chemical (EDC) and potential carcinogen.", "type": "CHEMICAL", "entities": [ "Atrazine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23358194", "text": "Studies show that EDCs can cause irreversible changes in tissue formation, decreased reproductive potential, obesity, and cancer.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23358194", "text": "The U.S. Environmental Protection Agency considers an atrazine concentration of ≤ 3 ppb in drinking water safe for consumption.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 54, 62 ] ] }, { "pmid": "23358194", "text": "The specific adverse human health effects associated with a developmental atrazine exposure and the underlying genetic mechanisms of these effects are not well defined.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 72, 80 ] ] }, { "pmid": "23358194", "text": "In this study, zebrafish embryos were exposed to a range of atrazine concentrations to establish toxicity.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 58, 66 ] ] }, { "pmid": "23358194", "text": "Morphological, transcriptomic, and protein alterations were then assessed at 72h postfertilization following developmental atrazine exposure at 0, 0.3, 3, or 30 ppb.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 121, 129 ] ] }, { "pmid": "23358194", "text": "A significant increase in head length was observed in all three atrazine treatments.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 62, 70 ] ] }, { "pmid": "23358194", "text": "Transcriptomic profiles revealed 21, 62, and 64 genes with altered expression in the 0.3, 3, and 30 ppb atrazine treatments, respectively.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 102, 110 ] ] }, { "pmid": "23358194", "text": "Altered genes were associated with neuroendocrine and reproductive system development, function, and disease; cell cycle control; and carcinogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23358194", "text": "There was a significant overlap (42 genes) between the 3 and 30 ppb differentially expressed gene lists, with two of these genes (CYP17A1 and SAMHD1) present in all three atrazine treatments.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 169, 177 ] ] }, { "pmid": "23358194", "text": "Increased transcript levels were translated to significant upregulation in protein expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23358194", "text": "Overall, this study identifies genetic and molecular targets altered in response to a developmental atrazine exposure to further define the biological pathways and mechanisms of toxicity.", "type": "CHEMICAL", "entities": [ "atrazine" ], "offsets": [ [ 98, 106 ] ] }, { "pmid": "20012638", "text": "Effects of bambuterol and terbutaline on isolated rat's tracheal smooth muscle.\n", "type": "CHEMICAL", "entities": [ "bambuterol", "terbutaline" ], "offsets": [ [ 11, 21 ], [ 26, 37 ] ] }, { "pmid": "20012638", "text": "Terbutaline (Bricanyl) and its prodrug Bambuterol (Bambec) are highly potent beta(2)-adrenoceptor agonists often used in asthma patients.", "type": "CHEMICAL", "entities": [ "Terbutaline", "Bricanyl", "Bambuterol", "Bambec" ], "offsets": [ [ 0, 11 ], [ 13, 21 ], [ 39, 49 ], [ 51, 57 ] ] }, { "pmid": "20012638", "text": "Terbutaline in the form of inhaled short-acting bronchodilator relieves asthmatic symptoms.", "type": "CHEMICAL", "entities": [ "Terbutaline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "20012638", "text": "However, the effects of bambuterol given intratracheally have rarely been explored.", "type": "CHEMICAL", "entities": [ "bambuterol" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "20012638", "text": "To verify the effect of bambuterol and terbutaline, which act on the tracheal smooth muscle directly in vitro, we used our preparation to test the effects of bambuterol on isolated rat's tracheal smooth muscle compared with terbutaline.", "type": "CHEMICAL", "entities": [ "bambuterol", "terbutaline", "bambuterol", "terbutaline" ], "offsets": [ [ 24, 34 ], [ 39, 50 ], [ 158, 168 ], [ 224, 235 ] ] }, { "pmid": "20012638", "text": "The following assessments of bambuterol and terbutaline were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6)", "type": "CHEMICAL", "entities": [ "bambuterol", "terbutaline" ], "offsets": [ [ 29, 39 ], [ 44, 55 ] ] }, { "pmid": "20012638", "text": "M methacholine as a parasympathetic mimetic; (3) effect of the drugs on electrically induced tracheal smooth muscle contractions.", "type": "CHEMICAL", "entities": [ "methacholine" ], "offsets": [ [ 2, 14 ] ] }, { "pmid": "20012638", "text": "The results indicated that adding bambuterol induced a significant further contraction to 10(-6)", "type": "CHEMICAL", "entities": [ "bambuterol" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "20012638", "text": "M methacholine-induced contraction when the preparation was increased to 10(-4)", "type": "CHEMICAL", "entities": [ "methacholine" ], "offsets": [ [ 2, 14 ] ] }, { "pmid": "20012638", "text": "M.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "20012638", "text": "But terbutaline elicited a relaxation response at a dose of 10(-6) M or more.", "type": "CHEMICAL", "entities": [ "terbutaline" ], "offsets": [ [ 4, 15 ] ] }, { "pmid": "20012638", "text": "Both bambuterol and terbutaline could inhibit electrical field stimulation (EFS) induced spike contraction.", "type": "CHEMICAL", "entities": [ "bambuterol", "terbutaline" ], "offsets": [ [ 5, 15 ], [ 20, 31 ] ] }, { "pmid": "20012638", "text": "Terbutaline had an anti-cholinergic effect that could relieve asthmatic symptoms.", "type": "CHEMICAL", "entities": [ "Terbutaline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "20012638", "text": "But the effect of bambuterol acting on tracheal smooth muscle directly was controversial.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "8894610", "text": "(+/-)-tamsulosin, an alpha 1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart.\n", "type": "CHEMICAL", "entities": [ "(+/-)-tamsulosin", "inositol phosphates" ], "offsets": [ [ 0, 16 ], [ 122, 141 ] ] }, { "pmid": "8894610", "text": "The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium.", "type": "CHEMICAL", "entities": [ "inositol phosphates", "(+/-)-tamsulosin", "oxymetazoline" ], "offsets": [ [ 138, 157 ], [ 17, 33 ], [ 277, 290 ] ] }, { "pmid": "8894610", "text": "Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol.", "type": "CHEMICAL", "entities": [ "Phenylephrine", "(+/-)-bupranolol", "S(-)-timolol" ], "offsets": [ [ 0, 13 ], [ 127, 143 ], [ 147, 159 ] ] }, { "pmid": "8894610", "text": "The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity.", "type": "CHEMICAL", "entities": [ "(+/-)-tamsulosin", "phenylephrine", "(+/-)-tamsulosin" ], "offsets": [ [ 34, 50 ], [ 68, 81 ], [ 126, 142 ] ] }, { "pmid": "8894610", "text": "At 100 nM and higher, it suppressed the maximal response to phenylephrine.", "type": "CHEMICAL", "entities": [ "phenylephrine" ], "offsets": [ [ 60, 73 ] ] }, { "pmid": "8894610", "text": "(+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine.", "type": "CHEMICAL", "entities": [ "phenylephrine", "chlorethylclonidine", "(+/-)-tamsulosin", "chlorethylclonidine", "(+/-)-Tamsulosin" ], "offsets": [ [ 74, 87 ], [ 156, 175 ], [ 209, 225 ], [ 276, 295 ], [ 0, 16 ] ] }, { "pmid": "8894610", "text": "(+/-)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by alpha 1-adrenoceptors, did not affect the accumulation of [3H]inositol phosphates that was induced by 10 microM phenylephrine.", "type": "CHEMICAL", "entities": [ "(+/-)-Tamsulosin", "[3H]inositol phosphates", "phenylephrine" ], "offsets": [ [ 0, 16 ], [ 175, 198 ], [ 229, 242 ] ] }, { "pmid": "8894610", "text": "Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine.", "type": "CHEMICAL", "entities": [ "Oxymetazoline", "phenylephrine", "inositol monophosphate", "phenylephrine" ], "offsets": [ [ 0, 13 ], [ 59, 72 ], [ 135, 157 ], [ 169, 182 ] ] }, { "pmid": "8894610", "text": "These results indicate that the positive inotropic effect, mediated via (+/-)-tamsulosin- and oxymetazoline-sensitive subtype of alpha 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.", "type": "CHEMICAL", "entities": [ "(+/-)-tamsulosin", "oxymetazoline", "inositol phosphates" ], "offsets": [ [ 72, 88 ], [ 94, 107 ], [ 233, 252 ] ] }, { "pmid": "23313376", "text": "Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway.\n", "type": "CHEMICAL", "entities": [ "Pterostilbene" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "23313376", "text": "Osteosarcoma is a high-grade malignant bone tumor.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313376", "text": "Pterostilbene (PTE) is a natural, dimethylated analog of resveratrol with higher bioavailability.", "type": "CHEMICAL", "entities": [ "resveratrol", "Pterostilbene", "PTE" ], "offsets": [ [ 57, 68 ], [ 0, 13 ], [ 15, 18 ] ] }, { "pmid": "23313376", "text": "While PTE has been shown to have potent antitumor activity against various types of cancer, the molecular mechanisms underlying the effects of PTE remain largely unknown.", "type": "CHEMICAL", "entities": [ "PTE", "PTE" ], "offsets": [ [ 6, 9 ], [ 143, 146 ] ] }, { "pmid": "23313376", "text": "The Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway plays a crucial role in tumorigenesis and immune development.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23313376", "text": "In this study, we assessed the antitumor activity of PTE against human osteosarcoma cells and explored the role of JAK2/STAT3 and apoptosis-related signaling pathways on the activity of PTE.", "type": "CHEMICAL", "entities": [ "PTE", "PTE" ], "offsets": [ [ 53, 56 ], [ 186, 189 ] ] }, { "pmid": "23313376", "text": "PTE treatment resulted in a dose- and time-dependent inhibition of osteosarcoma cell viability.", "type": "CHEMICAL", "entities": [ "PTE" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23313376", "text": "Additionally, PTE exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration and mitochondrial membrane potential (MMP) but also by increases in the apoptotic index, reactive oxygen species (ROS) and several biochemical parameters.", "type": "CHEMICAL", "entities": [ "PTE", "oxygen" ], "offsets": [ [ 14, 17 ], [ 223, 229 ] ] }, { "pmid": "23313376", "text": "Furthermore, PTE treatment directly inhibited the phosphorylation of JAK2 at Tyr 1007 and the downstream activation of STAT3.", "type": "CHEMICAL", "entities": [ "PTE", "Tyr" ], "offsets": [ [ 13, 16 ], [ 77, 80 ] ] }, { "pmid": "23313376", "text": "PTE also down-regulated the expression of STAT3 target genes, including the anti-apoptotic proteins Bcl-xL and Mcl-1, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, Bak, cytosolic Cytochrome c, and cleaved Caspase3) and cyclin-dependent kinase inhibitors such as p21 and p27.", "type": "CHEMICAL", "entities": [ "PTE" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23313376", "text": "PTE, used in combination with a known JAK2/STAT3 inhibitor, AG490, further decreased the viability of osteosarcoma cells.", "type": "CHEMICAL", "entities": [ "PTE", "AG490" ], "offsets": [ [ 0, 3 ], [ 60, 65 ] ] }, { "pmid": "23313376", "text": "Taken together, PTE is a potent inhibitor of osteosarcoma cell growth that targets the JAK2/STAT3 signaling pathway.", "type": "CHEMICAL", "entities": [ "PTE" ], "offsets": [ [ 16, 19 ] ] }, { "pmid": "23313376", "text": "These data suggest that inhibition of JAK2/STAT3 signaling is a novel mechanism of action for PTE during therapeutic intervention in osteosarcoma cancers.", "type": "CHEMICAL", "entities": [ "PTE" ], "offsets": [ [ 94, 97 ] ] }, { "pmid": "23435910", "text": "Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats.\n", "type": "CHEMICAL", "entities": [ "sinapic acid", "dimethylnitrosamine" ], "offsets": [ [ 10, 22 ], [ 31, 50 ] ] }, { "pmid": "23435910", "text": "Sinapic acid is a member of the phenylpropanoid family and is abundant in cereals, nuts, oil seeds, and berries.", "type": "CHEMICAL", "entities": [ "Sinapic acid", "phenylpropanoid" ], "offsets": [ [ 0, 12 ], [ 32, 47 ] ] }, { "pmid": "23435910", "text": "It exhibits a wide range of pharmacological properties.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435910", "text": "In this study, we investigated the hepatoprotective and antifibrotic effects of sinapic acid on dimethylnitrosamine (DMN)-induced chronic liver injury in rats.", "type": "CHEMICAL", "entities": [ "sinapic acid", "dimethylnitrosamine", "DMN" ], "offsets": [ [ 80, 92 ], [ 96, 115 ], [ 117, 120 ] ] }, { "pmid": "23435910", "text": "Sinapic acid remarkably prevented DMN-induced loss of body weight.", "type": "CHEMICAL", "entities": [ "Sinapic acid", "DMN" ], "offsets": [ [ 0, 12 ], [ 34, 37 ] ] }, { "pmid": "23435910", "text": "This was accompanied by a significant increase in levels of serum alanine transaminase, aspartate transaminase, and liver malondialdehyde content.", "type": "CHEMICAL", "entities": [ "alanine", "aspartate", "malondialdehyde" ], "offsets": [ [ 66, 73 ], [ 88, 97 ], [ 122, 137 ] ] }, { "pmid": "23435910", "text": "Furthermore, sinapic acid reduced hepatic hydroxyproline content, which correlated with a reduction in the expression of type I collagen mRNA and histological analysis of collagen in liver tissue.", "type": "CHEMICAL", "entities": [ "sinapic acid", "hydroxyproline" ], "offsets": [ [ 13, 25 ], [ 42, 56 ] ] }, { "pmid": "23435910", "text": "Additionally, the expression of hepatic fibrosis-related factors such as α-smooth muscle actin and transforming growth factor-β1 (TGF-β1), were reduced in rats treated with sinapic acid.", "type": "CHEMICAL", "entities": [ "sinapic acid" ], "offsets": [ [ 173, 185 ] ] }, { "pmid": "23435910", "text": "Sinapic acid exhibited strong scavenging activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23435910", "text": "In conclusion, we find that sinapic acid exhibits hepatoprotective and antifibrotic effects against DMN-induced liver injury, most likely due to its antioxidant activities of scavenging radicals, its capacity to suppress TGF-β1 and its ability to attenuate activation of hepatic stellate cells.", "type": "CHEMICAL", "entities": [ "sinapic acid", "DMN" ], "offsets": [ [ 25, 37 ], [ 97, 100 ] ] }, { "pmid": "23435910", "text": "This suggests that sinapic acid is a potentially useful agent for the protection against liver fibrosis and cirrhosis.", "type": "CHEMICAL", "entities": [ "sinapic acid" ], "offsets": [ [ 15, 27 ] ] }, { "pmid": "17624589", "text": "Glutathione S-transferase M1 and P1 polymorphisms and risk of breast cancer and fibrocystic breast conditions in Chinese women.\n", "type": "CHEMICAL", "entities": [ "Glutathione", "S" ], "offsets": [ [ 0, 11 ], [ 12, 13 ] ] }, { "pmid": "17624589", "text": "Enzymes encoded by the glutathione S-tranferase mu 1 (GSTM1) and pi 1 (GSTP1) genes, which are expressed in breast tissue, catalyze the detoxification of endogenous and exogenous electrophiles.", "type": "CHEMICAL", "entities": [ "glutathione", "S" ], "offsets": [ [ 23, 34 ], [ 35, 36 ] ] }, { "pmid": "17624589", "text": "Reduced enzyme activity, due to carriage of the GSTM1 deletion or the GSTP1 Ile105Val Val allele, may therefore affect susceptibility to breast cancer and related conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "In a case-control study of Chinese women, we examined whether these polymorphisms were associated with risk of breast cancer and fibrocystic breast conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "Women diagnosed with breast cancer (n=615) or fibrocystic breast conditions (n=467) were compared to women without clinical breast disease (n=878).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "We also examined whether these associations differed by menopausal status or by presence of proliferation in the extra-tumoral epithelium among women with breast cancer and in lesions among women with fibrocystic conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "No overall association of either GST polymorphism with risk of breast cancer or fibrocystic breast conditions was observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "There was some evidence of slightly elevated cancer risk associated with carriage of the GSTM1 null genotype and at least one GSTP1 105-Val allele (OR=1.33, 95% CI, 0.99-1.80), compared to carriage of the GSTM1 non-null and GSTP1 Ile/Ile genotypes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "This relationship was stronger in women who had breast cancer with extra-tumoral tissue proliferation (OR=1.77, 95% CI, 1.03-3.04).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "Our results suggest that GSTM1 and GSTP1 genotypes do not individually influence susceptibility to breast cancer or fibrocystic breast conditions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17624589", "text": "The observed increased risk of breast cancer associated with joint carriage of the GSTM1 null genotype and GSTP1 105-Val allele needs confirmation in other studies.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588300", "text": "Candesartan cilexetil--a review of effects on cardiovascular complications in hypertension and chronic heart failure.\n", "type": "CHEMICAL", "entities": [ "Candesartan cilexetil" ], "offsets": [ [ 0, 21 ] ] }, { "pmid": "17588300", "text": "UNLABELLED: Therapeutic interventions that block the renin-angiotensin-aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk actors to established cardiovascular diseases.", "type": "CHEMICAL", "entities": [ "angiotensin", "aldosterone" ], "offsets": [ [ 59, 70 ], [ 71, 82 ] ] }, { "pmid": "17588300", "text": "In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade.", "type": "CHEMICAL", "entities": [ "angiotensin", "angiotensin" ], "offsets": [ [ 17, 28 ], [ 118, 129 ] ] }, { "pmid": "17588300", "text": "The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24-h blood pressure (BP) control with a trough:peak ratio close to 100%.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 8, 19 ] ] }, { "pmid": "17588300", "text": "SCOPE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588300", "text": "A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).", "type": "CHEMICAL", "entities": [ "candesartan cilexetil" ], "offsets": [ [ 156, 177 ] ] }, { "pmid": "17588300", "text": "FINDINGS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588300", "text": "Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor.", "type": "CHEMICAL", "entities": [ "candesartan", "angiotensin II" ], "offsets": [ [ 26, 37 ], [ 89, 103 ] ] }, { "pmid": "17588300", "text": "Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy.", "type": "CHEMICAL", "entities": [ "calcium", "candesartan" ], "offsets": [ [ 102, 109 ], [ 39, 50 ] ] }, { "pmid": "17588300", "text": "Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction < or = 40% as add-on therapy to an ACEi or when an ACEi is not tolerated.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 14, 25 ] ] }, { "pmid": "17588300", "text": "Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 60, 71 ] ] }, { "pmid": "17588300", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17588300", "text": "There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complications across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 58, 69 ] ] }, { "pmid": "17588300", "text": "Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "23590882", "text": "Interacting Glutamate Receptor-Like Proteins in Phloem Regulate Lateral Root Initiation in Arabidopsis.\n", "type": "CHEMICAL", "entities": [ "Glutamate" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23590882", "text": "Molecular, genetic, and electrophysiological evidence indicates that at least one of the plant Glu receptor-like molecules, GLR3.4, functions as an amino acid-gated Ca(2+) channel at the plasma membrane.", "type": "CHEMICAL", "entities": [ "amino acid", "Ca(2+)" ], "offsets": [ [ 148, 158 ], [ 165, 171 ] ] }, { "pmid": "23590882", "text": "The aspect of plant physiology, growth, or development to which GLR3.4 contributes is an open question.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "Protein localization studies performed here provide important information.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "In roots, GLR3.4 and the related GLR3.2 protein were present primarily in the phloem, especially in the vicinity of the sieve plates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "GLR3.3 was expressed in most cells of the growing primary root but was not enriched in the phloem, including the sieve plate area.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "GLR3.2 and GLR3.4 physically interacted with each other better than with themselves as evidenced by a biophotonic assay performed in human embryonic kidney cells and Nicotiana benthamiana leaf cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "GLR3.3 interacted poorly with itself or the other two GLRs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "Mutations in GLR3.2, GLR3.4, or GLR3.2 and GLR3.4 caused the same and equally severe phenotype, namely, a large overproduction and aberrant placement of lateral root primordia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "Loss of GLR3.3 did not affect lateral root primordia.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23590882", "text": "These results support the hypothesis that apoplastic amino acids acting through heteromeric GLR3.2/GLR3.4 channels affect lateral root development via Ca(2+) signaling in the phloem.", "type": "CHEMICAL", "entities": [ "amino acids", "Ca(2+)" ], "offsets": [ [ 53, 64 ], [ 151, 157 ] ] }, { "pmid": "23159790", "text": "Purification and structural characterisation of phospholipase A1 (Vespapase, Ves a 1) from Thai banded tiger wasp (Vespa affinis) venom.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "The Thai banded tiger wasp (Vespa affinis) is one of the most dangerous vespid species in Southeast Asia, and stinging accidents involving this species still cause fatalities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "In the present study, four forms of V. affinis phospholipase A(1) were identified through a proteomics approach.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "Two of these enzymes were purified by reverse-phase chromatography, and their biochemical properties were characterised.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "These enzymes, designated Ves a 1s, are not glycoproteins and exist as 33441.5 and 33474.4 Da proteins, which corresponded with the 34-kDa band observed via SDS-PAGE.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "The thermal stabilities of these enzymes were stronger than snake venom.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "Using an in vivo assay, no difference was found in the toxicities of the different isoforms.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "Furthermore, the toxicity of these enzymes does not appear to be correlated with their PLA(1) activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "The cDNAs of the full-length version of Ves a 1s revealed that the Ves a 1 gene consists of a 1005-bp ORF, which encodes 334 amino acid residues, and 67- and 227-bp 5' and 3' UTRs, respectively.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 125, 135 ] ] }, { "pmid": "23159790", "text": "The two isoforms are different by three nucleotide substitutions, resulting in the replacement of two amino acids.", "type": "CHEMICAL", "entities": [ "nucleotide", "amino acids" ], "offsets": [ [ 40, 50 ], [ 102, 113 ] ] }, { "pmid": "23159790", "text": "Through sequence alignment, these enzymes were classified as members of the pancreatic lipase family.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "The structural modelling of Ves a 1 used the rat pancreatic lipase-related protein 2 (1bu8A) as a template because it has PLA(1) activity, which demonstrated that this enzyme belongs to the α/β hydrolase fold family.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "The Ves a 1 structure, which is composed of seven α-helixes and eleven β-strands, contains the β-strand/ɛSer/α-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence.", "type": "CHEMICAL", "entities": [ "Gly", "Ser", "Gly" ], "offsets": [ [ 152, 155 ], [ 158, 161 ], [ 164, 167 ] ] }, { "pmid": "23159790", "text": "The typical surface structures that play important roles in substrate selectivity (the lid domain and the β9 loop) were shortened in the Ves a 1 structure, which suggests that this enzyme may only exhibit phospholipase activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23159790", "text": "Moreover, the observed insertion of proline into the lid domain of the Ves a 1 structure is rare.", "type": "CHEMICAL", "entities": [ "proline" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "23159790", "text": "We therefore propose that this proline residue might be involved in the stability and activity of Ves a 1s.", "type": "CHEMICAL", "entities": [ "proline" ], "offsets": [ [ 23, 30 ] ] }, { "pmid": "15982930", "text": "Thalidomide inhibits growth of tumors through COX-2 degradation independent of antiangiogenesis.\n", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15982930", "text": "Thalidomide is an antiangiogenic drug and is clinically useful in a number of cancers.", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15982930", "text": "However, the molecular mechanism by which thalidomide exerts its antitumor effects is poorly understood.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "15982930", "text": "This study was designed to clarify the relationship between antiangiogenesis and antitumor effects of thalidomide and to explore the molecular mechanism for its antitumor activity.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 102, 113 ] ] }, { "pmid": "15982930", "text": "We evaluated the effects of thalidomide on the growth of human tumor cells expressing (MCF-7 and HL-60) or not expressing (HeLa and K562) COX-2 in vitro.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 28, 39 ] ] }, { "pmid": "15982930", "text": "We also studied the effects of thalidomide on COX-1, COX-2 or bcl-2 expression, TNFalpha, VEGF, GSH and cytochrome c in these cells.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "15982930", "text": "Thalidomide could inhibit tumor growth in a concentration-dependent manner in MCF-7 and HL-60; its IC50s for them were 18.36+/-2.34 and 22.14+/-2.15 microM, respectively, while this effect was not observed in HeLa and K562.", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15982930", "text": "Thalidomide reduced COX-2 expression accompanied by a decrease of bcl-2 protein, TNFalpha, VEGF, GSH and an increased cytochrome c, but had no effect on that of COX-1, in MCF-7 and HL-60.", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15982930", "text": "Moreover, cells not expressing COX-2 were insensitive to the growth-inhibitory and effects on cytokines of thalidomide.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 107, 118 ] ] }, { "pmid": "15982930", "text": "In our mouse xenograft model of OVCAR-3 and HCT-8, we found that thalidomide could decrease intratumoral microvessel density in both tumors; it exerted antitumor effects only on OVCAR-3 expressing COX-2 but did not on HCT-8 not expressing COX-2.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 65, 76 ] ] }, { "pmid": "15982930", "text": "Effect of thalidomide on COX-1 and COX-2 in vivo was consistent with that of in vitro.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "15982930", "text": "These results demonstrated that thalidomide might inhibit growth of tumors through COX-2 degradation independent of antiangiogenesis.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 32, 43 ] ] }, { "pmid": "23614730", "text": "Toxicological impact of inhaled electric mosquito-repellent liquid on the rat: a hematological, cytokine indications, oxidative stress and tumor markers.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "Abstract Context: High malaria burden has led to the increased use of insecticides in the tropics and subtropics.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "This study thus aimed at assessing the hematological effects alteration of pyrethroid insecticide exposure using the experimental animal model.", "type": "CHEMICAL", "entities": [ "pyrethroid" ], "offsets": [ [ 75, 85 ] ] }, { "pmid": "23614730", "text": "Objective: A commonly available Electric Mosquito-Repellent Liquid pyrethroid insecticide containing prallethrin 1.6% w/w is widely used for mosquito control in Saudi Arabia.", "type": "CHEMICAL", "entities": [ "pyrethroid", "prallethrin" ], "offsets": [ [ 67, 77 ], [ 101, 112 ] ] }, { "pmid": "23614730", "text": "The immunotoxic effects after inhalation exposures to the preparation for a continuous period of 24, 48, and 72 h were investigated in rats.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "Methods and materials: Rats were exposed to prallethrin 1.6% w/w by inhalation for 72 consecutive hours.", "type": "CHEMICAL", "entities": [ "prallethrin" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "23614730", "text": "Total blood count, blood indices of creatine kinase (CK), gamma-glutamyltranspeptidase (γ-GT), superoxide dismutase (SOD), nitric oxide (NO), malondialdehyde (MDA), interleukin (IL)-2, tumor necrosis factors (TNF)α, alpha-fetoprotein (AFP), carbohydrate antigen (CA) 19.9 and carcinoembrionic antigen (CEA) were assayed.", "type": "CHEMICAL", "entities": [ "creatine", "superoxide", "nitric oxide", "NO", "malondialdehyde", "MDA", "carbohydrate" ], "offsets": [ [ 34, 42 ], [ 93, 103 ], [ 121, 133 ], [ 135, 137 ], [ 140, 155 ], [ 157, 160 ], [ 239, 251 ] ] }, { "pmid": "23614730", "text": "Results:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "The administration of prallethrin 1.6% w/w created significant increased changes in the levels of total WBC, lymphocytes, RBC, hemoglobin, packed cell volume, platelets, mean corpuscular volume, and mean corpuscular hemoglobin in rats after 24, 48, and", "type": "CHEMICAL", "entities": [ "prallethrin" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "23614730", "text": "72 h of continuous inhalation; however, there was a significant reduction in neutrophils at transient reduction in the monocytes after 24 and 48 h to return to normal after 72 h.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "Significant increases in the levels of CK, γ-GT, SOD, NO, MDA, AFP, IL-2, and TNFα were recorded.", "type": "CHEMICAL", "entities": [ "NO", "MDA" ], "offsets": [ [ 44, 46 ], [ 48, 51 ] ] }, { "pmid": "23614730", "text": "CA and CEA did not exhibit any change.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23614730", "text": "Conclusions: Continuous inhalation to prallethrin 1.6% insecticides poses toxicity on hematological variables.", "type": "CHEMICAL", "entities": [ "prallethrin" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "23614730", "text": "It is also concluded that pyrethroid group of insecticide may cause hematological, biochemical, cytokine disturbances and possible mutagenic damage to the tissues.", "type": "CHEMICAL", "entities": [ "pyrethroid" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "23455314", "text": "Contribution of the m1 transmembrane helix and pre-m1 region to positive allosteric modulation and gating of N-methyl-d-aspartate receptors.\n", "type": "CHEMICAL", "entities": [ "N-methyl-d-aspartate" ], "offsets": [ [ 109, 129 ] ] }, { "pmid": "23455314", "text": "N-methyl-d-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions.", "type": "CHEMICAL", "entities": [ "N-methyl-d-aspartate", "NMDA" ], "offsets": [ [ 0, 20 ], [ 22, 26 ] ] }, { "pmid": "23455314", "text": "NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23455314", "text": "Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 144, 148 ] ] }, { "pmid": "23455314", "text": "Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator.", "type": "CHEMICAL", "entities": [ "(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone", "CIQ" ], "offsets": [ [ 54, 155 ], [ 157, 160 ] ] }, { "pmid": "23455314", "text": "We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore.", "type": "CHEMICAL", "entities": [ "CIQ", "amino", "NMDA" ], "offsets": [ [ 13, 16 ], [ 38, 43 ], [ 67, 71 ] ] }, { "pmid": "23455314", "text": "Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating.", "type": "CHEMICAL", "entities": [ "CIQ" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23455314", "text": "We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 90, 94 ] ] }, { "pmid": "23455314", "text": "These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.", "type": "CHEMICAL", "entities": [ "NMDA", "NMDA" ], "offsets": [ [ 65, 69 ], [ 134, 138 ] ] }, { "pmid": "23556446", "text": "Association of ATP-binding cassette transporter variants with the risk of Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 15, 18 ] ] }, { "pmid": "23556446", "text": "Aim: A number of studies have demonstrated that ABCB1 and BCRP (ABCG2) actively transport Aβ.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "We aimed to investigate the association of genetic variants of selected multidrug transporters with Alzheimer's disease (AD) in histopathologically confirmed AD cases and controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Materials & methods: DNA from brain tissue of 71 AD cases with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological stages B/C and 81 controls was genotyped for selected variants in ABCA1, ABCA7, ABCB1, ABCC2 and ABCG2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "In addition, the APOE4 status was analyzed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Results: The novel ABCA7 SNP, rs3752246, tended to be associated with AD in our study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Variants in ABCB1 were significantly less frequent in AD cases older than 65 years of age and among females.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "This association of ABCB1 2677G>T (rs2032582) was more pronounced in APOE4-negative cases (p = 0.005).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "However, only ABCC2 3972C>T (rs3740066) was significantly associated with AD risk after logistic regression analysis including all variants.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Other transporters showed a lack of association.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Conclusion: Our results support the hypothesis that ABCB1 and possibly other ABC-transporters are involved in the process of Aβ accumulation in the aging brain and may modulate the risk for AD in an allele-specific manner, and thus might represent a new target for prevention and treatment of AD.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23556446", "text": "Original submitted 8 October 2012; Revision submitted 22 January 2013.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256442", "text": "Dandelion leaf extract protects against liver injury induced by methionine- and choline-deficient diet in mice.\n", "type": "CHEMICAL", "entities": [ "methionine", "choline" ], "offsets": [ [ 64, 74 ], [ 80, 87 ] ] }, { "pmid": "23256442", "text": "We investigated the hepatoprotective effects of the extract of dandelion leaves (EDL) on a murine model of methionine- and choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH).", "type": "CHEMICAL", "entities": [ "methionine", "choline" ], "offsets": [ [ 107, 117 ], [ 123, 130 ] ] }, { "pmid": "23256442", "text": "C57BL/6 mice were fed for 4 weeks with one of the following diets: control diet (Cont), MCD diet (MCD), MCD diet supplemented with EDL at 200 mg/kg body weight·daily (MCD+D200), and MCD diet supplemented with EDL at 500 mg/kg body weight·daily (MCD+D500).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256442", "text": "Hepatic function was assessed by evaluating the following parameters: liver histology; plasma levels of alanine aminotransferase (ALT), triglyceride (TG), malondialdehyde (MDA), and reduced glutathione (GSH); expression levels of TNF-α and IL-6; and levels of caspase-3 and pJNK/JNK protein.", "type": "CHEMICAL", "entities": [ "alanine", "triglyceride", "malondialdehyde", "MDA", "reduced glutathione", "GSH" ], "offsets": [ [ 102, 109 ], [ 134, 146 ], [ 153, 168 ], [ 170, 173 ], [ 180, 199 ], [ 201, 204 ] ] }, { "pmid": "23256442", "text": "Histopathological evaluations revealed that addition of EDL to the MCD diet dampens the severity of the clinical signs of NASH.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256442", "text": "Moreover, EDL led to a significant decrease in the serum levels of ALT, hepatic TG, and MDA, and in the expression levels of TNF-α, and IL-6; on the contrary, the levels of reduced GSH increased.", "type": "CHEMICAL", "entities": [ "reduced GSH", "MDA" ], "offsets": [ [ 170, 181 ], [ 85, 88 ] ] }, { "pmid": "23256442", "text": "At the post-transcriptional level, EDL significantly decreased the activation of procaspase-3 to active caspase-3, and the phosphorylation of JNK.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23256442", "text": "These results suggest that the beneficial effects of EDL on NASH are mainly due to its antioxidant and anti-inflammatory activities.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325667", "text": "A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.\n", "type": "CHEMICAL", "entities": [ "imatinib", "tyrosine" ], "offsets": [ [ 49, 57 ], [ 8, 16 ] ] }, { "pmid": "17325667", "text": "KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325667", "text": "Despite excellent responses to imatinib mesylate (IM), patients are relapsing.", "type": "CHEMICAL", "entities": [ "imatinib mesylate", "IM" ], "offsets": [ [ 31, 48 ], [ 50, 52 ] ] }, { "pmid": "17325667", "text": "We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM.", "type": "CHEMICAL", "entities": [ "IM", "IM", "IM" ], "offsets": [ [ 16, 18 ], [ 62, 64 ], [ 128, 130 ] ] }, { "pmid": "17325667", "text": "Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance.", "type": "CHEMICAL", "entities": [ "IM", "IM" ], "offsets": [ [ 64, 66 ], [ 155, 157 ] ] }, { "pmid": "17325667", "text": "Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'.", "type": "CHEMICAL", "entities": [ "IM", "tyrosine" ], "offsets": [ [ 36, 38 ], [ 91, 99 ] ] }, { "pmid": "17325667", "text": "Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC).", "type": "CHEMICAL", "entities": [ "IM" ], "offsets": [ [ 17, 19 ] ] }, { "pmid": "17325667", "text": "Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325667", "text": "In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 18, 26 ] ] }, { "pmid": "17325667", "text": "The kinase switch is associated with a morphological change from spindle to epithelioid.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17325667", "text": "Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor.", "type": "CHEMICAL", "entities": [ "IM", "MP470" ], "offsets": [ [ 93, 95 ], [ 121, 126 ] ] }, { "pmid": "17325667", "text": "MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.", "type": "CHEMICAL", "entities": [ "MP470", "docetaxel", "taxotere" ], "offsets": [ [ 0, 5 ], [ 22, 31 ], [ 33, 41 ] ] }, { "pmid": "9466983", "text": "Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "9466983", "text": "L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units.", "type": "CHEMICAL", "entities": [ "calcium", "glucosamine" ], "offsets": [ [ 58, 65 ], [ 160, 171 ] ] }, { "pmid": "9466983", "text": "We now show that these HS chains can also bind P-selectin, but not E-selectin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations.", "type": "CHEMICAL", "entities": [ "ethylenediamine tetraacetic acid", "EDTA" ], "offsets": [ [ 58, 90 ], [ 92, 96 ] ] }, { "pmid": "9466983", "text": "Porcine intestinal mucosal (mast cell-derived) heparin (PIM-heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations.", "type": "CHEMICAL", "entities": [ "calcium", "calcium", "EDTA" ], "offsets": [ [ 126, 133 ], [ 206, 213 ], [ 305, 309 ] ] }, { "pmid": "9466983", "text": "Analysis of defined heparin fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns.", "type": "CHEMICAL", "entities": [ "tetradecasaccharides" ], "offsets": [ [ 89, 109 ] ] }, { "pmid": "9466983", "text": "L-selectin binding fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups.", "type": "CHEMICAL", "entities": [ "free amino" ], "offsets": [ [ 143, 153 ] ] }, { "pmid": "9466983", "text": "The P-selectin binding component includes this fraction as well as some less highly modified regions.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Thus, endothelium-derived HS chains and mast cell-derived heparins could play a role in modulating the biology of selectins in vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "In contrast, two low molecular weight heparins currently considered as clinical replacements for unfractionated heparin are much poorer inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Thus, patients undergoing heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight heparins may come at some loss of this effect.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "9466983", "text": "Low-dose unfractionated heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23239825", "text": "Differentiation of opioid drug effects by hierarchical multi-site phosphorylation.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23239825", "text": "Differences in the ability of opioid drugs to promote regulated endocytosis of μ-opioid receptors are related to their tendency to produce drug tolerance and dependence.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23239825", "text": "Here we show that drug-specific differences in receptor internalization are determined by a conserved, 10-residue sequence in the receptor's carboxyl-terminal cytoplasmic tail.", "type": "CHEMICAL", "entities": [ "carboxyl" ], "offsets": [ [ 140, 148 ] ] }, { "pmid": "23239825", "text": "Diverse opioids induce receptor phosphorylation at serine (S)375, present in the middle of this sequence, but opioids differ markedly in their ability to drive higher-order phosphorylation on flanking residues [threonine (T)370, T376, and T379].", "type": "CHEMICAL", "entities": [ "serine", "threonine" ], "offsets": [ [ 50, 56 ], [ 210, 219 ] ] }, { "pmid": "23239825", "text": "Multi-phosphorylation is required for the endocytosis-promoting activity of this sequence and occurs both sequentially and hierarchically, with S375 representing the initiating site.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23239825", "text": "Higher-order phosphorylation involving T370, T376, and T379 specifically requires GRK2/3 isoforms, and the same sequence controls opioid receptor internalization in neurons.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23239825", "text": "These results reveal a biochemical mechanism differentiating the endocytic activity of opioid drugs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "Effects of changeover from voglibose to acarbose on postprandial triglycerides in type 2 diabetes mellitus patients.\n", "type": "CHEMICAL", "entities": [ "voglibose", "acarbose", "triglycerides" ], "offsets": [ [ 27, 36 ], [ 40, 48 ], [ 65, 78 ] ] }, { "pmid": "19568704", "text": "INTRODUCTION:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "In this study, we examined the effects of the alpha-glucosidase inhibitors acarbose and voglibose on postprandial plasma glucose and serum triglyceride levels in patients with type 2 diabetes mellitus.", "type": "CHEMICAL", "entities": [ "voglibose", "glucose", "acarbose" ], "offsets": [ [ 88, 97 ], [ 121, 128 ], [ 75, 83 ] ] }, { "pmid": "19568704", "text": "METHODS: Twenty-one Japanese patients with type 2 diabetes were enrolled in this study.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "Subjects had been treated with voglibose for at least 3 months.", "type": "CHEMICAL", "entities": [ "voglibose" ], "offsets": [ [ 31, 40 ] ] }, { "pmid": "19568704", "text": "They underwent a 400 kcal balanced food meal tolerance test before and 8 weeks after the changeover from voglibose to acarbose.", "type": "CHEMICAL", "entities": [ "voglibose", "acarbose" ], "offsets": [ [ 105, 114 ], [ 118, 126 ] ] }, { "pmid": "19568704", "text": "Subjects were divided into two groups: the first group (low-dose group; n=11) was changed over from 0.6 mg/day voglibose to 150 mg/day acarbose, and the other (high-dose group; n=10) from 0.9 mg/day voglibose to 300 mg/day acarbose.", "type": "CHEMICAL", "entities": [ "voglibose", "acarbose", "voglibose" ], "offsets": [ [ 111, 120 ], [ 135, 143 ], [ 199, 208 ] ] }, { "pmid": "19568704", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "The increment rate of postprandial plasma glucose ([plasma glucose 2 hours after test meal - fasting glucose]/fasting glucose) decreased from 34.7%+/-23.9% to 25.0%+/-24.6% (P=0.13) in the low-dose group, and decreased significantly from 56.1%+/-53.1% to 31.5%+/-36.0% (P=0.03) in the high-dose group after changeover.", "type": "CHEMICAL", "entities": [ "glucose", "glucose", "glucose", "glucose" ], "offsets": [ [ 42, 49 ], [ 59, 66 ], [ 101, 108 ], [ 118, 125 ] ] }, { "pmid": "19568704", "text": "However, there were no significant changes in blood glycated hemoglobin (HbA(1c)) levels before and after changeover in either group.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "The increment rate of postprandial serum triglyceride (TG) ([serum TG 2 hours after test meal - fasting TG]/fasting TG) decreased significantly only in the high-dose group (52.4%+/-60.0% to 24.3%+/-16.6%) (P=0.05).", "type": "CHEMICAL", "entities": [ "triglyceride", "TG", "TG", "TG", "TG" ], "offsets": [ [ 41, 53 ], [ 55, 57 ], [ 67, 69 ], [ 104, 106 ], [ 116, 118 ] ] }, { "pmid": "19568704", "text": "No significant changes in serum high-density lipoprotein cholesterol levels were observed in either group, whereas serum low-density lipoprotein cholesterol levels decreased significantly from 3.20+/-0.25 to 2.65+/-0.18 mmol/L (P=0.04), only in the high-dose group.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol" ], "offsets": [ [ 57, 68 ], [ 145, 156 ] ] }, { "pmid": "19568704", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19568704", "text": "In patients with type 2 diabetes our findings suggest that acarbose 300 mg/day is superior to voglibose 0.9 mg/day in improving postprandial hyperglycemia and hypertriglyceridemia.", "type": "CHEMICAL", "entities": [ "acarbose", "voglibose" ], "offsets": [ [ 59, 67 ], [ 94, 103 ] ] }, { "pmid": "23535516", "text": "Modulation of the JAK/ERK/STAT signaling in melanocortin-induced inhibition of local and systemic responses to myocardial ischemia/reperfusion.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "The janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) pathways have been shown to play a cardioprotective role.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "We previously gave evidence that melanocortins afford cardioprotection in conditions of myocardial ischemia/reperfusion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "Here we aimed to investigate the influence of melanocortins on the JAK/ERK/STAT signaling in cardiac and systemic responses to prolonged myocardial ischemia/reperfusion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30min.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "At the end of the 2-h reperfusion, western blot analysis of the cardioprotective transcription factors pJAK2, pERK1/2, pTyr-STAT3 and pSer-STAT3, the inflammatory mediator tumor necrosis factor-α (TNF-α), the pro-apoptotic factors BAX and c-jun N-terminal kinases (pJNK), the anti-apoptotic protein Bcl-XL, as well as of the cardioprotective enzyme heme oxygenase-1 (HO-1), was performed in the left ventricle and spleen.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 245, 246 ] ] }, { "pmid": "23535516", "text": "Intravenous treatment, during coronary artery occlusion, with the melanocortin analogs", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "[Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) and adrenocorticotropic hormone 1-24", "type": "CHEMICAL", "entities": [ "D-Phe" ], "offsets": [ [ 7, 12 ] ] }, { "pmid": "23535516", "text": "[ACTH-(1-24)], induced a left ventricle up-regulation of pJAK2, pERK1/2 and pTyr-STAT3 (JAK-dependent), and a reduction in pJNK and TNF-α levels; these effects of NDP-α-MSH and ACTH-(1-24) were associated with over-expression of the pro-survival proteins HO-1 and Bcl-XL, and marked decrease of the myocardial infarct size.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "Melanocortin treatment did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "BAX levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "In the spleen, NDP-α-MSH and ACTH-(1-24) induced similar effects on the expression of the above transcription factors/proteins, except for pERK1/2 (down-regulated) and HO-1 (unaffected).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23535516", "text": "Blockade of JAK and ERK pathways with AG490 and U0126, respectively, abrogated the myocardial infarct size reduction by NDP-α-MSH.", "type": "CHEMICAL", "entities": [ "AG490", "U0126" ], "offsets": [ [ 31, 36 ], [ 41, 46 ] ] }, { "pmid": "23535516", "text": "These results indicate that melanocortins inhibit local and systemic inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, with consequent reduction in myocardium infarct size, seemingly via activation of the JAK/STAT signaling and with modulation of an ERK (STAT unrelated) signaling pathway.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Neuroinflammation and oxidative stress are believed to be contributing factors to neurodegeneration in normal aging, as well as in age-related neurological disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Reactive microglia are found in increased numbers in aging brain and are prominently associated with lesions in such age-related degenerative conditions as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "In vitro, stimulated microglia or microglial-like cells secrete neurotoxic materials and are generators of free radicals through their respiratory burst system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Agents that suppress microglial activation are therefore candidates for neuroprotection.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "We have developed quantitative in vitro assays for measuring neurotoxicity of microglia or other mononuclear phagocytes.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Neuronal like SH-SY5Y cells are cultured in supernatants from activated cells of the human monocytic THP-1 line and their survival is followed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Respiratory burst is directly measured on the activated cells.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "We tested inhibitors of the cyclooxygenase (COX) or the 5-lipoxygenase (5-LOX) pathways as possible neuroprotective agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "The COX pathway generates inflammatory prostaglandins, while the 5-LOX pathway generates inflammatory leukotrienes.", "type": "CHEMICAL", "entities": [ "prostaglandins", "leukotrienes" ], "offsets": [ [ 39, 53 ], [ 102, 114 ] ] }, { "pmid": "12392782", "text": "We found that inhibitors of both these pathways suppressed neurotoxicity in a dose-dependent fashion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "They included the COX-1 inhibitor indomethacin; the COX-2 inhibitor NS-398; the mixed COX-1/COX-2 inhibitor ibuprofen; the nitric oxide (NO) derivatives of indomethacin, ibuprofen and flurbiprofen; the 5-LOX inhibitor REV 5901; and the 5-LOX activating protein (FLAP) inhibitor MK-886.", "type": "CHEMICAL", "entities": [ "NS-398", "ibuprofen", "nitric oxide", "NO", "indomethacin", "ibuprofen", "flurbiprofen", "REV 5901", "MK-886" ], "offsets": [ [ 68, 74 ], [ 108, 117 ], [ 123, 135 ], [ 137, 139 ], [ 156, 168 ], [ 170, 179 ], [ 184, 196 ], [ 218, 226 ], [ 278, 284 ] ] }, { "pmid": "12392782", "text": "The FLAP inhibitor also reduced respiratory burst activity in a more potent manner than indomethacin.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "Combinations of COX and 5-LOX inhibitors were more effective than single inhibitors.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "12392782", "text": "The data suggest that both COX inhibitors and 5-LOX inhibitors may be neuroprotective in vivo by suppressing toxic actions of microglia/macrophages, and that combinations of the two might have greater therapeutic potential than single inhibitors of either class.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "Cyperi Rhizoma inhibits the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reduction in nigrostriatal dopaminergenic neurons in estrogen-deprived mice.\n", "type": "CHEMICAL", "entities": [ "estrogen", "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine" ], "offsets": [ [ 134, 142 ], [ 28, 72 ] ] }, { "pmid": "23639362", "text": "ETHNOPHARMACOLOGICAL RELEVANCE:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "Cyperi Rhizoma has commonly been used for the treatment of gynecological and neuropsychiatric disorders in traditional medicine.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "The aim of this study was to evaluate the estrogenic properties and neuroprotective effects of Cyperi Rhizoma under estrogen-deprived condition in female mice.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 116, 124 ] ] }, { "pmid": "23639362", "text": "MATERIALS AND METHODS: To determine the estrogen-like effect of Cyperi Rhizoma extract (CRE), we measured luciferase expression after transfection of a promoter construct containing an estrogen response element (ERE) and treatment of CRE.", "type": "CHEMICAL", "entities": [ "estrogen", "estrogen" ], "offsets": [ [ 40, 48 ], [ 185, 193 ] ] }, { "pmid": "23639362", "text": "To evaluate the neuroprotective effect of CRE, we measured striatal dopamine, movement ability, tyrosine hydroxylase (TH) immunoreactivity, and apoptosis-related protein expression levels after treatment of CRE either with or without 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in ovariectomized female mice.", "type": "CHEMICAL", "entities": [ "dopamine", "tyrosine", "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine", "MPTP" ], "offsets": [ [ 68, 76 ], [ 96, 104 ], [ 234, 278 ], [ 280, 284 ] ] }, { "pmid": "23639362", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "CRE significantly induced the luciferase expression driven by an ERE in PC12 cells, a dopaminergic cell line, in a dose-dependent manner.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "In mice, MPTP significantly decreased the levels of dopamine in the striatum and behavior performance; in contrast, both CRE and 17β-estradiol benzoate (EB) recovered these parameters to normal levels.", "type": "CHEMICAL", "entities": [ "MPTP", "dopamine", "17β-estradiol benzoate" ], "offsets": [ [ 9, 13 ], [ 52, 60 ], [ 129, 151 ] ] }, { "pmid": "23639362", "text": "CRE and EB treatment also recovered TH immunopositive fibers and cells, respectively, from MPTP toxicity.", "type": "CHEMICAL", "entities": [ "MPTP" ], "offsets": [ [ 90, 94 ] ] }, { "pmid": "23639362", "text": "Additionally, MPTP significantly down-regulated Bcl-2 expression in the mitochondria of dopaminergic cells in the SN, followed by an increase in Bax expression, cytochrome C translocation to the cytosol, andcleaved-caspase-3 expression, whereas these were inhibited by CRE or EB treatment.", "type": "CHEMICAL", "entities": [ "MPTP" ], "offsets": [ [ 13, 17 ] ] }, { "pmid": "23639362", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23639362", "text": "These findings provide the first evidence that CRE has estrogen-like and neuroprotective effects on dopaminergic neurons in estrogen-deprived mice treated with MPTP-toxin.", "type": "CHEMICAL", "entities": [ "estrogen", "estrogen", "MPTP" ], "offsets": [ [ 54, 62 ], [ 123, 131 ], [ 159, 163 ] ] }, { "pmid": "16291771", "text": "New progestagens for contraceptive use.\n", "type": "CHEMICAL", "entities": [ "progestagens" ], "offsets": [ [ 4, 16 ] ] }, { "pmid": "16291771", "text": "The progestins have different pharmacologic properties depending upon the parent molecule, usually testosterone or progesterone (P), from which they are derived.", "type": "CHEMICAL", "entities": [ "progesterone", "progestins", "testosterone" ], "offsets": [ [ 115, 127 ], [ 4, 14 ], [ 99, 111 ] ] }, { "pmid": "16291771", "text": "Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16291771", "text": "In hormonal contraceptives, progestins represent the major agent designed for suppressing ovulation and are used in combination with estrogen (E) usually ethinyl-estradiol (EE).", "type": "CHEMICAL", "entities": [ "estrogen", "ethinyl-estradiol", "EE" ], "offsets": [ [ 133, 141 ], [ 154, 171 ], [ 173, 175 ] ] }, { "pmid": "16291771", "text": "The development of new generations of progestins with improved selectivity profiles has been a great challenge.", "type": "CHEMICAL", "entities": [ "progestins" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "16291771", "text": "Steroidal and nonsteroidal progesterone receptor (PR) agonists have been synthesized as well, although the latter are still in a very early stage of development.", "type": "CHEMICAL", "entities": [ "Steroidal", "progesterone" ], "offsets": [ [ 0, 9 ], [ 27, 39 ] ] }, { "pmid": "16291771", "text": "Several new progestins, have been synthesized in the last two decades.", "type": "CHEMICAL", "entities": [ "progestins" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "16291771", "text": "These include dienogest (DNG), drospirenone (DRSP), Nestorone (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG).", "type": "CHEMICAL", "entities": [ "dienogest", "DNG", "drospirenone", "DRSP", "Nestorone", "NES", "nomegestrol acetate", "NOMAc", "trimegestone", "TMG" ], "offsets": [ [ 14, 23 ], [ 25, 28 ], [ 31, 43 ], [ 45, 49 ], [ 52, 61 ], [ 63, 66 ], [ 69, 88 ], [ 90, 95 ], [ 101, 113 ], [ 115, 118 ] ] }, { "pmid": "16291771", "text": "These new progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone P. DRSP differs from the classic progestins as it is derived from spirolactone.", "type": "CHEMICAL", "entities": [ "DRSP", "progestins", "spirolactone", "progestins" ], "offsets": [ [ 145, 149 ], [ 175, 185 ], [ 208, 220 ], [ 10, 20 ] ] }, { "pmid": "16291771", "text": "It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "16291771", "text": "The antiovulatory potency of the different progestins varies.", "type": "CHEMICAL", "entities": [ "progestins" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "16291771", "text": "TMG and NES are the most potent progestins synthesized to date, followed by two of the older progestins, keto-desogestrel (keto-DSG) and levonorgestrel (LNG).", "type": "CHEMICAL", "entities": [ "TMG", "NES", "progestins", "progestins", "keto-desogestrel", "keto-DSG", "levonorgestrel", "LNG" ], "offsets": [ [ 0, 3 ], [ 8, 11 ], [ 32, 42 ], [ 93, 103 ], [ 105, 121 ], [ 123, 131 ], [ 137, 151 ], [ 153, 156 ] ] }, { "pmid": "16291771", "text": "The new molecules TMG, DRSP and DNG also have antiandrogenic activity.", "type": "CHEMICAL", "entities": [ "TMG", "DRSP", "DNG" ], "offsets": [ [ 18, 21 ], [ 23, 27 ], [ 32, 35 ] ] }, { "pmid": "16291771", "text": "Striking differences exist regarding the side effects among the progestins and the combination with EE leads to other reactions related to the E itself and whether the associated progestin counterbalances, more or less, the estrogenic action.", "type": "CHEMICAL", "entities": [ "progestins", "EE", "progestin" ], "offsets": [ [ 64, 74 ], [ 100, 102 ], [ 179, 188 ] ] }, { "pmid": "16291771", "text": "The 19-norprogesterone molecules and the new molecules DRSP and DNG are not androgenic and, therefore, have no negative effect on the lipid profile.", "type": "CHEMICAL", "entities": [ "19-norprogesterone", "DRSP", "DNG" ], "offsets": [ [ 4, 22 ], [ 55, 59 ], [ 64, 67 ] ] }, { "pmid": "16291771", "text": "Given their pharmacological properties, it is likely that the new progestins may have neutral effects on metabolic or vascular risks.", "type": "CHEMICAL", "entities": [ "progestins" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "16291771", "text": "However, this hypothesis must be confirmed in large clinical trials.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386390", "text": "Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in insulin-treated Japanese patients with type 2 diabetes mellitus.\n", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 40, 51 ] ] }, { "pmid": "23386390", "text": "The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 34, 45 ] ] }, { "pmid": "23386390", "text": "Seventy-one patients were evaluated (38 men and 33 women aged 63.9±10.2 years).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386390", "text": "They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386390", "text": "Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors and metformin.", "type": "CHEMICAL", "entities": [ "sulfonylureas", "metformin" ], "offsets": [ [ 31, 44 ], [ 75, 84 ] ] }, { "pmid": "23386390", "text": "The hemoglobin A1c (HbA1c) of all patients improved significantly from 8.1±1.2% to 7.6±1.1% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced from 27.3±15.8 U/day to 24.5±16.5 U/day (p<0.001).", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 128, 139 ] ] }, { "pmid": "23386390", "text": "Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23386390", "text": "The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 119, 130 ] ] }, { "pmid": "23386390", "text": "These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient's demographic profile.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "23386390", "text": "Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 106, 117 ] ] }, { "pmid": "23386390", "text": "The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain.", "type": "CHEMICAL", "entities": [ "sitagliptin" ], "offsets": [ [ 63, 74 ] ] }, { "pmid": "23194826", "text": "Effect of blood-retinal barrier development on formation of selenite nuclear cataract in rat.\n", "type": "CHEMICAL", "entities": [ "selenite" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23194826", "text": "Selenite cataract, as an experimental animal model of nuclear cataract to mimic human senile cataract, is produced only when overdose selenite is injected to neonatal rats before eyelid opening.", "type": "CHEMICAL", "entities": [ "Selenite", "selenite" ], "offsets": [ [ 0, 8 ], [ 134, 142 ] ] }, { "pmid": "23194826", "text": "To clarify the cause of age differences on selenite cataract formation in rats, mRNA expression of GPx1, MsrA and MsrB1, as well as GPx activity in Wistar rat lens at different ages were assayed, level of lipid peroxidation, extent of lens damage induced by sodium selenite and barricade function of blood-retinal barrier (BRB) were investigated.", "type": "CHEMICAL", "entities": [ "selenite", "sodium selenite" ], "offsets": [ [ 43, 51 ], [ 258, 273 ] ] }, { "pmid": "23194826", "text": "The results showed that mRNA expressions and activity of antioxidant enzymes in neonatal rat lens before eyelid opening were the highest and then decreased with age, and revealed by transmission electron microscopy (TEM) using lanthanum hydroxide as tracer that higher selenite content entering eyes injured lens and resulted in cataract formation for immature BRB before eyelid opening, moreover, a little selenite content entering eyes was not enough to induce cataract formation after eyelid opening because of mature BRB.", "type": "CHEMICAL", "entities": [ "lanthanum hydroxide", "selenite", "selenite" ], "offsets": [ [ 227, 246 ], [ 269, 277 ], [ 407, 415 ] ] }, { "pmid": "19482847", "text": "Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "OBJECTIVE: Inhibition of interleukin-1 activity improves nitro-oxidative stress, endothelial and coronary function.", "type": "CHEMICAL", "entities": [ "nitro" ], "offsets": [ [ 57, 62 ] ] }, { "pmid": "19482847", "text": "The authors investigated (a) the association of nitro-oxidative stress and endothelial function with myocardial deformation, (b) the effects of anakinra, an interleukin-1a receptor antagonist on myocardial deformation in patients with rheumatoid arthritis (RA).", "type": "CHEMICAL", "entities": [ "nitro" ], "offsets": [ [ 48, 53 ] ] }, { "pmid": "19482847", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "The authors compared 46 RA patients to 23 normal controls.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "23 patients received anakinra (150 mg subcutaneously once daily) and 23 patients a 5-mg increase of prednisolone dose for 30 days.", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 100, 112 ] ] }, { "pmid": "19482847", "text": "At baseline and post-treatment this study assessed (a) the left ventricular (LV) longitudinal, circumferential and radial strain and strain rate, using speckle tracking echocardiography, (b) the coronary flow reserve (CFR), (c) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) and (d) nitrotyrosine (NT) and malondialdehyde blood levels.", "type": "CHEMICAL", "entities": [ "nitrotyrosine", "NT", "malondialdehyde" ], "offsets": [ [ 314, 327 ], [ 329, 331 ], [ 337, 352 ] ] }, { "pmid": "19482847", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "Patients had impaired baseline myocardial deformation indices compared to controls (p<0.05).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "CFR and NT levels were related to longitudinal strain, systolic and diastolic strain rate, circumferential strain and systolic strain rate (p<0.05).", "type": "CHEMICAL", "entities": [ "NT" ], "offsets": [ [ 8, 10 ] ] }, { "pmid": "19482847", "text": "FMD was related to longitudinal and circumferential diastolic strain rate (p<0.01).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "Compared to baseline, anakinra-treated patients increased the longitudinal strain (-17.8% (3.7%) vs -22.1% (3.5%)), systolic (-1.02 (0.23) l/s vs -1.25 (0.23) l/s) and diastolic (0.96 (0.37) l/s vs 1.20 (0.39) l/s) longitudinal strain rate, circumferential strain and strain rate (p<0.05 for all comparisons).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "19482847", "text": "No significant changes were observed among prednisolone-treated patients CONCLUSIONS:", "type": "CHEMICAL", "entities": [ "prednisolone" ], "offsets": [ [ 43, 55 ] ] }, { "pmid": "19482847", "text": "Myocardial deformation is impaired in RA patients and is related to nitro-oxidative stress and endothelial dysfunction.", "type": "CHEMICAL", "entities": [ "nitro" ], "offsets": [ [ 68, 73 ] ] }, { "pmid": "19482847", "text": "Chronic inhibition of IL-1 improves LV deformation in parallel with endothelial function and nitro-oxidative stress.", "type": "CHEMICAL", "entities": [ "nitro" ], "offsets": [ [ 93, 98 ] ] }, { "pmid": "16766717", "text": "A molecular mechanism of pyruvate protection against cytotoxicity of reactive oxygen species in osteoblasts.\n", "type": "CHEMICAL", "entities": [ "pyruvate", "oxygen" ], "offsets": [ [ 25, 33 ], [ 78, 84 ] ] }, { "pmid": "16766717", "text": "We demonstrated previously that exogenous pyruvate has a protective action against cell death by hydrogen peroxide in cultured osteoblasts through a mechanism associated with its antioxidative property.", "type": "CHEMICAL", "entities": [ "pyruvate", "hydrogen peroxide" ], "offsets": [ [ 42, 50 ], [ 97, 114 ] ] }, { "pmid": "16766717", "text": "In the present study, we have evaluated possible participation of monocarboxylate transporters (MCTs) responsible for the bidirectional membrane transport of pyruvate in the cytoprotective property in osteoblasts.", "type": "CHEMICAL", "entities": [ "pyruvate" ], "offsets": [ [ 158, 166 ] ] }, { "pmid": "16766717", "text": "Expression of the MCT2 isoform was found in cultured rat calvarial osteoblasts and in osteoblasts located on mouse tibia at both mRNA and protein levels.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "16766717", "text": "The accumulation of [14C]pyruvate occurred in a temperature- and pH-dependent manner in osteoblasts cultured for 7 days with high sensitivity to a specific MCT inhibitor, whereas pyruvate was released into extracellular spaces from cultured osteoblasts in a fashion sensitive to the MCT inhibitor.", "type": "CHEMICAL", "entities": [ "[14C]pyruvate", "pyruvate" ], "offsets": [ [ 20, 33 ], [ 179, 187 ] ] }, { "pmid": "16766717", "text": "Transient overexpression of the MCT2 isoform led to reduced vulnerability to the cytotoxicity of hydrogen peroxide with an increased activity of [14C]pyruvate accumulation in murine osteoblastic MC3T3-E1 cells.", "type": "CHEMICAL", "entities": [ "[14C]pyruvate", "hydrogen peroxide" ], "offsets": [ [ 145, 158 ], [ 97, 114 ] ] }, { "pmid": "16766717", "text": "Ovariectomy significantly decreased the content of pyruvate in femoral bone marrows in mice in vivo, whereas daily i.p. administration of pyruvate at 0.25 g/kg significantly prevented alterations of several histomorphometric parameters as well as cancellous bone loss in femurs by ovariectomy on 28 days after the operation.", "type": "CHEMICAL", "entities": [ "pyruvate", "pyruvate" ], "offsets": [ [ 51, 59 ], [ 138, 146 ] ] }, { "pmid": "16766717", "text": "These results suggest that MCTs may be functionally expressed by osteoblasts to play a pivotal role in mechanisms related to the cytoprotective property of pyruvate.", "type": "CHEMICAL", "entities": [ "pyruvate" ], "offsets": [ [ 156, 164 ] ] }, { "pmid": "23300287", "text": "Lower Adiponectin Levels at First Trimester of Pregnancy Are Associated With Increased Insulin Resistance and Higher Risk of Developing Gestational Diabetes Mellitus.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "OBJECTIVETo evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "RESEARCH DESIGN AND METHODSWe performed anthropometric measurements and collected blood samples at 1st (6-13 weeks) and 2nd (24-28 weeks) trimesters.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "Diagnosis of GDM was made at 2nd trimester, based on a 75-g oral glucose tolerance test (International Association of Diabetes and Pregnancy Study Group criteria).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 64, 71 ] ] }, { "pmid": "23300287", "text": "Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUC(insulin/glucose)), and β-cell compensation (insulin secretion sensitivity index-2).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 205, 212 ] ] }, { "pmid": "23300287", "text": "Adiponectin was measured by radioimmunoassay.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "RESULTSAmong the 445 participants included in this study, 38 women developed GDM.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 121, 128 ] ] }, { "pmid": "23300287", "text": "Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA(1c) at 1st trimester).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = -0.22, P < 0.0001) and Matsuda index (r = 0.28, P < 0.0001, and r = 0.29, P < 0.0001).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23300287", "text": "After adjustment for confounding factors, we found no significant association with HOMA-B and AUC(insulin/glucose).CONCLUSIONSPregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 99, 106 ] ] }, { "pmid": "23201337", "text": "Reduced plasma oxytocin levels in female patients with borderline personality disorder.\n", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "23201337", "text": "The neuropeptide oxytocin is involved in social cognition and interaction across species and plays a crucial role in the regulation of affiliative behaviors.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 17, 25 ] ] }, { "pmid": "23201337", "text": "Oxytocin levels in cerebrospinal fluid (CSF), but also in plasma or urine, have been shown to be negatively associated with childhood traumata, aggressive behavior, and suicide attempts.", "type": "CHEMICAL", "entities": [ "Oxytocin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23201337", "text": "Recently, an altered activity of the oxytocin system has been discussed to play a prominent role in borderline personality disorder (BPD), which is thought to be closely related to traumatic experiences in childhood and is characterized by (para)suicidal behaviors as well as aggressive outbursts.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "23201337", "text": "In the present study, we compared plasma oxytocin levels of women with and without BPD in the follicular phase and assessed the relationship between oxytocin concentrations and childhood traumata.", "type": "CHEMICAL", "entities": [ "oxytocin", "oxytocin" ], "offsets": [ [ 41, 49 ], [ 149, 157 ] ] }, { "pmid": "23201337", "text": "Women diagnosed with BPD had significantly reduced oxytocin concentrations, even after controlling for estrogen, progesterone, and contraceptive intake.", "type": "CHEMICAL", "entities": [ "oxytocin", "estrogen", "progesterone" ], "offsets": [ [ 51, 59 ], [ 103, 111 ], [ 113, 125 ] ] }, { "pmid": "23201337", "text": "In addition, plasma oxytocin correlated negatively with experiences of childhood traumata, in particular with emotional neglect and abuse.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 20, 28 ] ] }, { "pmid": "23201337", "text": "The results of mediation analyses do not support a model of oxytocin being a prominent mediator in the link between childhood trauma and BPD.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23201337", "text": "Thus, the findings indicate dysregulations in the oxytocin system of patients diagnosed with BPD with more longitudinal research being necessary to disentangle the relationship between childhood adversities, oxytocin system, and psychopathology.", "type": "CHEMICAL", "entities": [ "oxytocin", "oxytocin" ], "offsets": [ [ 50, 58 ], [ 208, 216 ] ] }, { "pmid": "17034586", "text": "Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "Cytokines may be crucially involved in the pathogenesis of inflammatory bowel diseases (IBD), but it remains controversial whether interferon (IFN)-gamma, a typical proinflammatory cytokine, is an essential mediator to cause the disorders.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "In the present study, IFN-gamma(-/-) and wild-type (WT) C57BL/6 mice were fed 2.5% dextran sodium sulphate (DSS) in drinking water for 7 days, in order to investigate DSS-induced intestinal inflammation.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "The DSS-treated WT mice exhibited a robust production of IFN-gamma in the gut, a remarkable loss of body weight, as well as high rate of mortality (60%).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "In striking contrast, IFN-gamma deficient mice did not develop DSS-induced colitis, as indicated by the maintenance of body weight and survival rate of 100%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "Severe intestinal inflammation was demonstrated exclusively in WT animals in terms of the shortening of the bowel as well as the elevation of the disease activity index, myeloperoxidase (MPO) activity and serum haptoglobin level.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "Histological study of DSS-treated WT intestine revealed disruption of mucosal epithelium and massive infiltration of inflammatory cells, while the organ from IFN-gamma(-/-) mice remained virtually normal in appearance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "Enzyme-linked immunosorbent assay (ELISA) analyses indicated abundant production of three chemokines, i.e. monokine induced by interferon-gamma (MIG), interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), in the DSS-irritated intestine of WT but not of IFN-gamma(-/-) mice.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17034586", "text": "The present results demonstrate clearly that IFN-gamma plays indispensable roles in the initiation of DSS colitis, and some chemokines are produced in an IFN-gamma-dependent fashion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18686730", "text": "Formoterol in the management of chronic obstructive pulmonary disease.\n", "type": "CHEMICAL", "entities": [ "Formoterol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18686730", "text": "Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "18686730", "text": "There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting beta2-agonists, and long-acting beta2-agonists such as formoterol.", "type": "CHEMICAL", "entities": [ "methylxanthines", "formoterol" ], "offsets": [ [ 64, 79 ], [ 149, 159 ] ] }, { "pmid": "18686730", "text": "Significant research has been performed to investigate the efficacy, safety and tolerability of formoterol in the therapeutic field of COPD.", "type": "CHEMICAL", "entities": [ "formoterol" ], "offsets": [ [ 96, 106 ] ] }, { "pmid": "18686730", "text": "Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilatory duration is comparable to salmeterol.", "type": "CHEMICAL", "entities": [ "Formoterol", "salbutamol", "salmeterol" ], "offsets": [ [ 0, 10 ], [ 83, 93 ], [ 150, 160 ] ] }, { "pmid": "18686730", "text": "In addition, formoterol presents with a clear superiority in lung function improvement compared with either ipratropium bromide or oral theophylline, while its efficacy improves when administered in combination with ipratropium.", "type": "CHEMICAL", "entities": [ "formoterol", "ipratropium bromide", "theophylline", "ipratropium" ], "offsets": [ [ 13, 23 ], [ 108, 127 ], [ 136, 148 ], [ 216, 227 ] ] }, { "pmid": "18686730", "text": "Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, whereas it exerts synergistic effect with tiotropium.", "type": "CHEMICAL", "entities": [ "Formoterol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18686730", "text": "Moreover, formoterol reduces exacerbations, increases days free of use of rescue medication and improves patients' quality of life and disease symptoms.", "type": "CHEMICAL", "entities": [ "formoterol" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "18686730", "text": "Formoterol has a favorable safety profile and is better tolerated than theophylline.", "type": "CHEMICAL", "entities": [ "Formoterol", "theophylline" ], "offsets": [ [ 0, 10 ], [ 71, 83 ] ] }, { "pmid": "18686730", "text": "Collectively, data extracted from multicenter clinical trials support formoterol as a valid therapeutic option in the treatment of COPD.", "type": "CHEMICAL", "entities": [ "formoterol" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "23247008", "text": "Comparative genomics, molecular evolution and computational modeling of ALDH1B1 and ALDH2.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "Vertebrate ALDH2 genes encode mitochondrial enzymes capable of metabolizing acetaldehyde and other biological aldehydes in the body.", "type": "CHEMICAL", "entities": [ "aldehydes", "acetaldehyde" ], "offsets": [ [ 110, 119 ], [ 76, 88 ] ] }, { "pmid": "23247008", "text": "Mammalian ALDH1B1, another mitochondrial enzyme sharing 72% identity with ALDH2, is also capable of metabolizing acetaldehyde but has a tissue distribution and pattern of activity distinct from that of ALDH2.", "type": "CHEMICAL", "entities": [ "acetaldehyde" ], "offsets": [ [ 113, 125 ] ] }, { "pmid": "23247008", "text": "Bioinformatic analyses of several vertebrate genomes were undertaken using known ALDH2 and ALDH1B1 amino acid sequences.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 99, 109 ] ] }, { "pmid": "23247008", "text": "Phylogenetic analysis of many representative vertebrate species (including fish, amphibians, birds and mammals) indicated the presence of ALDH1B1 in many mammalian species and in frogs (Xenopus tropicalis); no evidence was found for ALDH1B1 in the genomes of birds, reptiles or fish.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "Predicted vertebrate ALDH2 and ALDH1B1 subunit sequences and structures were highly conserved, including residues previously shown to be involved in catalysis and coenzyme binding for human ALDH2.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "Studies of ALDH1B1 sequences supported the hypothesis that the ALDH1B1 gene originated in early vertebrates from a retrotransposition of the vertebrate ALDH2 gene.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "Given the high degree of similarity between ALDH2 and ALDH1B1, it is surprising that individuals with an inactivating mutation in ALDH2 (ALDH2*2) do not exhibit a compensatory increase in ALDH1B1 activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "We hypothesized that the similarity between the two ALDHs would allow for dominant negative heterotetramerization between the inactive ALDH2 mutants and ALDH1B1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23247008", "text": "Computational-based molecular modeling studies examining predicted protein-protein interactions indicated that heterotetramerization between ALDH2 and ALDH1B1 subunits was highly probable and may partially explain a lack of compensation by ALDH1B1 in ALDH2(∗)2 individuals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "Influence of chain length and double bond on the aqueous behavior of choline carboxylate soaps.\n", "type": "CHEMICAL", "entities": [ "choline carboxylate" ], "offsets": [ [ 69, 88 ] ] }, { "pmid": "23368901", "text": "In preceding studies, we demonstrated that choline carboxylates ChC(m) with alkyl chain lengths of m", "type": "CHEMICAL", "entities": [ "choline carboxylates", "ChC(m)", "alkyl" ], "offsets": [ [ 43, 63 ], [ 64, 70 ], [ 76, 81 ] ] }, { "pmid": "23368901", "text": "= 12 - 18 are highly water-soluble (for m = 12, soluble up to 93 wt % soap and 0 °C).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "In addition, choline soaps are featured by an extraordinary lyotropic phase behavior.", "type": "CHEMICAL", "entities": [ "choline" ], "offsets": [ [ 12, 19 ] ] }, { "pmid": "23368901", "text": "With decreasing water concentration, the following phases were found: micellar phase (L(1)), discontinuous cubic phase (I(1)' and I(1)\"), hexagonal phase (H(1)), bicontinuous cubic phase (V(1)), and lamellar phase (L(α)).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "The present work is also focused on the lyotropic phase behavior of choline soaps but with shorter alkyl chains or different alkyl chain properties.", "type": "CHEMICAL", "entities": [ "choline", "alkyl", "alkyl" ], "offsets": [ [ 66, 73 ], [ 97, 102 ], [ 123, 128 ] ] }, { "pmid": "23368901", "text": "We have investigated the aqueous phase behavior of choline soaps with C(8) and C(10) chain-lengths (choline octanoate and choline decanoate) and with a C(18) chain-length with a cis-double bond (choline oleate).", "type": "CHEMICAL", "entities": [ "choline", "C(8)", "C(10)", "choline octanoate", "choline decanoate", "C(18)", "choline oleate" ], "offsets": [ [ 49, 56 ], [ 68, 72 ], [ 77, 82 ], [ 98, 115 ], [ 120, 137 ], [ 150, 155 ], [ 193, 207 ] ] }, { "pmid": "23368901", "text": "We found that choline decanoate follows the lyotropic phase behavior of the longer-chain homologues mentioned above.", "type": "CHEMICAL", "entities": [ "choline decanoate" ], "offsets": [ [ 12, 29 ] ] }, { "pmid": "23368901", "text": "Choline octanoate in water shows no discontinuous cubic phases, but an extended, isotropic micellar solution phase.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "In addition, choline octanoate is at the limit between a surfactant and a hydrotrope.", "type": "CHEMICAL", "entities": [ "choline octanoate" ], "offsets": [ [ 11, 28 ] ] }, { "pmid": "23368901", "text": "The double bond in choline oleate leads also to a better solubility in water and a decrease of the solubilization temperature.", "type": "CHEMICAL", "entities": [ "choline oleate" ], "offsets": [ [ 17, 31 ] ] }, { "pmid": "23368901", "text": "It also influences the Gaussian curvature of the aggregates which results in a loss of discontinuous cubic phases in the binary phase diagram.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "The different lyotropic mesophases were identified by the penetration scan technique with polarizing light microscope and visual observations.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "To clarify the structural behavior small (SAXS) and wide (WAXS) angle X-ray scattering were performed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23368901", "text": "To further characterize the extended, isotropic micellar solution phase in the binary phase diagram of choline octanoate viscosity and conductivity measurements were also carried out.", "type": "CHEMICAL", "entities": [ "choline octanoate" ], "offsets": [ [ 101, 118 ] ] }, { "pmid": "23633521", "text": "Loss of Kruppel-like Factor 3 (KLF3/BKLF) leads to upregulation of the insulin-sensitizing factor adipolin (FAM132A/CTRP12/C1qdc2).\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "Krüppel-like Factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "Here we report that KLF3 null mice are lean and protected from diet-induced obesity and glucose intolerance.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 87, 94 ] ] }, { "pmid": "23633521", "text": "On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "Despite significant reductions in body weight and adiposity, wildtype and knockout animals show equivalent energy intake, expenditure and excretion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3(+/+) and Klf3(-/-)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "Further, plasma adipolin levels were significantly increased in Klf3(-/-)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "mice compared to wild-type littermates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23633521", "text": "Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "2083404", "text": "Salicylate pre-treatment attenuates intensity of bronchial and nasal symptoms precipitated by aspirin in aspirin-intolerant patients.\n", "type": "CHEMICAL", "entities": [ "Salicylate", "aspirin", "aspirin" ], "offsets": [ [ 0, 10 ], [ 105, 112 ], [ 94, 101 ] ] }, { "pmid": "2083404", "text": "Aspirin (ASA) and other non-steroidal anti-inflammatory drugs, which are cyclooxygenase (COX) inhibitors, precipitate asthmatic attacks in ASA-intolerant patients, while sodium salicylate, hardly active on COX by itself, is well tolerated by these patients.", "type": "CHEMICAL", "entities": [ "Aspirin", "ASA", "sodium salicylate", "steroidal", "ASA" ], "offsets": [ [ 0, 7 ], [ 139, 142 ], [ 170, 187 ], [ 28, 37 ], [ 9, 12 ] ] }, { "pmid": "2083404", "text": "However, salicylate moiety appears to interfere with aspirin inhibitory action on platelets and vascular COX.", "type": "CHEMICAL", "entities": [ "salicylate", "aspirin" ], "offsets": [ [ 9, 19 ], [ 53, 60 ] ] }, { "pmid": "2083404", "text": "Such interaction, if present at the level of respiratory tract, may be of interest to pathogenesis of ASA-induced asthma.", "type": "CHEMICAL", "entities": [ "ASA" ], "offsets": [ [ 102, 105 ] ] }, { "pmid": "2083404", "text": "We performed a double-blind, placebo-controlled, randomized cross-over study on the effect of choline magnesium trisalicylate (CMT, trilisate) pre-treatment on ASA-induced adverse reactions in nine patients.", "type": "CHEMICAL", "entities": [ "choline magnesium trisalicylate", "CMT", "trilisate", "ASA" ], "offsets": [ [ 94, 125 ], [ 127, 130 ], [ 132, 141 ], [ 160, 163 ] ] }, { "pmid": "2083404", "text": "Pulmonary function tests, nasal symptoms score, PNIF and serum salicylate levels were monitored following challenges with threshold doses of ASA.", "type": "CHEMICAL", "entities": [ "salicylate", "ASA" ], "offsets": [ [ 63, 73 ], [ 141, 144 ] ] }, { "pmid": "2083404", "text": "Trilisate administered at a dose of 3000 mg daily for 3 days, offered a moderate protection against ASA-induced symptoms; it diminished the severity and/or delayed the appearance of FEV1 fall.", "type": "CHEMICAL", "entities": [ "Trilisate", "ASA" ], "offsets": [ [ 0, 9 ], [ 100, 103 ] ] }, { "pmid": "2083404", "text": "Maximal decreases in FEV1 as well as reaction intensity indexes were significantly lower (P less than 0.02 and P less than 0.002, respectively) after trilisate pre-treatment as compared to placebo.", "type": "CHEMICAL", "entities": [ "trilisate" ], "offsets": [ [ 150, 159 ] ] }, { "pmid": "2083404", "text": "Trilisate also attenuated nasal symptoms in three out of five patients.", "type": "CHEMICAL", "entities": [ "Trilisate" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "2083404", "text": "Although the precise mechanism of the protective action of trilisate is unknown, our data support the possibility of interaction between salicylate and ASA on cyclo-oxygenase locus in the respiratory tract in ASA-intolerant patients.", "type": "CHEMICAL", "entities": [ "trilisate", "salicylate", "ASA", "ASA" ], "offsets": [ [ 59, 68 ], [ 137, 147 ], [ 152, 155 ], [ 209, 212 ] ] }, { "pmid": "11986668", "text": "Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice.\n", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11986668", "text": "Minocycline mediates neuroprotection in experimental models of neurodegeneration.", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11986668", "text": "It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK).", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 68, 80 ] ] }, { "pmid": "11986668", "text": "Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 9, 20 ] ] }, { "pmid": "11986668", "text": "Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 100, 111 ] ] }, { "pmid": "11986668", "text": "Here we report that minocycline delays disease onset and extends survival in ALS mice.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "11986668", "text": "Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 28, 39 ] ] }, { "pmid": "11986668", "text": "We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 13, 24 ] ] }, { "pmid": "11986668", "text": "Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria.", "type": "CHEMICAL", "entities": [ "Minocycline" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11986668", "text": "Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "11986668", "text": "Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS.", "type": "CHEMICAL", "entities": [ "minocycline" ], "offsets": [ [ 32, 43 ] ] }, { "pmid": "23380082", "text": "Use of the Combination Index to determine interactions between plant-derived phenolic acids on hepatotoxicity endpoints in human and rat hepatoma cells.\n", "type": "CHEMICAL", "entities": [ "phenolic acids" ], "offsets": [ [ 77, 91 ] ] }, { "pmid": "23380082", "text": "The beneficial or adverse effects of isolated phytochemicals are not always concordant with effects of the botanical dietary supplements from which they were derived.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "This disparity could be due to interactions between the various phytochemicals present in the whole plant.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "The phenolic acids, rosmarinic acid (RA), caffeic acid (CA) and ferulic acid (FA) are widely present in foods and dietary supplements, and they are assumed to exert various beneficial biological effects.", "type": "CHEMICAL", "entities": [ "phenolic acids", "rosmarinic acid", "caffeic acid", "ferulic acid" ], "offsets": [ [ 4, 18 ], [ 20, 35 ], [ 42, 54 ], [ 64, 76 ] ] }, { "pmid": "23380082", "text": "However, there is little data on the potential biological interactions of these three phenolic acids which commonly occur together and are linked metabolically.", "type": "CHEMICAL", "entities": [ "phenolic acids" ], "offsets": [ [ 86, 100 ] ] }, { "pmid": "23380082", "text": "In the present study, liver toxicity of the three phenolic acids was assessed on the three compounds singly and in various binary and one ternary combinations.", "type": "CHEMICAL", "entities": [ "phenolic acids" ], "offsets": [ [ 50, 64 ] ] }, { "pmid": "23380082", "text": "A series of in vitro endpoints relevant to liver toxicity were evaluated in both a human (HepG2/C3A) and rat (MH1C1) hepatocyte cell line.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "The Combination Index (CI) was calculated for each endpoint from both the concentration responses of the single compounds and the responses of the various binary and ternary mixtures.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "Both synergistic and antagonistic interactions were observed for some endpoints and some combinations of test agents.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "Interactions were most prevalent in measures of oxidative stress and cytochrome P450 activities in both cell types.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "There was only a 53% concordance between the rat and human cells which may be suggestive of species differences.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23380082", "text": "The data suggest an approach for better characterizing the beneficial or adverse effects of complex botanical products through evaluation of interactions between individual phytochemical components.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Heterogeneous expression and polymorphic genotype of glutathione S-transferases in human lung.\n", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "7974294", "text": "BACKGROUND:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics by conjugation with glutathione.", "type": "CHEMICAL", "entities": [ "glutathione", "Glutathione" ], "offsets": [ [ 104, 115 ], [ 0, 11 ] ] }, { "pmid": "7974294", "text": "One of the mu class genes of this superfamily of enzymes, GSTM1, is polymorphic because of a partial gene deletion.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "This results in a failure to express GSTM1 in approximately 50% of individuals.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Several studies have linked GSTM1 null status to an increased risk of lung carcinoma.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "This study investigated the expression and distribution of GST isoenzymes in human lung, and developed a polymerase chain reaction (PCR) assay which would allow genotyping of archival, paraffin embedded lung tissue.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "METHODS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Distribution was examined using a panel of polyclonal anti-GST antibodies for immunohistochemistry in normal tissue of 21 tumour-bearing lungs.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "DNA for PCR was extracted from paraffin blocks and a control group of 350 blood lysates.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "As a positive control each assay amplified part of GSTM4, a mu class gene which is not polymorphic but which shows strong sequence homology to GSTM1.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "The presence of GST in bronchoalveolar lavage fluid was sought by Western analysis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "RESULTS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Proximal airways contained pi class GST, alpha class GST, and mu class GST with expression concentrated in the brush border.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "In distal airspaces no alpha GST was expressed but pi GST and mu GST were present in alveolar cells and also alveolar macrophages.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Pi class GST was present in bronchoalveolar lavage fluid.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "The PCR assay enabled genotypic determination using DNA extracted from archival material.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Of the control group 56% were null at the GSTM1 locus.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "CONCLUSIONS:", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "The distribution of GST isoenzymes in the lung is heterogeneous with an apparent decrease in GST in distal lung.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "7974294", "text": "Since GSTM1 status has already been associated with susceptibility to disease, the PCR assay developed will allow further studies of the relation between genotype and structural disorders in the lung using archival pathological material.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578952", "text": "Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice.\n", "type": "CHEMICAL", "entities": [ "Monoacylglycerol", "corticosterone" ], "offsets": [ [ 0, 16 ], [ 61, 75 ] ] }, { "pmid": "23578952", "text": "The hypothalamus-pituitary-adrenal-axis is strongly controlled by the endocannabinoid system.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578952", "text": "The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far.", "type": "CHEMICAL", "entities": [ "2-arachidonoylglycerol", "corticosterone" ], "offsets": [ [ 32, 54 ], [ 68, 82 ] ] }, { "pmid": "23578952", "text": "Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses.", "type": "CHEMICAL", "entities": [ "monoacylglycerol", "JZL184", "corticosterone" ], "offsets": [ [ 54, 70 ], [ 88, 94 ], [ 123, 137 ] ] }, { "pmid": "23578952", "text": "Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone.", "type": "CHEMICAL", "entities": [ "corticosterone", "JZL184", "corticosterone", "metyrapone", "JZL184", "corticosterone" ], "offsets": [ [ 23, 37 ], [ 66, 72 ], [ 112, 126 ], [ 147, 157 ], [ 225, 231 ], [ 249, 263 ] ] }, { "pmid": "23578952", "text": "We found that in the elevated plus-maze, the effects of JZL184 on \"classical\" anxiety-related measures were abolished by corticosterone synthesis blockade.", "type": "CHEMICAL", "entities": [ "JZL184", "corticosterone" ], "offsets": [ [ 56, 62 ], [ 121, 135 ] ] }, { "pmid": "23578952", "text": "By contrast, effects on the \"ethological\" measures of anxiety (i.e. risk assessment) were not affected by metyrapone.", "type": "CHEMICAL", "entities": [ "metyrapone" ], "offsets": [ [ 106, 116 ] ] }, { "pmid": "23578952", "text": "In the open-field, the locomotion-enhancing effects of the compound were not changed either.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23578952", "text": "These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone.", "type": "CHEMICAL", "entities": [ "monoacylglycerol", "corticosterone" ], "offsets": [ [ 25, 41 ], [ 99, 113 ] ] }, { "pmid": "23578952", "text": "This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade.", "type": "CHEMICAL", "entities": [ "monoacylglycerol" ], "offsets": [ [ 97, 113 ] ] }, { "pmid": "23643933", "text": "Induction of the liver cancer-down-regulated long noncoding RNA uc002mbe.2 mediates trichostatin-induced apoptosis of liver cancer cells.\n", "type": "CHEMICAL", "entities": [ "trichostatin" ], "offsets": [ [ 84, 96 ] ] }, { "pmid": "23643933", "text": "Differential expression of long non-coding RNAs (lncRNAs) plays critical roles in hepatocarcinogenesis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "Considerable attention has focused on the antitumor effect of histone deacetylase inhibitor (Trichostatin A, TSA) as well as the coding gene expression-induced apoptosis of cancer cells.", "type": "CHEMICAL", "entities": [ "Trichostatin A", "TSA" ], "offsets": [ [ 93, 107 ], [ 109, 112 ] ] }, { "pmid": "23643933", "text": "However, it is not known whether lncRNA has a role in TSA-induced apoptosis of human hepatocellular carcinoma (HCC) cells.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 54, 57 ] ] }, { "pmid": "23643933", "text": "The global expression of lncRNAs and coding genes was analyzed with the Human LncRNA Array V2.0 after 24h treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "Expression was verified in cell lines and tissues by quantitative real-time PCR.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "The data showed that 4.8% (959) of lncRNA and 6.1% (1849) of protein coding gene were significantly differentially expressed.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "The differential expressions of lncRNA and protein coding genes had distinguishable hierarchical clustering expression profiling pattern.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "Among these differentially expressed lncRNAs, the greatest change was noted for uc002mbe.2, which had more than 300 folds induction upon TSA treatment.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 137, 140 ] ] }, { "pmid": "23643933", "text": "TSA selectively induced uc002mbe.2 in four studied HCC cell lines.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23643933", "text": "Compared with normal human hepatocytes and adjacent noncancerous tissues, uc002mbe.2 expression level was significantly lower in the HCC cell lines and liver cancer tissues.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23643933", "text": "The TSA-induced uc002mbe.2 expression was positively correlated with the apoptotic effect of TSA in HCC cells.", "type": "CHEMICAL", "entities": [ "TSA", "TSA" ], "offsets": [ [ 4, 7 ], [ 93, 96 ] ] }, { "pmid": "23643933", "text": "In addition, knockdown the expression of uc002mbe.2 significantly reduced TSA-induced apoptosis of Huh7cells.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 74, 77 ] ] }, { "pmid": "23643933", "text": "Therefore, TSA-induced apoptosis of HCC cells is uc002mbe.2 dependent and reduced expression of uc002mbe.2 may be associated with liver carcinogenesis.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 11, 14 ] ] }, { "pmid": "23347038", "text": "The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells.\n", "type": "CHEMICAL", "entities": [ "M6P", "mannose 6-phosphate" ], "offsets": [ [ 41, 44 ], [ 4, 23 ] ] }, { "pmid": "23347038", "text": "The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis.", "type": "CHEMICAL", "entities": [ "M6P", "mannose 6-phosphate" ], "offsets": [ [ 4, 7 ], [ 9, 28 ] ] }, { "pmid": "23347038", "text": "It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells.", "type": "CHEMICAL", "entities": [ "M6P" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23347038", "text": "We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system.", "type": "CHEMICAL", "entities": [ "M6P" ], "offsets": [ [ 33, 36 ] ] }, { "pmid": "23347038", "text": "The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells.", "type": "CHEMICAL", "entities": [ "M6P" ], "offsets": [ [ 50, 53 ] ] }, { "pmid": "23347038", "text": "In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested.", "type": "CHEMICAL", "entities": [ "M6P" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "23347038", "text": "These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion.", "type": "CHEMICAL", "entities": [ "M6P", "M6P" ], "offsets": [ [ 54, 57 ], [ 68, 71 ] ] }, { "pmid": "23347038", "text": "The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor.", "type": "CHEMICAL", "entities": [ "M6P", "M6P", "carbohydrate" ], "offsets": [ [ 71, 74 ], [ 130, 133 ], [ 255, 267 ] ] }, { "pmid": "10730683", "text": "Orlistat, a new lipase inhibitor for the management of obesity.\n", "type": "CHEMICAL", "entities": [ "Orlistat" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "10730683", "text": "Orlistat, a weight-loss agent with a novel mechanism of action, recently was approved by the Food and Drug Administration for the treatment of obesity.", "type": "CHEMICAL", "entities": [ "Orlistat" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "10730683", "text": "It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10730683", "text": "In several trials lasting up to 2 years, orlistat was more effective than diet alone for weight reduction and maintenance of lost weight.", "type": "CHEMICAL", "entities": [ "orlistat" ], "offsets": [ [ 41, 49 ] ] }, { "pmid": "10730683", "text": "Orlistat treatment also results in modest improvements in total cholesterol, low-density lipoprotein, blood pressure, and fasting glucose and insulin concentrations.", "type": "CHEMICAL", "entities": [ "Orlistat", "cholesterol", "glucose" ], "offsets": [ [ 0, 8 ], [ 64, 75 ], [ 130, 137 ] ] }, { "pmid": "10730683", "text": "The major adverse effects are gastrointestinal, usually occur early in therapy, and tend to decrease with continued treatment.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10730683", "text": "Because orlistat may decrease the absorption of fat-soluble vitamins, a standard multiple-vitamin supplement is recommended daily during therapy to prevent abnormalities in vitamin serum concentrations.", "type": "CHEMICAL", "entities": [ "orlistat", "vitamins", "vitamin", "vitamin" ], "offsets": [ [ 8, 16 ], [ 60, 68 ], [ 90, 97 ], [ 173, 180 ] ] }, { "pmid": "10730683", "text": "The potential for severe gastrointestinal discomfort and the modest degree of weight loss may limit the agent's clinical utility.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "10730683", "text": "Its long-term safety and effectiveness for weight maintenance, cost-effectiveness of treatment, and overall reduction in obesity-related morbidity and mortality remain to be determined.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "The Atrial Natriuretic Peptide Genetic Variant Rs5068 Is Associated With a Favorable Cardiometabolic Phenotype in a Mediterranean Population.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "OBJECTIVEWe hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "RESEARCH DESIGN AND METHODSWe genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068.RESULTSGenotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "All subsequent analyses are AA versus AG+GG.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: -1.7 kg/m(2)", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "[0.8], P = 0.04).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "In the AG+GG group, males with HDL cholesterol levels <40 mg/dL are less frequent (P = 0.05) and obesity tends to be less prevalent (P = 0.07).", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "23637347", "text": "Importantly, the G allele is associated with a lower prevalence of metabolic syndrome (P = 0.02).", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "After adjusting for BMI, the above associations were attenuated.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "Independently of age, sex, and BMI, the minor allele is also associated with lower systolic blood pressure (-6.0 mmHg", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "[2.5], P = 0.02) and lower prevalence of hypertension (odds ratio 0.41", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "[95% CI 0.20-0.83], P = 0.01).CONCLUSIONSThe association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23637347", "text": "These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "The microsomal/peroxidase antigen: modulation of its expression in thyroid cells.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "Evidence has accumulated in the last few years that the expression of the microsomal/peroxidase antigen (M/TPO-Ag) in thyroid cells is induced by TSH, through pathways which involve intracellular cAMP accumulation and protein synthesis.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 196, 200 ] ] }, { "pmid": "1663395", "text": "These data have been found true in any thyroid system studied so far, both in terms of immunologic and enzymatic activity of TPO.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "TSH and cAMP also increase the levels of the specific mRNA for TPO in thyroid cells from different species.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 8, 12 ] ] }, { "pmid": "1663395", "text": "Whether this phenomenon is due to a direct transcriptional regulation of the TPO gene, as shown in dog thyroid cells, or to posttranscriptional effects, as it would appear in FRTL-5 cells, remains to be clarified by future experiments.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "Thyroid stimulating antibody (TSAb) of Graves' disease also stimulates the expression of M/TPO-Ag.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "This finding gives further support to the relevance of TSAb in the pathogenesis of hyperthyroidism and explains the well known observation that the \"microsomal\" antigen is particularly abundant in glands of Graves' patients.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "1663395", "text": "The modulation of M/TPO-Ag surface expression by TSH can explain the decrease of circulating anti-MAb observed during L-thyroxine therapy in hypothyroid patients with Hashimoto's thyroiditis.", "type": "CHEMICAL", "entities": [ "L-thyroxine" ], "offsets": [ [ 118, 129 ] ] }, { "pmid": "1663395", "text": "Other agents, such as methimazole and sodium iodide, which influence thyroid cell function, do not directly interfere with the expression of M/TPO-Ag.", "type": "CHEMICAL", "entities": [ "methimazole", "sodium iodide" ], "offsets": [ [ 22, 33 ], [ 38, 51 ] ] }, { "pmid": "1663395", "text": "Cytokines, such as gamma-interferon, interleukin-1, and interleukin-6 have been shown to inhibit the TSH-induced increase of TPO mRNA, but further investigations are required to elucidate the exact role of cytokines in the regulation of M/TPO-Ag expression.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23569204", "text": "Structural and functional characterization of a phosphatase domain within yeast general transcription factor TFIIIC.\n", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23569204", "text": "Saccharomyces cerevisiae τ55, a subunit of the RNA polymerase III-specific general transcription factor TFIIIC, comprises an N-terminal histidine phosphatase domain (τ55-HPD) whose catalytic activity and cellular function is poorly understood.", "type": "CHEMICAL", "entities": [ "N", "histidine" ], "offsets": [ [ 125, 126 ], [ 136, 145 ] ] }, { "pmid": "23569204", "text": "We solved the crystal structures of τ55-HPD and its closely related paralogue Huf and used in silico docking methods to identify phospho-serine and phospho-tyrosine containing peptides as possible substrates that were subsequently validated using in vitro phosphatase assays.", "type": "CHEMICAL", "entities": [ "phospho-serine", "phospho-tyrosine" ], "offsets": [ [ 127, 141 ], [ 146, 162 ] ] }, { "pmid": "23569204", "text": "A comparative phospho-proteomic study identified additional phosphopeptides as possible targets, which show the involvement of these two phosphatases in the regulation of a variety of cellular functions.", "type": "CHEMICAL", "entities": [ "phospho" ], "offsets": [ [ 11, 18 ] ] }, { "pmid": "23569204", "text": "Our results identify τ55-HPD and Huf as bona fide protein phosphatases, characterize their substrate specificities and provide a small set of regulated phosphosite targets in vivo.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506741", "text": "A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome.\n", "type": "CHEMICAL", "entities": [ "sodium", "benzo[d]imidazole" ], "offsets": [ [ 79, 85 ], [ 8, 25 ] ] }, { "pmid": "23506741", "text": "NLRP3 inflammasome has been reported to be associated with various kinds of immunological diseases including colitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506741", "text": "However, there are few drug candidates targeting inflammasomes for the treatment of colitis.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506741", "text": "In the present study, we aimed at examining the effect of 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole, a synthetic small molecular compound also named Fc11a-2, for the treatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice via targeting NLRP3 inflammasome.", "type": "CHEMICAL", "entities": [ "1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole", "Fc11a-2", "sulfate", "sodium" ], "offsets": [ [ 58, 104 ], [ 154, 161 ], [ 192, 199 ], [ 200, 206 ] ] }, { "pmid": "23506741", "text": "Treatment with Fc11a-2 dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "23506741", "text": "In addition, the disease activity index, histopathologic scores and myeloperoxidase activity were also significantly reduced by Fc11a-2 treatment.", "type": "CHEMICAL", "entities": [ "Fc11a-2" ], "offsets": [ [ 128, 135 ] ] }, { "pmid": "23506741", "text": "Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF-α, IL-1β, IL-18, IL-17A and IFN-γ, were markedly suppressed by Fc11a-2.", "type": "CHEMICAL", "entities": [ "Fc11a-2" ], "offsets": [ [ 162, 169 ] ] }, { "pmid": "23506741", "text": "Furthermore, a decreased CD11c(+) macrophage infiltration in colons and inactivation of caspase-1 in peritoneal macrophages were detected in Fc11a-2-treated mice.", "type": "CHEMICAL", "entities": [ "Fc11a" ], "offsets": [ [ 138, 143 ] ] }, { "pmid": "23506741", "text": "The mechanism of action of Fc11a-2 was related to the inhibition of the cleavage of pro-caspase-1, pro-IL-1β and pro-IL-18 which in turn suppressed the activation of NLRP3 inflammasome.", "type": "CHEMICAL", "entities": [ "Fc11a-2" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23506741", "text": "Taken together, our results demonstrate the ability of Fc11a-2 to inhibit NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel diseases.", "type": "CHEMICAL", "entities": [ "Fc11a-2" ], "offsets": [ [ 51, 58 ] ] }, { "pmid": "17611273", "text": "Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress.\n", "type": "CHEMICAL", "entities": [ "Methylphenidate" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "17611273", "text": "Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown.", "type": "CHEMICAL", "entities": [ "MPH", "methylphenidate", "MPH", "Ritalin" ], "offsets": [ [ 162, 165 ], [ 30, 45 ], [ 47, 50 ], [ 52, 59 ] ] }, { "pmid": "17611273", "text": "To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)-PND35.", "type": "CHEMICAL", "entities": [ "Ritalin", "MPH" ], "offsets": [ [ 18, 25 ], [ 78, 81 ] ] }, { "pmid": "17611273", "text": "At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology.", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 208, 211 ] ] }, { "pmid": "17611273", "text": "At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density.", "type": "CHEMICAL", "entities": [ "MPH", "catecholamine", "tyrosine", "norepinephrine" ], "offsets": [ [ 60, 63 ], [ 114, 127 ], [ 135, 143 ], [ 205, 219 ] ] }, { "pmid": "17611273", "text": "In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule).", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 30, 33 ] ] }, { "pmid": "17611273", "text": "In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats.", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 102, 105 ] ] }, { "pmid": "17611273", "text": "At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC.", "type": "CHEMICAL", "entities": [], "offsets": [] }, { "pmid": "17611273", "text": "Neither PND35 nor PND135 rats showed major structural differences with MPH exposure.", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 71, 74 ] ] }, { "pmid": "17611273", "text": "These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress.", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 80, 83 ] ] }, { "pmid": "17611273", "text": "Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood.", "type": "CHEMICAL", "entities": [ "MPH" ], "offsets": [ [ 113, 116 ] ] } ]