[ { "pmid": "10076535", "text": "Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor.\n", "type": "CHEMICAL", "entities": [ "Androgen", "estramustine phosphate", "EMP", "androgen" ], "offsets": [ [ 0, 8 ], [ 32, 54 ], [ 56, 59 ], [ 98, 106 ] ] }, { "pmid": "10076535", "text": "Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer.", "type": "CHEMICAL", "entities": [ "Estramustine phosphate" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "10076535", "text": "Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules", "type": "CHEMICAL", "entities": [ "Estramustine phosphate", "estramustine", "estromustine", "estrone", "beta-estradiol" ], "offsets": [ [ 0, 22 ], [ 80, 92 ], [ 94, 106 ], [ 108, 115 ], [ 121, 135 ] ] }, { "pmid": "10076535", "text": "We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells.", "type": "CHEMICAL", "entities": [ "[3H]methyltrienolone", "triamcinolone acetonide", "estramustine phosphate", "estramustine", "estromustine", "estrone", "beta-estradiol", "alpha-estradiol", "bicalutamide", "hydroxyflutamide", "androgen", "androgen" ], "offsets": [ [ 36, 56 ], [ 86, 109 ], [ 126, 148 ], [ 170, 182 ], [ 184, 196 ], [ 198, 205 ], [ 211, 225 ], [ 274, 289 ], [ 291, 303 ], [ 309, 325 ], [ 342, 350 ], [ 403, 411 ] ] }, { "pmid": "10076535", "text": "Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed.", "type": "CHEMICAL", "entities": [ "bicalutamide", "hydroxyflutamide", "estramustine phosphate", "androgen" ], "offsets": [ [ 32, 44 ], [ 49, 65 ], [ 78, 100 ], [ 120, 128 ] ] }, { "pmid": "10076535", "text": "The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012.", "type": "CHEMICAL", "entities": [ "alpha-estradiol", "beta-estradiol", "bicalutamide", "hydroxyflutamide", "estramustine phosphate", "estramustine", "estromustine", "estrone" ], "offsets": [ [ 152, 167 ], [ 186, 200 ], [ 219, 231 ], [ 254, 270 ], [ 34, 56 ], [ 64, 76 ], [ 95, 107 ], [ 126, 133 ] ] }, { "pmid": "10076535", "text": "The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells.", "type": "CHEMICAL", "entities": [ "bicalutamide", "estramustine" ], "offsets": [ [ 58, 70 ], [ 72, 84 ] ] }, { "pmid": "10076535", "text": "In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed.", "type": "CHEMICAL", "entities": [ "dihydrotestosterone" ], "offsets": [ [ 60, 79 ] ] }, { "pmid": "10076535", "text": "Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor.", "type": "CHEMICAL", "entities": [ "estramustine", "bicalutamide", "androgen" ], "offsets": [ [ 85, 97 ], [ 102, 114 ], [ 162, 170 ] ] }, { "pmid": "10076535", "text": "Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "estramustine" ], "offsets": [ [ 27, 39 ] ] }, { "pmid": "10076535", "text": "The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM).", "type": "CHEMICAL", "entities": [ "estramustine" ], "offsets": [ [ 98, 110 ] ] }, { "pmid": "10076535", "text": "Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR.", "type": "CHEMICAL", "entities": [ "hydroxyflutamide", "hydroxyflutamide" ], "offsets": [ [ 11, 27 ], [ 136, 152 ] ] }, { "pmid": "10076535", "text": "Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer.", "type": "CHEMICAL", "entities": [ "estramustine phosphate", "androgen", "estramustine phosphate" ], "offsets": [ [ 23, 45 ], [ 69, 77 ], [ 159, 181 ] ] }, { "pmid": "10089512", "text": "In order to address one aspect of the feasibility of performing time-resolved studies on AChE, a data set has been collected using the Laue technique on a trigonal crystal of Torpedo californica AChE soaked with the reversible inhibitor edrophonium, using a total X-ray exposure time of 24 ms. Electron-density maps obtained from the Laue data, which are of surprisingly good quality compared with similar maps from monochromatic data, show essentially the same features.", "type": "CHEMICAL", "entities": [ "edrophonium" ], "offsets": [ [ 237, 248 ] ] }, { "pmid": "10220509", "text": "Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites.\n", "type": "CHEMICAL", "entities": [ "prostaglandin" ], "offsets": [ [ 67, 80 ] ] }, { "pmid": "10220509", "text": "The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites.", "type": "CHEMICAL", "entities": [ "SC-236" ], "offsets": [ [ 72, 78 ] ] }, { "pmid": "10220509", "text": "In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis.", "type": "CHEMICAL", "entities": [ "sodium", "prostaglandins", "SC-236", "ketorolac" ], "offsets": [ [ 50, 56 ], [ 61, 75 ], [ 176, 182 ], [ 195, 204 ] ] }, { "pmid": "10220509", "text": "Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism.", "type": "CHEMICAL", "entities": [ "prostaglandins", "SC-236", "ketorolac" ], "offsets": [ [ 235, 249 ], [ 18, 24 ], [ 155, 164 ] ] }, { "pmid": "10220509", "text": "These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis.", "type": "CHEMICAL", "entities": [ "SC-236" ], "offsets": [ [ 29, 35 ] ] }, { "pmid": "10351938", "text": "Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils.\n", "type": "CHEMICAL", "entities": [ "leukotriene C4", "fluticasone propionate" ], "offsets": [ [ 38, 52 ], [ 66, 88 ] ] }, { "pmid": "10351938", "text": "We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro.", "type": "CHEMICAL", "entities": [ "LTC4", "fluticasone propionate", "FP", "leukotriene C4" ], "offsets": [ [ 219, 223 ], [ 64, 86 ], [ 88, 90 ], [ 203, 217 ] ] }, { "pmid": "10351938", "text": "Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB).", "type": "CHEMICAL", "entities": [ "FP", "formyl-met-leu-phe", "FMLP", "cytochalasin B", "CB" ], "offsets": [ [ 101, 103 ], [ 192, 210 ], [ 212, 216 ], [ 220, 234 ], [ 236, 238 ] ] }, { "pmid": "10351938", "text": "At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/=", "type": "CHEMICAL", "entities": [ "LTC4", "LTC4" ], "offsets": [ [ 20, 24 ], [ 111, 115 ] ] }, { "pmid": "10351938", "text": "10(-)8 M FP (p < 0.003).", "type": "CHEMICAL", "entities": [ "FP" ], "offsets": [ [ 9, 11 ] ] }, { "pmid": "10351938", "text": "FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP.", "type": "CHEMICAL", "entities": [ "FMLP", "CB", "FP" ], "offsets": [ [ 0, 4 ], [ 5, 7 ], [ 136, 138 ] ] }, { "pmid": "10351938", "text": "By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA).", "type": "CHEMICAL", "entities": [ "FP", "LTC4", "arachidonic acid", "AA" ], "offsets": [ [ 145, 147 ], [ 167, 171 ], [ 208, 224 ], [ 226, 228 ] ] }, { "pmid": "10351938", "text": "We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2).", "type": "CHEMICAL", "entities": [ "FP", "LTC4" ], "offsets": [ [ 13, 15 ], [ 72, 76 ] ] }, { "pmid": "10351938", "text": "Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression.", "type": "CHEMICAL", "entities": [ "LTC4", "FP" ], "offsets": [ [ 14, 18 ], [ 70, 72 ] ] }, { "pmid": "10424850", "text": "Desipramine treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells.\n", "type": "CHEMICAL", "entities": [ "Desipramine", "3H-nisoxetine", "norepinephrine" ], "offsets": [ [ 0, 11 ], [ 32, 45 ], [ 58, 72 ] ] }, { "pmid": "10424850", "text": "The antidepressant desipramine has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis.", "type": "CHEMICAL", "entities": [ "desipramine", "norepinephrine" ], "offsets": [ [ 19, 30 ], [ 98, 112 ] ] }, { "pmid": "10424850", "text": "In this study, we treated SK-N-SHSY5Y cells with 100 nM desipramine for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction.", "type": "CHEMICAL", "entities": [ "desipramine", "3H-nisoxetine" ], "offsets": [ [ 56, 67 ], [ 97, 110 ] ] }, { "pmid": "10424850", "text": "Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points).", "type": "CHEMICAL", "entities": [ "3H-nisoxetine" ], "offsets": [ [ 55, 68 ] ] }, { "pmid": "10424850", "text": "We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of desipramine to downregulate the NET.", "type": "CHEMICAL", "entities": [ "desipramine" ], "offsets": [ [ 97, 108 ] ] }, { "pmid": "10510456", "text": "Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.\n", "type": "CHEMICAL", "entities": [ "ether", "potassium", "cisapride" ], "offsets": [ [ 24, 29 ], [ 58, 67 ], [ 79, 88 ] ] }, { "pmid": "10510456", "text": "1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest.", "type": "CHEMICAL", "entities": [ "Cisapride" ], "offsets": [ [ 2, 11 ] ] }, { "pmid": "10510456", "text": "In a chronic transfection model using CHO-K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 52, 61 ] ] }, { "pmid": "10510456", "text": "4 Inactivation was significantly accelerated by cisapride in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 48, 57 ] ] }, { "pmid": "10510456", "text": "5 Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6", "type": "CHEMICAL", "entities": [ "K+", "cisapride", "K+" ], "offsets": [ [ 118, 120 ], [ 22, 31 ], [ 50, 52 ] ] }, { "pmid": "10510456", "text": "In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration.", "type": "CHEMICAL", "entities": [ "cisapride", "potassium" ], "offsets": [ [ 42, 51 ], [ 150, 159 ] ] }, { "pmid": "10510456", "text": "These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 104, 113 ] ] }, { "pmid": "10516958", "text": "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation.\n", "type": "CHEMICAL", "entities": [ "ziprasidone", "clozapine", "olanzapine" ], "offsets": [ [ 38, 49 ], [ 55, 64 ], [ 69, 79 ] ] }, { "pmid": "10516958", "text": "Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites.", "type": "CHEMICAL", "entities": [ "Ziprasidone" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "10516958", "text": "While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements.", "type": "CHEMICAL", "entities": [ "ziprasidone", "adenylate" ], "offsets": [ [ 53, 64 ], [ 105, 114 ] ] }, { "pmid": "10516958", "text": "The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus.", "type": "CHEMICAL", "entities": [ "ziprasidone", "serotonin" ], "offsets": [ [ 70, 81 ], [ 163, 172 ] ] }, { "pmid": "10516958", "text": "In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.)", "type": "CHEMICAL", "entities": [ "ziprasidone" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "10516958", "text": "as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.).", "type": "CHEMICAL", "entities": [ "clozapine", "olanzapine" ], "offsets": [ [ 35, 44 ], [ 81, 91 ] ] }, { "pmid": "10516958", "text": "Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine.", "type": "CHEMICAL", "entities": [ "WAY-100,635", "ziprasidone", "WAY-100,635", "clozapine", "olanzapine" ], "offsets": [ [ 40, 51 ], [ 90, 101 ], [ 139, 150 ], [ 199, 208 ], [ 213, 223 ] ] }, { "pmid": "10516958", "text": "Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity.", "type": "CHEMICAL", "entities": [ "serotonin", "desipramine", "DMI", "NE" ], "offsets": [ [ 86, 95 ], [ 165, 176 ], [ 178, 181 ], [ 186, 188 ] ] }, { "pmid": "10516958", "text": "DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine.", "type": "CHEMICAL", "entities": [ "DMI", "ziprasidone", "clozapine", "olanzapine" ], "offsets": [ [ 0, 3 ], [ 62, 73 ], [ 123, 132 ], [ 137, 147 ] ] }, { "pmid": "10516958", "text": "These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine.", "type": "CHEMICAL", "entities": [ "ziprasidone", "clozapine", "olanzapine" ], "offsets": [ [ 80, 91 ], [ 119, 128 ], [ 133, 143 ] ] }, { "pmid": "10516958", "text": "The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions.", "type": "CHEMICAL", "entities": [ "ziprasidone" ], "offsets": [ [ 64, 75 ] ] }, { "pmid": "10548268", "text": "Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors.\n", "type": "CHEMICAL", "entities": [ "ethanol", "monoamine" ], "offsets": [ [ 18, 25 ], [ 57, 66 ] ] }, { "pmid": "10548268", "text": "Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence.", "type": "CHEMICAL", "entities": [ "serotonin", "dopamine", "dopamine", "alcohol", "serotonin", "ethanol", "monoamine" ], "offsets": [ [ 184, 193 ], [ 198, 206 ], [ 23, 31 ], [ 277, 284 ], [ 36, 45 ], [ 64, 71 ], [ 104, 113 ] ] }, { "pmid": "10548268", "text": "The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol" ], "offsets": [ [ 109, 116 ], [ 172, 179 ] ] }, { "pmid": "10548268", "text": "The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement.", "type": "CHEMICAL", "entities": [ "phenelzine", "tranylcypromine", "nialamide", "ethanol" ], "offsets": [ [ 50, 60 ], [ 75, 90 ], [ 108, 117 ], [ 174, 181 ] ] }, { "pmid": "10548268", "text": "The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration.", "type": "CHEMICAL", "entities": [ "befloxatone", "clorgyline", "ethanol" ], "offsets": [ [ 32, 43 ], [ 97, 107 ], [ 136, 143 ] ] }, { "pmid": "10548268", "text": "However, befloxatone-induced effects leveled off at a 50% decrease.", "type": "CHEMICAL", "entities": [ "befloxatone" ], "offsets": [ [ 9, 20 ] ] }, { "pmid": "10548268", "text": "The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice.", "type": "CHEMICAL", "entities": [ "pargyline", "l-deprenyl", "ethanol", "ethanol" ], "offsets": [ [ 35, 44 ], [ 60, 70 ], [ 124, 131 ], [ 225, 232 ] ] }, { "pmid": "10548268", "text": "In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration.", "type": "CHEMICAL", "entities": [ "ethanol", "serotonin", "dopamine", "ethanol" ], "offsets": [ [ 81, 88 ], [ 179, 188 ], [ 193, 201 ], [ 241, 248 ] ] }, { "pmid": "10561120", "text": "Hepatocytes rapidly removed resorufin from the culture medium.", "type": "CHEMICAL", "entities": [ "resorufin" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "10561120", "text": "The resorufin was not being conjugated or accumulated within the cells.", "type": "CHEMICAL", "entities": [ "resorufin" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "10561120", "text": "Dicumarol, a potent inhibitor of quinone oxidoreductase, at high concentration (500 microm ) caused only a 72% decrease in the utilization of resorufin.", "type": "CHEMICAL", "entities": [ "Dicumarol", "quinone", "resorufin" ], "offsets": [ [ 0, 9 ], [ 33, 40 ], [ 142, 151 ] ] }, { "pmid": "10577279", "text": "A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia.\n", "type": "CHEMICAL", "entities": [ "pyridoxine", "gamma-Aminolevulinate" ], "offsets": [ [ 111, 121 ], [ 43, 64 ] ] }, { "pmid": "10577279", "text": "A novel missense mutation, G663A, in exon 5 of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with pyridoxine-responsive sideroblastic anemia.", "type": "CHEMICAL", "entities": [ "pyridoxine", "delta-aminolevulinate" ], "offsets": [ [ 153, 163 ], [ 70, 91 ] ] }, { "pmid": "10577279", "text": "Activity of the mutant delta-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to pyridoxine treatment.", "type": "CHEMICAL", "entities": [ "delta-aminolevulinate", "pyridoxal 5'-phosphate", "pyridoxine" ], "offsets": [ [ 23, 44 ], [ 174, 196 ], [ 254, 264 ] ] }, { "pmid": "10587286", "text": "Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans.\n", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 68, 80 ] ] }, { "pmid": "10587286", "text": "This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme.", "type": "CHEMICAL", "entities": [ "rivastigmine", "ENA-713", "Exelon" ], "offsets": [ [ 188, 200 ], [ 202, 209 ], [ 211, 217 ] ] }, { "pmid": "10587286", "text": "Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg).", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 158, 170 ] ] }, { "pmid": "10587286", "text": "CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity.", "type": "CHEMICAL", "entities": [ "rivastigmine", "NAP 226-90", "[-] [3-([1-dimethylaminolethyl)-phenol]" ], "offsets": [ [ 89, 101 ], [ 121, 131 ], [ 133, 172 ] ] }, { "pmid": "10587286", "text": "The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 25, 37 ] ] }, { "pmid": "10587286", "text": "The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57", "type": "CHEMICAL", "entities": [ "rivastigmine", "NAP 226-90" ], "offsets": [ [ 21, 33 ], [ 115, 125 ] ] }, { "pmid": "10587286", "text": "Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 36, 48 ] ] }, { "pmid": "10587286", "text": "Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 52, 64 ] ] }, { "pmid": "10587286", "text": "BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 52, 64 ] ] }, { "pmid": "10587286", "text": "This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 121, 133 ] ] }, { "pmid": "10593931", "text": "Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX.\nActivated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, factor IX, in an interaction requiring the factor XI A3 domain (Sun, Y., and Gailani, D. (1996) J. Biol.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "10593931", "text": "To identify key amino acids involved in factor IX activation, recombinant factor XIa proteins containing alanine substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay.", "type": "CHEMICAL", "entities": [ "amino acids", "alanine" ], "offsets": [ [ 16, 27 ], [ 105, 112 ] ] }, { "pmid": "10593931", "text": "Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the C terminus of the A3 domain markedly decreased factor XI coagulant activity.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 65, 66 ], [ 109, 110 ] ] }, { "pmid": "10593931", "text": "Clotting and kinetics studies using these chimeras confirmed the results obtained with alanine mutants.", "type": "CHEMICAL", "entities": [ "alanine" ], "offsets": [ [ 87, 94 ] ] }, { "pmid": "10593931", "text": "Amino acids between Ile(183) and Val(191) are necessary for proper factor IX activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation.", "type": "CHEMICAL", "entities": [ "Amino acids" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "10611634", "text": "Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors.", "type": "CHEMICAL", "entities": [ "serotonin", "5-HT", "5-HT", "5-HT", "dopamine", "yohimbine", "fluparoxan" ], "offsets": [ [ 110, 119 ], [ 121, 125 ], [ 132, 136 ], [ 142, 146 ], [ 155, 163 ], [ 34, 43 ], [ 59, 69 ] ] }, { "pmid": "10611634", "text": "Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats.", "type": "CHEMICAL", "entities": [ "yohimbine", "fluparoxan" ], "offsets": [ [ 67, 76 ], [ 93, 103 ] ] }, { "pmid": "10611634", "text": "Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors.", "type": "CHEMICAL", "entities": [ "Yohimbine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10611634", "text": "In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites.", "type": "CHEMICAL", "entities": [ "(35)S", "yohimbine" ], "offsets": [ [ 4, 9 ], [ 39, 48 ] ] }, { "pmid": "10611634", "text": "In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat.", "type": "CHEMICAL", "entities": [ "yohimbine", "5-HT", "WAY100,635" ], "offsets": [ [ 28, 37 ], [ 41, 45 ], [ 72, 82 ] ] }, { "pmid": "10611634", "text": "In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611.", "type": "CHEMICAL", "entities": [ "yohimbine", "5-HT", "5-HT", "GR46,611" ], "offsets": [ [ 38, 47 ], [ 51, 55 ], [ 124, 128 ], [ 142, 150 ] ] }, { "pmid": "10611634", "text": "In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs.", "type": "CHEMICAL", "entities": [ "yohimbine", "fluparoxan" ], "offsets": [ [ 18, 27 ], [ 29, 39 ] ] }, { "pmid": "10611634", "text": "While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT.", "type": "CHEMICAL", "entities": [ "fluparoxan", "noradrenaline", "NAD", "yohimbine", "dopamine", "DA", "5-HT" ], "offsets": [ [ 6, 16 ], [ 50, 63 ], [ 65, 68 ], [ 80, 89 ], [ 113, 121 ], [ 123, 125 ], [ 172, 176 ] ] }, { "pmid": "10611634", "text": "Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635.", "type": "CHEMICAL", "entities": [ "yohimbine", "WAY100,635" ], "offsets": [ [ 9, 18 ], [ 100, 110 ] ] }, { "pmid": "10611634", "text": "Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex.", "type": "CHEMICAL", "entities": [ "Fluparoxan", "DA", "NAD", "5-HT" ], "offsets": [ [ 0, 10 ], [ 45, 47 ], [ 52, 55 ], [ 65, 69 ] ] }, { "pmid": "10611634", "text": "In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635.", "type": "CHEMICAL", "entities": [ "yohimbine", "DA", "NAD", "5-HT", "WAY100,635" ], "offsets": [ [ 12, 21 ], [ 45, 47 ], [ 52, 55 ], [ 81, 85 ], [ 126, 136 ] ] }, { "pmid": "10611634", "text": "The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan.", "type": "CHEMICAL", "entities": [ "5-HT", "DA", "NAD", "fluparoxan" ], "offsets": [ [ 45, 49 ], [ 51, 53 ], [ 59, 62 ], [ 81, 91 ] ] }, { "pmid": "10611634", "text": "Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT.", "type": "CHEMICAL", "entities": [ "Yohimbine", "fluoxetine", "DA", "NAD", "5-HT" ], "offsets": [ [ 0, 9 ], [ 48, 58 ], [ 64, 66 ], [ 71, 74 ], [ 100, 104 ] ] }, { "pmid": "10611634", "text": "In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine.", "type": "CHEMICAL", "entities": [ "yohimbine", "DA", "NAD" ], "offsets": [ [ 56, 65 ], [ 75, 77 ], [ 82, 85 ] ] }, { "pmid": "10611634", "text": "However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.", "type": "CHEMICAL", "entities": [ "fluparoxan", "5-HT", "yohimbine", "5-HT", "fluoxetine", "5-HT" ], "offsets": [ [ 62, 72 ], [ 78, 82 ], [ 106, 115 ], [ 125, 129 ], [ 198, 208 ], [ 214, 218 ] ] }, { "pmid": "10640321", "text": "In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough.", "type": "CHEMICAL", "entities": [ "SB 227122", "citric acid" ], "offsets": [ [ 84, 93 ], [ 137, 148 ] ] }, { "pmid": "10640321", "text": "Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively.", "type": "CHEMICAL", "entities": [ "BRL 52974", "citric acid", "SB 227122", "codeine", "hydrocodone" ], "offsets": [ [ 163, 172 ], [ 210, 221 ], [ 78, 87 ], [ 110, 117 ], [ 122, 133 ] ] }, { "pmid": "10640321", "text": "The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated.", "type": "CHEMICAL", "entities": [ "naloxone", "codeine", "SB 227122" ], "offsets": [ [ 45, 53 ], [ 109, 116 ], [ 120, 129 ] ] }, { "pmid": "10640321", "text": "The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.).", "type": "CHEMICAL", "entities": [ "SB 244525", "SB 227122" ], "offsets": [ [ 31, 40 ], [ 95, 104 ] ] }, { "pmid": "10640321", "text": "In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.).", "type": "CHEMICAL", "entities": [ "beta-funaltrexamine", "norbinaltorphimine", "SB 227122" ], "offsets": [ [ 40, 59 ], [ 105, 123 ], [ 318, 327 ] ] }, { "pmid": "10640321", "text": "The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122.", "type": "CHEMICAL", "entities": [ "rimcazole", "dextromethorphan", "SB 227122" ], "offsets": [ [ 30, 39 ], [ 92, 108 ], [ 169, 178 ] ] }, { "pmid": "10640321", "text": "These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.", "type": "CHEMICAL", "entities": [ "SB 227122" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "10643177", "text": "New modes of therapy have recently been introduced, and data on the cyclooxygenase-2 (COX-2)-specific inhibitors celecoxib and rofecoxib suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib" ], "offsets": [ [ 113, 122 ], [ 127, 136 ] ] }, { "pmid": "10658902", "text": "Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid.\n", "type": "CHEMICAL", "entities": [ "brequinar sodium", "polyporic acid", "dihydroorotate", "atovaquone", "lawsone" ], "offsets": [ [ 105, 121 ], [ 126, 140 ], [ 40, 54 ], [ 72, 82 ], [ 84, 91 ] ] }, { "pmid": "10658902", "text": "Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate.", "type": "CHEMICAL", "entities": [ "dihydroorotate", "uridine monophosphate" ], "offsets": [ [ 22, 36 ], [ 131, 152 ] ] }, { "pmid": "10658902", "text": "The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects.", "type": "CHEMICAL", "entities": [ "isoxazol", "triazine", "cinchoninic acid", "(naphtho)quinone" ], "offsets": [ [ 83, 91 ], [ 93, 101 ], [ 103, 119 ], [ 124, 140 ] ] }, { "pmid": "10658902", "text": "Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions.", "type": "CHEMICAL", "entities": [ "dihydroorotate" ], "offsets": [ [ 113, 127 ] ] }, { "pmid": "10658902", "text": "Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds.", "type": "CHEMICAL", "entities": [ "dihydroorotate" ], "offsets": [ [ 86, 100 ] ] }, { "pmid": "10658902", "text": "1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity.", "type": "CHEMICAL", "entities": [ "1,4-Naphthoquinone", "5,8-hydroxy-naphthoquinone", "juglon", "plumbagin", "polyporic acid", "quinone" ], "offsets": [ [ 0, 18 ], [ 20, 46 ], [ 73, 79 ], [ 81, 90 ], [ 95, 109 ], [ 111, 118 ] ] }, { "pmid": "10658902", "text": "The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM).", "type": "CHEMICAL", "entities": [ "dichloroally-lawsone", "lapachol", "lawsone", "atovaquone" ], "offsets": [ [ 147, 167 ], [ 184, 192 ], [ 79, 86 ], [ 213, 223 ] ] }, { "pmid": "10658902", "text": "With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase.", "type": "CHEMICAL", "entities": [ "quinone", "dihydroorotate", "atovaquone", "dichloroally-lawsone", "dihydroorotate" ], "offsets": [ [ 20, 27 ], [ 48, 62 ], [ 78, 88 ], [ 112, 132 ], [ 197, 211 ] ] }, { "pmid": "10658902", "text": "Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme.", "type": "CHEMICAL", "entities": [ "Atovaquone" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10658902", "text": "Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases.", "type": "CHEMICAL", "entities": [ "Dichloroally]-lawsone", "dihydroorotate" ], "offsets": [ [ 0, 21 ], [ 168, 182 ] ] }, { "pmid": "10658902", "text": "Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem.", "type": "CHEMICAL", "entities": [ "brequinar", "dihydroorotate", "dihyroorotate", "isoxazol", "cinchoninic acid" ], "offsets": [ [ 19, 28 ], [ 97, 111 ], [ 194, 207 ], [ 243, 251 ], [ 256, 272 ] ] }, { "pmid": "10658902", "text": "With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM).", "type": "CHEMICAL", "entities": [ "dihydroorotate", "atovaquone", "dihydroorotate" ], "offsets": [ [ 30, 44 ], [ 46, 56 ], [ 97, 111 ] ] }, { "pmid": "10658902", "text": "1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%.", "type": "CHEMICAL", "entities": [ "polyporic acid", "quinone" ], "offsets": [ [ 7, 21 ], [ 33, 40 ] ] }, { "pmid": "10662748", "text": "Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.\n", "type": "CHEMICAL", "entities": [ "Sodium" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "10662748", "text": "A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome).", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 26, 32 ] ] }, { "pmid": "10662748", "text": "The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 126, 132 ] ] }, { "pmid": "10662748", "text": "The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C).", "type": "CHEMICAL", "entities": [ "ajmaline", "procainamide", "flecainide" ], "offsets": [ [ 26, 34 ], [ 46, 58 ], [ 74, 84 ] ] }, { "pmid": "10662748", "text": "Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C.", "type": "CHEMICAL", "entities": [ "Ajmaline", "procainamide", "flecainide" ], "offsets": [ [ 0, 8 ], [ 10, 22 ], [ 27, 37 ] ] }, { "pmid": "10662748", "text": "The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 211, 217 ] ] }, { "pmid": "10665814", "text": "Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels.\n", "type": "CHEMICAL", "entities": [ "Mibefradil", "calcium" ], "offsets": [ [ 54, 64 ], [ 74, 81 ] ] }, { "pmid": "10665814", "text": "The voltage gated calcium channel family is a major target for a range of therapeutic drugs.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "10665814", "text": "Mibefradil (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels.", "type": "CHEMICAL", "entities": [ "Mibefradil", "Ro 40-5967", "Ca2+", "Ca2+" ], "offsets": [ [ 0, 10 ], [ 12, 22 ], [ 100, 104 ], [ 157, 161 ] ] }, { "pmid": "10665814", "text": "However, this molecule has also been shown to inhibit other Ca2+ channel subtypes.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 60, 64 ] ] }, { "pmid": "10665814", "text": "To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of Mibefradil on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration.", "type": "CHEMICAL", "entities": [ "Mibefradil", "Mibefradil", "Ca2+", "Ca2+", "Ca2+" ], "offsets": [ [ 60, 70 ], [ 110, 120 ], [ 144, 148 ], [ 218, 222 ], [ 47, 51 ] ] }, { "pmid": "10665814", "text": "Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "10665814", "text": "Mibefradil blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by Mibefradil was consistent with high-affinity binding to the inactivated state.", "type": "CHEMICAL", "entities": [ "Mibefradil", "Mibefradil" ], "offsets": [ [ 0, 10 ], [ 192, 202 ] ] }, { "pmid": "10665814", "text": "Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the Mibefradil receptor site.", "type": "CHEMICAL", "entities": [ "Mibefradil" ], "offsets": [ [ 156, 166 ] ] }, { "pmid": "10665814", "text": "Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil.", "type": "CHEMICAL", "entities": [ "calcium", "Mibefradil" ], "offsets": [ [ 72, 79 ], [ 198, 208 ] ] }, { "pmid": "10673876", "text": "Use of tranexamic acid for an effective blood conservation strategy after total knee arthroplasty.\n", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 7, 22 ] ] }, { "pmid": "10673876", "text": "We have investigated the effect of treatment with tranexamic acid, an inhibitor of fibrinolysis, on blood loss, blood transfusion requirements and blood coagulation in a randomized, double-blind, placebo-controlled study of 42 patients after total knee arthroplasty.", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 50, 65 ] ] }, { "pmid": "10673876", "text": "Tranexamic acid 15 mg kg-1 (n = 21) or an equivalent volume of normal saline (n = 21) was given 30 min before surgery and subsequently every 8 h for 3 days.", "type": "CHEMICAL", "entities": [ "Tranexamic acid" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "10673876", "text": "Coagulation and fibrinolysis values, blood loss and blood units administered were measured before administration of tranexamic acid, 8 h after the end of surgery and at 24 and 72 h after operation.", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 116, 131 ] ] }, { "pmid": "10673876", "text": "Total blood loss in the tranexamic acid group was 678 (SD 352) ml compared with 1419 (607) ml in the control group (P < 0.001), and occurred primarily during the first 24 h after surgery.", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 24, 39 ] ] }, { "pmid": "10673876", "text": "Thirteen patients received 1-5 u. of packed red blood cells in the control group compared with two patients in the tranexamic acid group, who received 3 u. (P < 0.001).", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 115, 130 ] ] }, { "pmid": "10673876", "text": "Postoperative packed cell volume values were higher in the tranexamic acid group despite fewer blood transfusions.", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 59, 74 ] ] }, { "pmid": "10673876", "text": "Postoperative concentrations of plasminogen were decreased significantly in the tranexamic acid group (P < 0.001).", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 80, 95 ] ] }, { "pmid": "10673876", "text": "Thromboembolic complications occurred in two patients in the control group compared with none in the tranexamic acid group.", "type": "CHEMICAL", "entities": [ "tranexamic acid" ], "offsets": [ [ 101, 116 ] ] }, { "pmid": "10682715", "text": "Correlations between serotonin level and single-cell firing in the rat's nucleus raphe magnus.\n", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "10682715", "text": "The relation between serotonin release and electrical activity was examined in the nucleus raphe magnus of rats anesthetized with pentobarbital.", "type": "CHEMICAL", "entities": [ "serotonin", "pentobarbital" ], "offsets": [ [ 21, 30 ], [ 130, 143 ] ] }, { "pmid": "10682715", "text": "Serotonin levels were monitored through a carbon-fiber microelectrode by fast cyclic voltammetry (usually at 1 Hz).", "type": "CHEMICAL", "entities": [ "carbon", "Serotonin" ], "offsets": [ [ 42, 48 ], [ 0, 9 ] ] }, { "pmid": "10682715", "text": "During 3 min of pinching, serotonin slowly rose near seven of 14 on(M) cells and 26 of 46 off(M) cells; it fell near two off(M) cells; it was unchanged near all other cells, including six neutral(M) cells.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "10682715", "text": "On a finer spatiotemporal scale, near four of seven on(M) cells, 10 of 14 off(M) cells and 0 of four neutral(M) cells, average serotonin levels fell significantly within +/- 100 ms of spontaneous spikes.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 127, 136 ] ] }, { "pmid": "10682715", "text": "Lower serotonin may have caused the higher spike probability; the converse is theoretically unlikely, since delays between release and detection are estimated to exceed 100 ms. Increased serotonin and decreased firing were always seen following iontophoresis or intravenous injection (1 mg/kg) of the serotonin re-uptake inhibitor clomipramine (n = 7).", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin", "serotonin", "clomipramine" ], "offsets": [ [ 6, 15 ], [ 187, 196 ], [ 301, 310 ], [ 331, 343 ] ] }, { "pmid": "10682715", "text": "Iontophoresis of +/- propranolol, whose serotonergic actions include antagonism and partial agonism at 5-HT1 receptors, also increased serotonin and decreased firing (n=4).", "type": "CHEMICAL", "entities": [ "+/- propranolol", "serotonin" ], "offsets": [ [ 17, 32 ], [ 135, 144 ] ] }, { "pmid": "10682715", "text": "Methiothepin (intravenous, 1 mg/kg), whose serotonergic actions include 5-HT1 and 5-HT2 antagonism, typically raised serotonin levels (four of five cells) and always blocked inhibition by clomipramine (n = 3).", "type": "CHEMICAL", "entities": [ "Methiothepin", "serotonin", "clomipramine" ], "offsets": [ [ 0, 12 ], [ 117, 126 ], [ 188, 200 ] ] }, { "pmid": "10682715", "text": "Iontophoresis of glutamate always lowered serotonin and increased firing (n = 4).", "type": "CHEMICAL", "entities": [ "glutamate", "serotonin" ], "offsets": [ [ 17, 26 ], [ 42, 51 ] ] }, { "pmid": "10682715", "text": "Since serotonin levels and firing were usually inversely correlated, except near on(M) cells during pinch, we propose that serotonin is released from terminals of incoming nociceptive afferents.", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin" ], "offsets": [ [ 6, 15 ], [ 123, 132 ] ] }, { "pmid": "10682715", "text": "The released serotonin could contribute to the inhibition of off(M) cells and excitation of on(M) cells by noxious stimulation, since inhibitory 5-HT1a receptors and excitatory 5-HT2 receptors, respectively, have previously been shown to dominate their serotonergic responses.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "10701840", "text": "The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation.\n", "type": "CHEMICAL", "entities": [ "geldanamycin" ], "offsets": [ [ 29, 41 ] ] }, { "pmid": "10701840", "text": "Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin.", "type": "CHEMICAL", "entities": [ "benzoquinonoid ansamycin", "geldanamycin" ], "offsets": [ [ 115, 139 ], [ 140, 152 ] ] }, { "pmid": "10701840", "text": "In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes.", "type": "CHEMICAL", "entities": [ "geldanamycin" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "10701840", "text": "Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase.", "type": "CHEMICAL", "entities": [ "geldanamycin" ], "offsets": [ [ 10, 22 ] ] }, { "pmid": "10701840", "text": "Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT).", "type": "CHEMICAL", "entities": [ "Geldanamycin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "10701840", "text": "Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation.", "type": "CHEMICAL", "entities": [ "geldanamycin" ], "offsets": [ [ 15, 27 ] ] }, { "pmid": "10701840", "text": "Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation.", "type": "CHEMICAL", "entities": [ "geldanamycin" ], "offsets": [ [ 91, 103 ] ] }, { "pmid": "10709635", "text": "Carnitine biosynthesis.", "type": "CHEMICAL", "entities": [ "Carnitine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "10709635", "text": "Purification of gamma-butyrobetaine hydroxylase from rat liver.\n", "type": "CHEMICAL", "entities": [ "gamma-butyrobetaine" ], "offsets": [ [ 16, 35 ] ] }, { "pmid": "10709635", "text": "gamma-Butyrobetaine hydroxylase catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on Fe2+, alpha-ketoglutarate, ascorbate and oxygen.", "type": "CHEMICAL", "entities": [ "carnitine", "L-carnitine", "gamma-Butyrobetaine", "gamma-butyrobetaine", "Fe2+", "alpha-ketoglutarate", "ascorbate", "oxygen" ], "offsets": [ [ 58, 67 ], [ 99, 110 ], [ 0, 19 ], [ 116, 135 ], [ 161, 165 ], [ 167, 186 ], [ 188, 197 ], [ 202, 208 ] ] }, { "pmid": "10709635", "text": "Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable.", "type": "CHEMICAL", "entities": [ "gamma-butyrobetaine" ], "offsets": [ [ 66, 85 ] ] }, { "pmid": "10709635", "text": "We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures.", "type": "CHEMICAL", "entities": [ "gamma-butyrobetaine" ], "offsets": [ [ 81, 100 ] ] }, { "pmid": "10709635", "text": "The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT.", "type": "CHEMICAL", "entities": [ "DTT", "glycerol" ], "offsets": [ [ 123, 126 ], [ 104, 112 ] ] }, { "pmid": "10727528", "text": "Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism.\n", "type": "CHEMICAL", "entities": [ "Aspirin", "sodium salicylate" ], "offsets": [ [ 0, 7 ], [ 12, 29 ] ] }, { "pmid": "10727528", "text": "Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions.", "type": "CHEMICAL", "entities": [ "Aspirin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10727528", "text": "This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries.", "type": "CHEMICAL", "entities": [ "aspirin", "sodium salicylate" ], "offsets": [ [ 22, 29 ], [ 34, 51 ] ] }, { "pmid": "10727528", "text": "They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "10727528", "text": "Inhibition of the actions of ET-1 by salicylates is apparently competitive.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 37, 48 ] ] }, { "pmid": "10727528", "text": "Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors.", "type": "CHEMICAL", "entities": [ "Salicylates", "(125)I" ], "offsets": [ [ 0, 11 ], [ 20, 26 ] ] }, { "pmid": "10727528", "text": "Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1.", "type": "CHEMICAL", "entities": [ "Salicylic acid", "(125)I" ], "offsets": [ [ 0, 14 ], [ 40, 46 ] ] }, { "pmid": "10727528", "text": "It has no influence on the rate of association of (125)I-ET-1 to ETA receptors.", "type": "CHEMICAL", "entities": [ "(125)I" ], "offsets": [ [ 50, 56 ] ] }, { "pmid": "10727528", "text": "Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes.", "type": "CHEMICAL", "entities": [ "Salicylates", "(125)I" ], "offsets": [ [ 0, 11 ], [ 43, 49 ] ] }, { "pmid": "10727528", "text": "Salicylates potentiate relaxing actions of receptor antagonists such as bosentan.", "type": "CHEMICAL", "entities": [ "Salicylates", "bosentan" ], "offsets": [ [ 0, 11 ], [ 72, 80 ] ] }, { "pmid": "10727528", "text": "It is concluded that salicylates are allosteric inhibitors of ETA receptors.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "10727528", "text": "The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 142, 153 ] ] }, { "pmid": "10755406", "text": "A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C.\nMitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer.", "type": "CHEMICAL", "entities": [ "mitomycin C", "Mitomycin C", "MMC" ], "offsets": [ [ 93, 104 ], [ 106, 117 ], [ 119, 122 ] ] }, { "pmid": "10755406", "text": "Among the various enzymes, dicoumarol inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (NQO1) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity.", "type": "CHEMICAL", "entities": [ "MMC", "dicoumarol", "NAD(P)H", "quinone" ], "offsets": [ [ 148, 151 ], [ 27, 37 ], [ 60, 67 ], [ 68, 75 ] ] }, { "pmid": "10755406", "text": "However, the role of NQO1 in metabolic activation of MMC has been disputed.", "type": "CHEMICAL", "entities": [ "MMC" ], "offsets": [ [ 53, 56 ] ] }, { "pmid": "10755406", "text": "In this report, we present cellular and animal models to demonstrate that NQO1 may play only a minor role in metabolic activation of MMC.", "type": "CHEMICAL", "entities": [ "MMC" ], "offsets": [ [ 133, 136 ] ] }, { "pmid": "10755406", "text": "We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from NQO1.", "type": "CHEMICAL", "entities": [ "MMC" ], "offsets": [ [ 55, 58 ] ] }, { "pmid": "10755406", "text": "These cells showed significantly increased protection against menadione toxicity.", "type": "CHEMICAL", "entities": [ "menadione" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "10755406", "text": "However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells.", "type": "CHEMICAL", "entities": [ "MMC", "oxygen" ], "offsets": [ [ 75, 78 ], [ 85, 91 ] ] }, { "pmid": "10755406", "text": "The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice.", "type": "CHEMICAL", "entities": [ "MMC" ], "offsets": [ [ 130, 133 ] ] }, { "pmid": "10755406", "text": "The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase.", "type": "CHEMICAL", "entities": [ "MMC", "MMC" ], "offsets": [ [ 45, 48 ], [ 143, 146 ] ] }, { "pmid": "10755406", "text": "This activity, like NQO1, was inhibited by dicoumarol and immunologically related to NQO1.", "type": "CHEMICAL", "entities": [ "dicoumarol" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "10768100", "text": "Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes.\n", "type": "CHEMICAL", "entities": [ "Troglitazone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "10768100", "text": "In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes.", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 45, 57 ] ] }, { "pmid": "10768100", "text": "Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05).", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 111, 123 ] ] }, { "pmid": "10768100", "text": "In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05).", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 42, 54 ] ] }, { "pmid": "10768100", "text": "Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively).", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 90, 102 ] ] }, { "pmid": "10768100", "text": "This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level.", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "10768100", "text": "This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk.", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 59, 71 ] ] }, { "pmid": "10771044", "text": "We examined the effect of JTH-601 (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs.", "type": "CHEMICAL", "entities": [ "N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom", "ethyl", "4-methoxy-2,5,6-trimethylphenol hemifumarate", "JTH-601" ], "offsets": [ [ 60, 125 ], [ 126, 131 ], [ 155, 199 ], [ 26, 33 ] ] }, { "pmid": "10771044", "text": "In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively.", "type": "CHEMICAL", "entities": [ "phenylephrine", "noradrenaline" ], "offsets": [ [ 26, 39 ], [ 44, 57 ] ] }, { "pmid": "10771044", "text": "In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "JTH-601", "prazosin", "tamsulosin" ], "offsets": [ [ 18, 25 ], [ 27, 35 ], [ 92, 102 ] ] }, { "pmid": "10771044", "text": "values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin.", "type": "CHEMICAL", "entities": [ "prazosin", "tamsulosin" ], "offsets": [ [ 67, 75 ], [ 96, 106 ] ] }, { "pmid": "10771044", "text": "The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively.", "type": "CHEMICAL", "entities": [ "JTH-601", "prazosin", "tamsulosin" ], "offsets": [ [ 89, 96 ], [ 108, 116 ], [ 131, 141 ] ] }, { "pmid": "10771044", "text": "In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate.", "type": "CHEMICAL", "entities": [ "JTH-601" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "10771044", "text": "Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate.", "type": "CHEMICAL", "entities": [ "Tamsulosin", "JTH-601" ], "offsets": [ [ 0, 10 ], [ 83, 90 ] ] }, { "pmid": "10771044", "text": "JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "JTH-601" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10771044", "text": "JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system.", "type": "CHEMICAL", "entities": [ "JTH-601" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10831596", "text": "Severe impairment of salivation in Na+/K+/2Cl- cotransporter (NKCC1)-deficient mice.\n", "type": "CHEMICAL", "entities": [ "Na+", "K+", "2Cl-" ], "offsets": [ [ 35, 38 ], [ 39, 41 ], [ 42, 46 ] ] }, { "pmid": "10831596", "text": "The salivary fluid secretory mechanism is thought to require Na(+)/K(+)/2Cl(-) cotransporter-mediated Cl(-) uptake.", "type": "CHEMICAL", "entities": [ "Na(+)", "K(+)", "2Cl(-)", "Cl(-)" ], "offsets": [ [ 61, 66 ], [ 67, 71 ], [ 72, 78 ], [ 102, 107 ] ] }, { "pmid": "10831596", "text": "To directly test this possibility we studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of Na(+)/K(+)/2Cl(-) cotransporter isoform 1 (Nkcc1), the gene encoding the salivary Na(+)/K(+)/2Cl(-) cotransporter.", "type": "CHEMICAL", "entities": [ "Na(+)", "K(+)", "2Cl(-)", "Na(+)", "K(+)", "2Cl(-)" ], "offsets": [ [ 158, 163 ], [ 164, 168 ], [ 169, 175 ], [ 240, 245 ], [ 246, 250 ], [ 251, 257 ] ] }, { "pmid": "10831596", "text": "Consistent with defective Cl(-) uptake, a loss of bumetanide-sensitive Cl(-) influx was observed in parotid acinar cells from mice lacking NKCC1.", "type": "CHEMICAL", "entities": [ "Cl(-)", "bumetanide", "Cl(-)" ], "offsets": [ [ 26, 31 ], [ 50, 60 ], [ 71, 76 ] ] }, { "pmid": "10831596", "text": "Cl(-)/ HCO(3)(-) exchanger activity was increased in parotid acinar cells isolated from knockout mice suggesting that the residual saliva secreted by mice lacking NKCC1 is associated with anion exchanger-dependent Cl(-) uptake.", "type": "CHEMICAL", "entities": [ "Cl(-)", "HCO(3)(-)", "Cl(-)" ], "offsets": [ [ 0, 5 ], [ 7, 16 ], [ 214, 219 ] ] }, { "pmid": "10831596", "text": "Indeed, expression of the Cl(-)/ HCO(3)(-) exchanger AE2 was enhanced suggesting that this transporter compensates for the loss of functional Na(+)/K(+)/2Cl(-) cotransporter.", "type": "CHEMICAL", "entities": [ "Cl(-)", "HCO(3)(-)", "Na(+)", "K(+)", "2Cl(-)" ], "offsets": [ [ 26, 31 ], [ 33, 42 ], [ 142, 147 ], [ 148, 152 ], [ 153, 159 ] ] }, { "pmid": "10831596", "text": "Furthermore, the ability of the parotid gland to conserve NaCl was abolished in NKCC1-deficient mice.", "type": "CHEMICAL", "entities": [ "NaCl" ], "offsets": [ [ 58, 62 ] ] }, { "pmid": "10831596", "text": "This deficit was not associated with changes in the morphology of the ducts, but transcript levels for the alpha-, beta-, and gamma-subunits of the epithelial Na(+) channel were reduced.", "type": "CHEMICAL", "entities": [ "Na(+)" ], "offsets": [ [ 159, 164 ] ] }, { "pmid": "10831596", "text": "These data directly demonstrate that NKCC1 is the major Cl(-) uptake mechanism across the basolateral membrane of acinar cells and is critical for driving saliva secretion in vivo.", "type": "CHEMICAL", "entities": [ "Cl(-)" ], "offsets": [ [ 56, 61 ] ] }, { "pmid": "10907719", "text": "Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain.\n", "type": "CHEMICAL", "entities": [ "3H-NMPB", "3H-QNB" ], "offsets": [ [ 44, 51 ], [ 56, 62 ] ] }, { "pmid": "10907719", "text": "UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB).", "type": "CHEMICAL", "entities": [ "3H-NMPB", "acetylcholine", "3H-quinuclidinyl benzilate", "3H-QNB", "scopolamine", "biperiden", "3H-N-methyl piperidyl benzilate" ], "offsets": [ [ 322, 329 ], [ 32, 45 ], [ 335, 361 ], [ 363, 369 ], [ 127, 138 ], [ 159, 168 ], [ 289, 320 ] ] }, { "pmid": "10907719", "text": "Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors.", "type": "CHEMICAL", "entities": [ "3H-NMPB" ], "offsets": [ [ 132, 139 ] ] }, { "pmid": "10907719", "text": "3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB.", "type": "CHEMICAL", "entities": [ "3H-NMPB", "scopolamine", "3H-QNB" ], "offsets": [ [ 0, 7 ], [ 84, 95 ], [ 105, 111 ] ] }, { "pmid": "10907719", "text": "A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition.", "type": "CHEMICAL", "entities": [ "3H-NMPB", "3H-QNB", "biperiden" ], "offsets": [ [ 60, 67 ], [ 72, 78 ], [ 102, 111 ] ] }, { "pmid": "10907719", "text": "An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration.", "type": "CHEMICAL", "entities": [ "3H-QNB" ], "offsets": [ [ 92, 98 ] ] }, { "pmid": "10907719", "text": "The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding.", "type": "CHEMICAL", "entities": [ "3H-QNB" ], "offsets": [ [ 183, 189 ] ] }, { "pmid": "10907719", "text": "This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain.", "type": "CHEMICAL", "entities": [ "3H-NMPB", "3H-NMPB" ], "offsets": [ [ 63, 70 ], [ 144, 151 ] ] }, { "pmid": "10907719", "text": "KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse.", "type": "CHEMICAL", "entities": [ "QNB", "NMPB" ], "offsets": [ [ 25, 28 ], [ 30, 34 ] ] }, { "pmid": "10909982", "text": "Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene.\n", "type": "CHEMICAL", "entities": [ "troglitazone" ], "offsets": [ [ 103, 115 ] ] }, { "pmid": "10909982", "text": "Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting.", "type": "CHEMICAL", "entities": [ "fatty acids" ], "offsets": [ [ 81, 92 ] ] }, { "pmid": "10909982", "text": "Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 197, 207 ] ] }, { "pmid": "10909982", "text": "Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice.", "type": "CHEMICAL", "entities": [ "bezafibrate" ], "offsets": [ [ 55, 66 ] ] }, { "pmid": "10909982", "text": "4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice.", "type": "CHEMICAL", "entities": [ "4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid", "WY-14,643", "troglitazone" ], "offsets": [ [ 0, 55 ], [ 57, 66 ], [ 171, 183 ] ] }, { "pmid": "10909982", "text": "However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams.", "type": "CHEMICAL", "entities": [ "bezafibrate", "WY-14,643", "troglitazone" ], "offsets": [ [ 25, 36 ], [ 41, 50 ], [ 110, 122 ] ] }, { "pmid": "10909982", "text": "It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs.", "type": "CHEMICAL", "entities": [ "fatty acids" ], "offsets": [ [ 127, 138 ] ] }, { "pmid": "10909982", "text": "The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation.", "type": "CHEMICAL", "entities": [ "fatty acids" ], "offsets": [ [ 133, 144 ] ] }, { "pmid": "10935465", "text": "Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex.", "type": "CHEMICAL", "entities": [ "adenosine triphosphate", "ATP" ], "offsets": [ [ 57, 79 ], [ 80, 83 ] ] }, { "pmid": "10953053", "text": "Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels.\n", "type": "CHEMICAL", "entities": [ "Retigabine", "potassium" ], "offsets": [ [ 0, 10 ], [ 69, 78 ] ] }, { "pmid": "10953053", "text": "Retigabine [N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid; D-23129] is a novel anticonvulsant, unrelated to currently available antiepileptic agents, with activity in a broad range of seizure models.", "type": "CHEMICAL", "entities": [ "D-23129", "Retigabine", "N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid" ], "offsets": [ [ 68, 75 ], [ 0, 10 ], [ 12, 66 ] ] }, { "pmid": "10953053", "text": "In the present study, we sought to determine whether retigabine could enhance current through M-like currents in PC12 cells and KCNQ2/Q3 K(+) channels expressed in Chinese hamster ovary cells (CHO-KCNQ2/Q3).", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 137, 141 ] ] }, { "pmid": "10953053", "text": "In differentiated PC12 cells, retigabine enhanced a linopirdine-sensitive current.", "type": "CHEMICAL", "entities": [ "linopirdine" ], "offsets": [ [ 52, 63 ] ] }, { "pmid": "10953053", "text": "The effect of retigabine was associated with a slowing of M-like tail current deactivation in these cells.", "type": "CHEMICAL", "entities": [ "retigabine" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "10953053", "text": "Retigabine (0.1 to 10 microM) induced a potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3 cells but not in wild-type cells.", "type": "CHEMICAL", "entities": [ "Retigabine", "potassium" ], "offsets": [ [ 0, 10 ], [ 40, 49 ] ] }, { "pmid": "10953053", "text": "Retigabine-induced currents in CHO-KCNQ2/Q3 cells were inhibited by 60.6 +/- 11% (n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (10 mM).", "type": "CHEMICAL", "entities": [ "Retigabine", "linopirdine", "BaCl(2)" ], "offsets": [ [ 0, 10 ], [ 114, 125 ], [ 168, 175 ] ] }, { "pmid": "10953053", "text": "The mechanism by which retigabine enhanced KCNQ2/Q3 currents involved large, drug-induced, leftward shifts in the voltage dependence of channel activation (-33.1 +/- 2.6 mV, n = 4, by 10 microM retigabine).", "type": "CHEMICAL", "entities": [ "retigabine", "retigabine" ], "offsets": [ [ 23, 33 ], [ 194, 204 ] ] }, { "pmid": "10953053", "text": "Retigabine shifted the voltage dependence of channel activation with an EC(50) value of 1.6 +/- 0.3 microM (slope factor was 1.2 +/- 0.1, n = 4 to 5 cells per concentration).", "type": "CHEMICAL", "entities": [ "Retigabine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10953053", "text": "Retigabine (0.1 to 10 microM) also slowed the rate of channel deactivation, predominantly by increasing the contribution of a slowly deactivating tail current component.", "type": "CHEMICAL", "entities": [ "Retigabine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "10953053", "text": "Our findings identify KCNQ2/Q3 channels as a molecular target for retigabine and suggest that activation of KCNQ2/Q3 channels may be responsible for at least some of the anticonvulsant activity of this agent.", "type": "CHEMICAL", "entities": [ "retigabine" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "10980326", "text": "Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity.\n", "type": "CHEMICAL", "entities": [ "Serotonin", "[3H]paroxetine" ], "offsets": [ [ 0, 9 ], [ 70, 84 ] ] }, { "pmid": "10980326", "text": "The aim of this study was to investigate [3H]paroxetine binding and impulsivity in alcohol-dependent and age-matched control subjects in relation to a 5'-promoter region serotonin transporter (5-HTT) polymorphism (5-HTTLPR).", "type": "CHEMICAL", "entities": [ "[3H]paroxetine", "alcohol", "serotonin" ], "offsets": [ [ 41, 55 ], [ 83, 90 ], [ 170, 179 ] ] }, { "pmid": "10980326", "text": "5-HTTLPR S-genotype carriers in both alcohol-dependent and control subjects were expected to show significantly fewer binding sites and a lower dissociation constant.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "10980326", "text": "Influences of impulsive traits, chronic daily alcohol intake, duration of alcohol dependence, age of onset and age on [3H]paroxetine binding were also investigated.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol", "[3H]paroxetine" ], "offsets": [ [ 46, 53 ], [ 74, 81 ], [ 118, 132 ] ] }, { "pmid": "10980326", "text": "Inpatients meeting DSM IV alcohol dependence criteria and of German descent were recruited to avoid ethnic stratification effects.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 26, 33 ] ] }, { "pmid": "10980326", "text": "Blood samples were taken from both alcohol-dependent and control subjects to determine 5-HTTLPR genotypes using PCR of lymphocyte DNA, and to perform platelet [3H]paroxetine binding (binding capacity: B(max); and dissociation constant: K(D)).", "type": "CHEMICAL", "entities": [ "[3H]paroxetine", "alcohol" ], "offsets": [ [ 159, 173 ], [ 35, 42 ] ] }, { "pmid": "10980326", "text": "Impulsivity was assessed using the Barratt impulsiveness scale version 5 (BIS-5) in alcohol-dependent subjects only.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 84, 91 ] ] }, { "pmid": "10980326", "text": "Alcohol-dependent subjects were subdivided into low or high impulsivity groups using a median-split of the BIS-5 scale.", "type": "CHEMICAL", "entities": [ "Alcohol" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "10980326", "text": "[3H]paroxetine binding was investigated in 72 control subjects and 72 patients, of which five patients met type 2 alcohol dependence criteria.", "type": "CHEMICAL", "entities": [ "[3H]paroxetine", "alcohol" ], "offsets": [ [ 0, 14 ], [ 114, 121 ] ] }, { "pmid": "10980326", "text": "A significant influence of duration of alcohol dependence was found on the [3H]paroxetine binding K(D) but not B(max.)", "type": "CHEMICAL", "entities": [ "alcohol", "[3H]paroxetine" ], "offsets": [ [ 39, 46 ], [ 75, 89 ] ] }, { "pmid": "10980326", "text": "Neither alcohol-dependent nor control subjects showed any differences in B(max) or K(D).", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 8, 15 ] ] }, { "pmid": "10980326", "text": "This was the first study to investigate platelet [3H]paroxetine binding in alcohol-dependent and age-matched control subjects in relation to the 5-HTTLPR genotype.", "type": "CHEMICAL", "entities": [ "[3H]paroxetine", "alcohol" ], "offsets": [ [ 49, 63 ], [ 75, 82 ] ] }, { "pmid": "10980326", "text": "No differences concerning 5-HTTLPR-alleles were found in these groups Furthermore, no significant interaction between these parameters and impulsivity was shown in alcohol-dependent subjects.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 164, 171 ] ] }, { "pmid": "10980326", "text": "These results do not support previous results of altered [3H]paroxetine binding sites in alcohol-dependent subjects or 5-HTTLPR S-allele carriers.", "type": "CHEMICAL", "entities": [ "[3H]paroxetine" ], "offsets": [ [ 57, 71 ] ] }, { "pmid": "10980326", "text": "K(D) might be influenced by duration of alcohol dependence, but not sufficiently to yield differences between alcohol-dependent and control subjects.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 40, 47 ], [ 110, 117 ] ] }, { "pmid": "11006278", "text": "Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2).\n", "type": "CHEMICAL", "entities": [ "prostaglandin endoperoxide H2", "Arachidonic acid" ], "offsets": [ [ 101, 130 ], [ 0, 16 ] ] }, { "pmid": "11006278", "text": "By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2).", "type": "CHEMICAL", "entities": [ "arachidonic acid", "prostaglandin endoperoxide H(2)" ], "offsets": [ [ 119, 135 ], [ 221, 252 ] ] }, { "pmid": "11006278", "text": "Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands.", "type": "CHEMICAL", "entities": [ "nitroxide" ], "offsets": [ [ 59, 68 ] ] }, { "pmid": "11006278", "text": "However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "flurbiprofen", "SC-58125" ], "offsets": [ [ 92, 108 ], [ 110, 122 ], [ 128, 136 ] ] }, { "pmid": "11006278", "text": "Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes.", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 107, 116 ] ] }, { "pmid": "11006278", "text": "The finding that arachidonate can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism.", "type": "CHEMICAL", "entities": [ "arachidonate" ], "offsets": [ [ 17, 29 ] ] }, { "pmid": "11054378", "text": "Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta.\n", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 37, 50 ] ] }, { "pmid": "11054378", "text": "Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling.", "type": "CHEMICAL", "entities": [ "5-aminosalicylic acid", "sulfasalazine" ], "offsets": [ [ 69, 90 ], [ 96, 109 ] ] }, { "pmid": "11054378", "text": "The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation.", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 69, 82 ] ] }, { "pmid": "11054378", "text": "The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays.", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 15, 28 ] ] }, { "pmid": "11054378", "text": "The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins.", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 21, 34 ] ] }, { "pmid": "11054378", "text": "NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine.", "type": "CHEMICAL", "entities": [ "12-O-tetradecanoylphorbol-13-acetate", "sulfasalazine" ], "offsets": [ [ 63, 99 ], [ 260, 273 ] ] }, { "pmid": "11054378", "text": "Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro.", "type": "CHEMICAL", "entities": [ "Sulfasalazine" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "11054378", "text": "In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect.", "type": "CHEMICAL", "entities": [ "sulfasalazine", "5-aminosalicylic acid", "sulfapyridine", "4-aminosalicylic acid" ], "offsets": [ [ 29, 42 ], [ 44, 65 ], [ 71, 84 ], [ 88, 109 ] ] }, { "pmid": "11054378", "text": "Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine.", "type": "CHEMICAL", "entities": [ "N", "sulfasalazine" ], "offsets": [ [ 71, 72 ], [ 124, 137 ] ] }, { "pmid": "11054378", "text": "The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate.", "type": "CHEMICAL", "entities": [ "adenosine triphosphate" ], "offsets": [ [ 159, 181 ] ] }, { "pmid": "11054378", "text": "These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding.", "type": "CHEMICAL", "entities": [ "sulfasalazine", "adenosine triphosphate" ], "offsets": [ [ 20, 33 ], [ 95, 117 ] ] }, { "pmid": "11054378", "text": "The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine.", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 147, 160 ] ] }, { "pmid": "11078056", "text": "COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness.", "type": "CHEMICAL", "entities": [ "prostaglandins" ], "offsets": [ [ 15, 29 ] ] }, { "pmid": "11078056", "text": "Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation.", "type": "CHEMICAL", "entities": [ "prostaglandin" ], "offsets": [ [ 34, 47 ] ] }, { "pmid": "11078056", "text": "In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well.", "type": "CHEMICAL", "entities": [ "indomethacin", "aspirin", "sulindac" ], "offsets": [ [ 67, 79 ], [ 13, 20 ], [ 54, 62 ] ] }, { "pmid": "11078056", "text": "Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1.", "type": "CHEMICAL", "entities": [ "meloxicam", "celecoxib", "SC-58635", "rofecoxib", "MK-0966" ], "offsets": [ [ 36, 45 ], [ 47, 56 ], [ 58, 66 ], [ 73, 82 ], [ 84, 91 ] ] }, { "pmid": "11078056", "text": "For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2.", "type": "CHEMICAL", "entities": [ "meloxicam" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "11078056", "text": "NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2.", "type": "CHEMICAL", "entities": [ "NS-398" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "11078056", "text": "This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen.", "type": "CHEMICAL", "entities": [ "flurbiprofen" ], "offsets": [ [ 193, 205 ] ] }, { "pmid": "11106255", "text": "The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells.\n", "type": "CHEMICAL", "entities": [ "aromatic-L-amino acid" ], "offsets": [ [ 4, 25 ] ] }, { "pmid": "11106255", "text": "The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 94, 103 ] ] }, { "pmid": "11106255", "text": "In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem.", "type": "CHEMICAL", "entities": [ "tryptophan", "aromatic-L-amino acid" ], "offsets": [ [ 24, 34 ], [ 51, 72 ] ] }, { "pmid": "11106255", "text": "To assess the feasibility of targeting these high AAAD levels for chemotherapy, AAAD inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells.", "type": "CHEMICAL", "entities": [ "carbidopa", "alpha-methyl-dopahydrazine", "alpha-monofluoromethyldopa", "MFMD", "3-hydroxybenzylhydrazine", "NSD-1015" ], "offsets": [ [ 96, 105 ], [ 107, 133 ], [ 136, 162 ], [ 164, 168 ], [ 175, 199 ], [ 201, 209 ] ] }, { "pmid": "11106255", "text": "Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation.", "type": "CHEMICAL", "entities": [ "Carbidopa", "MFMD", "NSD-1015" ], "offsets": [ [ 0, 9 ], [ 14, 18 ], [ 91, 99 ] ] }, { "pmid": "11106255", "text": "On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively).", "type": "CHEMICAL", "entities": [ "carbidopa" ], "offsets": [ [ 40, 49 ] ] }, { "pmid": "11106255", "text": "Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines.", "type": "CHEMICAL", "entities": [ "Carbidopa" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11106255", "text": "For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), AAAD activity was correlated with the potency of carbidopa-induced cytotoxicity.", "type": "CHEMICAL", "entities": [ "carbidopa" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "11106255", "text": "However, carcinoid cell death was not solely attributable to complete inhibition of either AAAD activity or the serotonin synthetic pathway.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "11106255", "text": "In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan.", "type": "CHEMICAL", "entities": [ "topotecan", "carbidopa", "carbidopa" ], "offsets": [ [ 270, 279 ], [ 68, 77 ], [ 117, 126 ] ] }, { "pmid": "11141093", "text": "Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors.\n", "type": "CHEMICAL", "entities": [ "Hexahydrochromeno[4,3-b]pyrrole" ], "offsets": [ [ 0, 31 ] ] }, { "pmid": "11141093", "text": "In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting AChE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system.", "type": "CHEMICAL", "entities": [ "diamide", "2-methoxybenzyl", "tricyclic", "caproctamine", "diamine" ], "offsets": [ [ 71, 78 ], [ 178, 193 ], [ 236, 245 ], [ 43, 55 ], [ 63, 70 ] ] }, { "pmid": "11141093", "text": "Since this compound retains good AChE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human AChE and BChE.", "type": "CHEMICAL", "entities": [ "hexahydrochromeno[4,3-b]pyrrole", "hexahydropyrrolo[2,3-b]indole of physostigmine", "carbamates" ], "offsets": [ [ 66, 97 ], [ 127, 173 ], [ 212, 222 ] ] }, { "pmid": "11141093", "text": "The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively.", "type": "CHEMICAL", "entities": [ "6-carbamate", "physostigmine" ], "offsets": [ [ 4, 15 ], [ 42, 55 ] ] }, { "pmid": "11155778", "text": "Brugada syndrome without mutation of the cardiac sodium channel gene in a Taiwanese patient.\n", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 49, 55 ] ] }, { "pmid": "11155778", "text": "Intravenous procainamide administration did not aggravate ST-segment elevation when ECG had shown coved ST elevation in the right precordial leads.", "type": "CHEMICAL", "entities": [ "procainamide" ], "offsets": [ [ 12, 24 ] ] }, { "pmid": "11155778", "text": "Molecular study did not reveal the same mutations in the cardiac sodium channel gene (SCN5A) as previously reported in Brugada syndrome.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 65, 71 ] ] }, { "pmid": "11161433", "text": "In addition, corticosterone levels in splenic tissue or serum and CYP11A1 mRNA expression (mRNA encoding cholesterol side-chain cleavage p450 enzyme) in CD4+ T cells were increased in these mice.", "type": "CHEMICAL", "entities": [ "corticosterone", "cholesterol" ], "offsets": [ [ 13, 27 ], [ 105, 116 ] ] }, { "pmid": "11161433", "text": "When the anti-corticosterone drug aminoglutethimide (CYP11A1 inhibitor) was administered to B16F10 mice, corticosterone levels in splenic tissue or serum and CYP11A1 mRNA expression were decreased at 14 days after tumor inoculation.", "type": "CHEMICAL", "entities": [ "aminoglutethimide", "corticosterone" ], "offsets": [ [ 34, 51 ], [ 105, 119 ] ] }, { "pmid": "11161433", "text": "In addition, Th1 cell responses were restored and pulmonary metastasis was reduced by aminoglutethimide.", "type": "CHEMICAL", "entities": [ "aminoglutethimide" ], "offsets": [ [ 86, 103 ] ] }, { "pmid": "11161433", "text": "Moreover, it was suggested that promotion of CYP11A1 mRNA expression in Th2 cells was partially involved due to an increase in level of corticosterone in splenic tissue and the breakdown of Th cell responses locally in the splenic tissue, which then affected the maintenance of Th2 cell functions in the microenvironment of tumor-bearing mice.", "type": "CHEMICAL", "entities": [ "corticosterone" ], "offsets": [ [ 136, 150 ] ] }, { "pmid": "11181577", "text": "Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 35, 39 ] ] }, { "pmid": "11181577", "text": "The present mutation consists of a homozygous G-->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon.", "type": "CHEMICAL", "entities": [ "tryptophan" ], "offsets": [ [ 155, 165 ] ] }, { "pmid": "11181577", "text": "Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 72, 83 ] ] }, { "pmid": "11181577", "text": "Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive NADH-->UQ oxidoreductase activity of complex I, which was insensitive to cAMP stimulation.", "type": "CHEMICAL", "entities": [ "NADH", "cAMP" ], "offsets": [ [ 90, 94 ], [ 163, 167 ] ] }, { "pmid": "11212269", "text": "We report here that a human degradation-resistant GLP-2 analogue, h[Gly2]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil.", "type": "CHEMICAL", "entities": [ "Gly2", "irinotecan hydrochloride", "5-fluorouracil" ], "offsets": [ [ 68, 72 ], [ 279, 303 ], [ 326, 340 ] ] }, { "pmid": "11212269", "text": "h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan.", "type": "CHEMICAL", "entities": [ "Gly2" ], "offsets": [ [ 2, 6 ] ] }, { "pmid": "11212269", "text": "Furthermore, h[Gly2]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GLP-2 receptor.", "type": "CHEMICAL", "entities": [ "Gly2", "ADP-ribose" ], "offsets": [ [ 15, 19 ], [ 128, 138 ] ] }, { "pmid": "11255924", "text": "On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 32, 40 ] ] }, { "pmid": "11255924", "text": "The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as DA uptake inhibitors.", "type": "CHEMICAL", "entities": [ "dopamine", "DA" ], "offsets": [ [ 63, 71 ], [ 198, 200 ] ] }, { "pmid": "11255924", "text": "Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 119, 121 ] ] }, { "pmid": "11255924", "text": "Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 47, 54 ] ] }, { "pmid": "11255924", "text": "The same compounds were compared in standard in vitro DA uptake assays using monkey caudate tissue.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 54, 56 ] ] }, { "pmid": "11255924", "text": "The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine.", "type": "CHEMICAL", "entities": [ "cocaine", "dimethocaine", "procaine", "chloroprocaine" ], "offsets": [ [ 68, 75 ], [ 78, 90 ], [ 93, 101 ], [ 104, 118 ] ] }, { "pmid": "11255924", "text": "Tetracaine did not maintain self-administration.", "type": "CHEMICAL", "entities": [ "Tetracaine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "11255924", "text": "For inhibiting DA uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine.", "type": "CHEMICAL", "entities": [ "DA", "cocaine", "dimethocaine", "tetracaine", "procaine", "chloro-procaine" ], "offsets": [ [ 15, 17 ], [ 48, 55 ], [ 58, 70 ], [ 73, 83 ], [ 86, 94 ], [ 97, 112 ] ] }, { "pmid": "11255924", "text": "At maximum, these compounds were equally effective in blocking DA uptake.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 63, 65 ] ] }, { "pmid": "11255924", "text": "Lidocaine did not inhibit DA uptake.", "type": "CHEMICAL", "entities": [ "DA", "Lidocaine" ], "offsets": [ [ 26, 28 ], [ 0, 9 ] ] }, { "pmid": "11255924", "text": "The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 95, 97 ] ] }, { "pmid": "11255924", "text": "Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as DA uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo.", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 111, 113 ] ] }, { "pmid": "11255924", "text": "Effects at sodium channels may limit the reinforcing effects of local anesthetics.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "11292635", "text": "Contribution of the Na+-K+-2Cl- cotransporter NKCC1 to Cl- secretion in rat OMCD.\n", "type": "CHEMICAL", "entities": [ "Na+", "K+", "2Cl-", "Cl-" ], "offsets": [ [ 20, 23 ], [ 24, 26 ], [ 27, 31 ], [ 55, 58 ] ] }, { "pmid": "11292635", "text": "In rat kidney the \"secretory\" isoform of the Na+-K+-2Cl- cotransporter (NKCC1) localizes to the basolateral membrane of the alpha-intercalated cell.", "type": "CHEMICAL", "entities": [ "Na+", "K+", "2Cl-" ], "offsets": [ [ 45, 48 ], [ 49, 51 ], [ 52, 56 ] ] }, { "pmid": "11292635", "text": "The purpose of this study was to determine whether rat outer medullary collecting duct (OMCD) secretes Cl- and whether transepithelial Cl- transport occurs, in part, through Cl- uptake across the basolateral membrane mediated by NKCC1 in series with Cl- efflux across the apical membrane.", "type": "CHEMICAL", "entities": [ "Cl-", "Cl-", "Cl-", "Cl-" ], "offsets": [ [ 103, 106 ], [ 135, 138 ], [ 174, 177 ], [ 250, 253 ] ] }, { "pmid": "11292635", "text": "OMCD tubules from rats treated with deoxycorticosterone pivalate were perfused in vitro in symmetrical HCO/CO2-buffered solutions.", "type": "CHEMICAL", "entities": [ "deoxycorticosterone pivalate", "HCO", "CO2" ], "offsets": [ [ 36, 64 ], [ 103, 106 ], [ 107, 110 ] ] }, { "pmid": "11292635", "text": "Cl- secretion was observed in this segment, accompanied by a lumen positive transepithelial potential.", "type": "CHEMICAL", "entities": [ "Cl-" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "11292635", "text": "Bumetanide (100 microM), when added to the bath, reduced Cl- secretion by 78%, although the lumen positive transepithelial potential and fluid flux were unchanged.", "type": "CHEMICAL", "entities": [ "Bumetanide", "Cl-" ], "offsets": [ [ 0, 10 ], [ 57, 60 ] ] }, { "pmid": "11292635", "text": "Bumetanide-sensitive Cl- secretion was dependent on extracellular Na+ and either K+ or NH, consistent with the ion dependency of NKCC1-mediated Cl- transport.", "type": "CHEMICAL", "entities": [ "Bumetanide", "Cl-", "Na+", "K+", "NH", "Cl-" ], "offsets": [ [ 0, 10 ], [ 21, 24 ], [ 66, 69 ], [ 81, 83 ], [ 87, 89 ], [ 144, 147 ] ] }, { "pmid": "11292635", "text": "In conclusion, OMCD tubules from deoxycorticosterone pivalate-treated rats secrete Cl- into the luminal fluid through NKCC1-mediated Cl- uptake across the basolateral membrane in series with Cl- efflux across the apical membrane.", "type": "CHEMICAL", "entities": [ "deoxycorticosterone pivalate", "Cl-", "Cl-", "Cl-" ], "offsets": [ [ 33, 61 ], [ 83, 86 ], [ 133, 136 ], [ 191, 194 ] ] }, { "pmid": "11292635", "text": "The physiological role of NKCC1-mediated Cl- uptake remains to be determined.", "type": "CHEMICAL", "entities": [ "Cl-" ], "offsets": [ [ 41, 44 ] ] }, { "pmid": "11344206", "text": "There are 2 forms of PHA1: the autosomal recessive form with symptoms persisting into adulthood, caused by mutations in the amiloride-sensitive luminal sodium channel, and the autosomal dominant or sporadic form, which shows milder symptoms that remit with age.", "type": "CHEMICAL", "entities": [ "amiloride", "sodium" ], "offsets": [ [ 124, 133 ], [ 152, 158 ] ] }, { "pmid": "11344206", "text": "This mutation is the first described in exon 9 and impairs the last 27 amino acids of the hormone-binding domain.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 71, 82 ] ] }, { "pmid": "11350861", "text": "The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist.\n", "type": "CHEMICAL", "entities": [ "AS-8112", "dopamine" ], "offsets": [ [ 43, 50 ], [ 60, 68 ] ] }, { "pmid": "11350861", "text": "The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study.", "type": "CHEMICAL", "entities": [ "dopamine", "5-hydroxytryptamine", "AS-8112", "(R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate" ], "offsets": [ [ 198, 206 ], [ 218, 237 ], [ 47, 54 ], [ 56, 176 ] ] }, { "pmid": "11350861", "text": "In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04).", "type": "CHEMICAL", "entities": [ "AS-8112", "2-methyl-5HT" ], "offsets": [ [ 30, 37 ], [ 105, 117 ] ] }, { "pmid": "11350861", "text": "Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide.", "type": "CHEMICAL", "entities": [ "granisetron", "ondansetron", "AS-8112", "metoclopramide" ], "offsets": [ [ 105, 116 ], [ 118, 129 ], [ 130, 137 ], [ 139, 153 ] ] }, { "pmid": "11350861", "text": "In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.).", "type": "CHEMICAL", "entities": [ "AS-8112", "dopamine", "R(+)-7-OH-DPAT", "R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline" ], "offsets": [ [ 9, 16 ], [ 90, 98 ], [ 120, 134 ], [ 136, 184 ] ] }, { "pmid": "11350861", "text": "Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia.", "type": "CHEMICAL", "entities": [ "Domperidone", "haloperidol", "dopamine", "R(+)-7-OH-DPAT" ], "offsets": [ [ 0, 11 ], [ 16, 27 ], [ 53, 61 ], [ 90, 104 ] ] }, { "pmid": "11350861", "text": "In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively.", "type": "CHEMICAL", "entities": [ "R(+)-7-OH-DPAT", "AS-8112", "apomorphine", "morphine", "cisplatin" ], "offsets": [ [ 73, 87 ], [ 20, 27 ], [ 89, 100 ], [ 102, 110 ], [ 114, 123 ] ] }, { "pmid": "11350861", "text": "Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens.", "type": "CHEMICAL", "entities": [ "AS-8112" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "11350861", "text": "AS-8112 (0.3 mg kg(-1) i.v.)", "type": "CHEMICAL", "entities": [ "AS-8112" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "11350861", "text": "significantly inhibited emesis induced by cyclophosphamide and doxorubicin.", "type": "CHEMICAL", "entities": [ "cyclophosphamide", "doxorubicin" ], "offsets": [ [ 42, 58 ], [ 63, 74 ] ] }, { "pmid": "11350861", "text": "In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity.", "type": "CHEMICAL", "entities": [ "dopamine", "AS-8112" ], "offsets": [ [ 35, 43 ], [ 15, 22 ] ] }, { "pmid": "11369259", "text": "Recent studies have indicated that the basic residues Arg(93), Lys(96), Arg(125), Arg(165), Lys(169), Lys(236), and Arg(240) (chymotrypsin numbering) constitute an exosite in the catalytic domain of factor Xa that can effectively bind heparin only if the acidic N-terminal Gla domain of the proteinase was neutralized by physiological levels of calcium.", "type": "CHEMICAL", "entities": [ "Arg", "Arg", "Lys", "Lys", "Arg", "N", "calcium", "Arg", "Lys" ], "offsets": [ [ 72, 75 ], [ 82, 85 ], [ 92, 95 ], [ 102, 105 ], [ 116, 119 ], [ 262, 263 ], [ 345, 352 ], [ 54, 57 ], [ 63, 66 ] ] }, { "pmid": "11369259", "text": "Binding of a full-length heparin chain to this site of factor Xa in the presence of calcium makes a significant contribution to acceleration of the proteinase inhibition by antithrombin through a ternary complex bridging or template mechanism.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 84, 91 ] ] }, { "pmid": "11369259", "text": "Moreover, certain basic residues of this site, particularly Arg(165) and Lys(169), play a key role in factor Va and/or prothrombin recognition by factor Xa in the prothrombinase complex.", "type": "CHEMICAL", "entities": [ "Arg", "Lys" ], "offsets": [ [ 60, 63 ], [ 73, 76 ] ] }, { "pmid": "11398914", "text": "Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis.\n", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11398914", "text": "Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day.", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11398914", "text": "Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin.", "type": "CHEMICAL", "entities": [ "celecoxib", "meloxicam", "diclofenac", "indomethacin", "Rofecoxib" ], "offsets": [ [ 49, 58 ], [ 60, 69 ], [ 71, 81 ], [ 86, 98 ], [ 0, 9 ] ] }, { "pmid": "11398914", "text": "In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications].", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "11398914", "text": "In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone.", "type": "CHEMICAL", "entities": [ "rofecoxib", "paracetamol", "acetaminophen", "celecoxib", "ibuprofen", "diclofenac", "naproxen", "nabumetone" ], "offsets": [ [ 50, 59 ], [ 125, 136 ], [ 138, 151 ], [ 157, 166 ], [ 198, 207 ], [ 209, 219 ], [ 221, 229 ], [ 234, 244 ] ] }, { "pmid": "11398914", "text": "Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "11398914", "text": "In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 118, 127 ] ] }, { "pmid": "11398914", "text": "Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose.", "type": "CHEMICAL", "entities": [ "Rofecoxib", "celecoxib", "celecoxib" ], "offsets": [ [ 0, 9 ], [ 36, 45 ], [ 128, 137 ] ] }, { "pmid": "11398914", "text": "In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain.", "type": "CHEMICAL", "entities": [ "rofecoxib", "ibuprofen", "diclofenac", "naproxen sodium" ], "offsets": [ [ 120, 129 ], [ 77, 86 ], [ 88, 98 ], [ 103, 118 ] ] }, { "pmid": "11398914", "text": "Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed.", "type": "CHEMICAL", "entities": [ "naproxen sodium", "rofecoxib", "rofecoxib", "morphine" ], "offsets": [ [ 9, 24 ], [ 62, 71 ], [ 160, 169 ], [ 224, 232 ] ] }, { "pmid": "11398914", "text": "Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis.", "type": "CHEMICAL", "entities": [ "Rofecoxib", "naproxen" ], "offsets": [ [ 0, 9 ], [ 30, 38 ] ] }, { "pmid": "11398914", "text": "Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "11398914", "text": "Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs.", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11398914", "text": "The most common adverse events in rofecoxib recipients were nausea, dizziness and headache.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "11398914", "text": "In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "11398914", "text": "Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis.", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11398914", "text": "Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population.", "type": "CHEMICAL", "entities": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "11398914", "text": "Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "11456284", "text": "Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT).", "type": "CHEMICAL", "entities": [ "thiazide", "NaCl" ], "offsets": [ [ 104, 112 ], [ 123, 127 ] ] }, { "pmid": "11456284", "text": "Different forms of therapy, potassium and magnesium substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized IGF-I levels in the three patients with short stature.", "type": "CHEMICAL", "entities": [ "potassium", "magnesium", "spironolactone", "indomethacin" ], "offsets": [ [ 28, 37 ], [ 42, 51 ], [ 66, 80 ], [ 85, 97 ] ] }, { "pmid": "11474486", "text": "Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively.", "type": "CHEMICAL", "entities": [ "Fibrates", "thiazolidinediones" ], "offsets": [ [ 0, 8 ], [ 13, 31 ] ] }, { "pmid": "11474486", "text": "Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma.", "type": "CHEMICAL", "entities": [ "Fibrates", "thiazolidinediones" ], "offsets": [ [ 0, 8 ], [ 82, 100 ] ] }, { "pmid": "11474486", "text": "These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 53, 61 ] ] }, { "pmid": "11474486", "text": "To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction.", "type": "CHEMICAL", "entities": [ "fenofibrate", "rosiglitazone", "GW2331" ], "offsets": [ [ 153, 164 ], [ 196, 209 ], [ 246, 252 ] ] }, { "pmid": "11474486", "text": "All 3 compounds decreased serum glucose and triglyceride levels.", "type": "CHEMICAL", "entities": [ "glucose", "triglyceride" ], "offsets": [ [ 32, 39 ], [ 44, 56 ] ] }, { "pmid": "11474486", "text": "Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs.", "type": "CHEMICAL", "entities": [ "Fenofibrate", "GW2331", "acyl-coenzyme A", "CoA", "enoyl-CoA", "phosphoenolpyruvate" ], "offsets": [ [ 0, 11 ], [ 16, 22 ], [ 45, 60 ], [ 62, 65 ], [ 79, 88 ], [ 136, 155 ] ] }, { "pmid": "11474486", "text": "Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue.", "type": "CHEMICAL", "entities": [ "Rosiglitazone", "glucose", "phosphoenolpyruvate" ], "offsets": [ [ 0, 13 ], [ 157, 164 ], [ 183, 202 ] ] }, { "pmid": "11474486", "text": "The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues.", "type": "CHEMICAL", "entities": [ "glucose", "triglyceride" ], "offsets": [ [ 133, 140 ], [ 145, 157 ] ] }, { "pmid": "11513839", "text": "Serotonergic effects and extracellular brain levels of eletriptan, zolmitriptan and sumatriptan in rat brain.\n", "type": "CHEMICAL", "entities": [ "eletriptan", "zolmitriptan", "sumatriptan" ], "offsets": [ [ 55, 65 ], [ 67, 79 ], [ 84, 95 ] ] }, { "pmid": "11513839", "text": "In vivo microdialysis was used to assess the central serotonergic effects and extracellular brain levels of the 5-HT(1B/1D) receptor agonists eletriptan, zolmitriptan and sumatriptan in rats after intravenous and intracerebral administration, while their binding affinities and functional potencies were determined at 5-HT(1B), 5-HT(1D) and 5-HT(1A) receptors.", "type": "CHEMICAL", "entities": [ "sumatriptan", "eletriptan", "zolmitriptan" ], "offsets": [ [ 171, 182 ], [ 142, 152 ], [ 154, 166 ] ] }, { "pmid": "11513839", "text": "In vitro studies showed that all three triptans are high affinity, full agonists at 5-HT(1B/1D) receptors, but that sumatriptan is functionally less potent as a 5-HT(1B/1D) agonist than zolmitriptan and eletriptan.", "type": "CHEMICAL", "entities": [ "triptans", "sumatriptan", "zolmitriptan", "eletriptan" ], "offsets": [ [ 39, 47 ], [ 116, 127 ], [ 186, 198 ], [ 203, 213 ] ] }, { "pmid": "11513839", "text": "Local intracortical perfusion with the compounds via the dialysis probe decreased cortical 5-HT (5-hydroxytryptamine, serotonin) release with ED(50) values of approximately 0.1 microM for eletriptan and zolmitriptan and 0.5 microM for sumatriptan.", "type": "CHEMICAL", "entities": [ "5-HT", "5-hydroxytryptamine", "serotonin", "eletriptan", "zolmitriptan", "sumatriptan" ], "offsets": [ [ 91, 95 ], [ 97, 116 ], [ 118, 127 ], [ 188, 198 ], [ 203, 215 ], [ 235, 246 ] ] }, { "pmid": "11513839", "text": "At 3.2 mg/kg i.v., both eletriptan and zolmitriptan decreased 5-HT levels by about 35%, while sumatriptan had no effect, despite the fact that maximal sumatriptan concentrations in cortical dialysates were higher (8.8 nM at 20 min) than those of zolmitriptan (5.9 nM at 20 min) and eletriptan (2.6 nM at 40 min).", "type": "CHEMICAL", "entities": [ "zolmitriptan", "eletriptan", "zolmitriptan", "5-HT", "sumatriptan", "sumatriptan", "eletriptan" ], "offsets": [ [ 246, 258 ], [ 24, 34 ], [ 39, 51 ], [ 62, 66 ], [ 94, 105 ], [ 151, 162 ], [ 282, 292 ] ] }, { "pmid": "11513839", "text": "The observation that eletriptan and zolmitriptan produce almost identical central serotonergic effects, after intracerebral as well as after systemic administration, is in agreement with their comparable functional 5-HT(1B/1D) receptor agonist potencies and their free levels in cortical dialysates after 3.2 mg/kg i.v.", "type": "CHEMICAL", "entities": [ "eletriptan", "zolmitriptan" ], "offsets": [ [ 21, 31 ], [ 36, 48 ] ] }, { "pmid": "11513839", "text": "On the other hand, the lack of central serotonergic effects of 3.2 mg/kg i.v. sumatriptan is likely due to its weaker functional 5-HT(1B/1D) receptor agonist potency than eletriptan and zolmitriptan, rather than lower brain levels, consistent with sumatriptan's fivefold lower potency after intracerebral administration.", "type": "CHEMICAL", "entities": [ "sumatriptan", "eletriptan", "zolmitriptan" ], "offsets": [ [ 78, 89 ], [ 171, 181 ], [ 186, 198 ] ] }, { "pmid": "11544332", "text": "We have previously isolated from human hemofiltrate an N-terminally truncated form of the hemofiltrate CC chemokine 1 (HCC-1), and characterized HCC-1[9-74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 55, 56 ] ] }, { "pmid": "11551210", "text": "Cembranoid and long-chain alkanol sites on the nicotinic acetylcholine receptor and their allosteric interaction.\n", "type": "CHEMICAL", "entities": [ "Cembranoid", "long-chain alkanol", "acetylcholine" ], "offsets": [ [ 0, 10 ], [ 15, 33 ], [ 57, 70 ] ] }, { "pmid": "11551210", "text": "Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral nicotinic acetylcholine receptor (AChR) by binding to one or more specific sites on the AChR.", "type": "CHEMICAL", "entities": [ "Long-chain alkanols", "acetylcholine" ], "offsets": [ [ 0, 19 ], [ 130, 143 ] ] }, { "pmid": "11551210", "text": "Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo.", "type": "CHEMICAL", "entities": [ "Cembranoids" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11551210", "text": "In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact.", "type": "CHEMICAL", "entities": [ "[3H]tenocyclidine", "[3H]TCP", "phencyclidine", "PCP", "cembranoid", "long-chain alkanol" ], "offsets": [ [ 15, 32 ], [ 34, 41 ], [ 97, 110 ], [ 112, 115 ], [ 147, 157 ], [ 162, 180 ] ] }, { "pmid": "11551210", "text": "These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site.", "type": "CHEMICAL", "entities": [ "[3H]TCP" ], "offsets": [ [ 91, 98 ] ] }, { "pmid": "11551210", "text": "This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine.", "type": "CHEMICAL", "entities": [ "cembranoid", "procaine", "quinacrine" ], "offsets": [ [ 5, 15 ], [ 98, 106 ], [ 111, 121 ] ] }, { "pmid": "11551210", "text": "Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site.", "type": "CHEMICAL", "entities": [ "cembranoid" ], "offsets": [ [ 97, 107 ] ] }, { "pmid": "11551210", "text": "In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other.", "type": "CHEMICAL", "entities": [ "long-chain alkanols", "[3H]TCP", "alkanol" ], "offsets": [ [ 13, 32 ], [ 41, 48 ], [ 111, 118 ] ] }, { "pmid": "11551210", "text": "Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding.", "type": "CHEMICAL", "entities": [ "cembranoid", "alkanol", "[3H]TCP" ], "offsets": [ [ 39, 49 ], [ 74, 81 ], [ 183, 190 ] ] }, { "pmid": "11587223", "text": "Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug.\n", "type": "CHEMICAL", "entities": [ "Sulfasalazine", "cystine" ], "offsets": [ [ 0, 13 ], [ 81, 88 ] ] }, { "pmid": "11587223", "text": "Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment.", "type": "CHEMICAL", "entities": [ "cyst(e)ine", "cyst(e)ine", "non-essential amino acid" ], "offsets": [ [ 9, 19 ], [ 148, 158 ], [ 39, 63 ] ] }, { "pmid": "11587223", "text": "Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy.", "type": "CHEMICAL", "entities": [ "cystine" ], "offsets": [ [ 68, 75 ] ] }, { "pmid": "11587223", "text": "Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells.", "type": "CHEMICAL", "entities": [ "cystine", "cysteine", "cyst(e)ine" ], "offsets": [ [ 97, 104 ], [ 116, 124 ], [ 29, 39 ] ] }, { "pmid": "11587223", "text": "Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter.", "type": "CHEMICAL", "entities": [ "Sulfasalazine" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "11587223", "text": "It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid.", "type": "CHEMICAL", "entities": [ "cystine", "sulfapyridine", "5-aminosalicylic acid" ], "offsets": [ [ 143, 150 ], [ 199, 212 ], [ 217, 238 ] ] }, { "pmid": "11587223", "text": "Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures.", "type": "CHEMICAL", "entities": [ "Sulfasalazine" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "11587223", "text": "In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects.", "type": "CHEMICAL", "entities": [ "sulfasalazine" ], "offsets": [ [ 18, 31 ] ] }, { "pmid": "11587223", "text": "Reduced, macrophage-mediated supply of cysteine was probably involved.", "type": "CHEMICAL", "entities": [ "cysteine" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "11587223", "text": "The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.", "type": "CHEMICAL", "entities": [ "cystine", "sulfasalazine", "cyst(e)ine" ], "offsets": [ [ 10, 17 ], [ 60, 73 ], [ 199, 209 ] ] }, { "pmid": "11588409", "text": "Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor.\n", "type": "CHEMICAL", "entities": [ "omapatrilat", "thiazide" ], "offsets": [ [ 110, 121 ], [ 71, 79 ] ] }, { "pmid": "11588409", "text": "The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors.", "type": "CHEMICAL", "entities": [ "thiazide", "calcium", "angiotensin" ], "offsets": [ [ 83, 91 ], [ 118, 125 ], [ 143, 154 ] ] }, { "pmid": "11588409", "text": "Omapatrilat, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase.", "type": "CHEMICAL", "entities": [ "Omapatrilat" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "11588409", "text": "Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin.", "type": "CHEMICAL", "entities": [ "omapatrilat", "bradykinin" ], "offsets": [ [ 34, 45 ], [ 179, 189 ] ] }, { "pmid": "11588409", "text": "A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone.", "type": "CHEMICAL", "entities": [ "omapatrilat", "hydrochlorothiazide", "hydrochlorothiazide" ], "offsets": [ [ 150, 161 ], [ 176, 195 ], [ 226, 245 ] ] }, { "pmid": "11588409", "text": "The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo.", "type": "CHEMICAL", "entities": [ "omapatrilat" ], "offsets": [ [ 125, 136 ] ] }, { "pmid": "11588409", "text": "Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters.", "type": "CHEMICAL", "entities": [ "creatinine", "potassium" ], "offsets": [ [ 67, 77 ], [ 79, 88 ] ] }, { "pmid": "11588409", "text": "Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8.", "type": "CHEMICAL", "entities": [ "omapatrilat", "hydrochlorothiazide" ], "offsets": [ [ 7, 18 ], [ 40, 59 ] ] }, { "pmid": "11688549", "text": "Neonatal red blood cells: amiloride-insensitive Na+-H+ transport isoform would express Na+-Li+ exchange.\n", "type": "CHEMICAL", "entities": [ "amiloride", "Na+", "H+", "Na+", "Li+" ], "offsets": [ [ 26, 35 ], [ 48, 51 ], [ 52, 54 ], [ 87, 90 ], [ 91, 94 ] ] }, { "pmid": "11688549", "text": "Neonatal red cells (umbilical cord blood) were in vitro incubated in isotonic media (thiocyanate as predominant anion).", "type": "CHEMICAL", "entities": [ "thiocyanate" ], "offsets": [ [ 85, 96 ] ] }, { "pmid": "11688549", "text": "This experimental condition was selected as it was known that this chaotropic anion induced activation of Na+-H+ exchange.", "type": "CHEMICAL", "entities": [ "Na+", "H+" ], "offsets": [ [ 106, 109 ], [ 110, 112 ] ] }, { "pmid": "11688549", "text": "The transport amiloride-sensitive mechanism, that decreased the acidic intracellular pH change occurring in this medium, would correspond to Na+-H+ exchange (NHE1 isoform).", "type": "CHEMICAL", "entities": [ "amiloride", "Na+", "H+" ], "offsets": [ [ 14, 23 ], [ 141, 144 ], [ 145, 147 ] ] }, { "pmid": "11688549", "text": "However, the Na+-Li+ exchange, also determined in the cells in the above-mentioned medium was not affected by amiloride.", "type": "CHEMICAL", "entities": [ "Na+", "Li+", "amiloride" ], "offsets": [ [ 13, 16 ], [ 17, 20 ], [ 110, 119 ] ] }, { "pmid": "11688549", "text": "The present data suggest that an amiloride insensitive Na+-H+ exchange isoform would express Na+-Li+ countertransport in these cells.", "type": "CHEMICAL", "entities": [ "Na+", "H+", "Na+", "Li+", "amiloride" ], "offsets": [ [ 55, 58 ], [ 59, 61 ], [ 93, 96 ], [ 97, 100 ], [ 33, 42 ] ] }, { "pmid": "11689471", "text": "Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts.\n", "type": "CHEMICAL", "entities": [ "Aspirin", "salicylate" ], "offsets": [ [ 0, 7 ], [ 12, 22 ] ] }, { "pmid": "11689471", "text": "Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human.", "type": "CHEMICAL", "entities": [ "Salicylic acid", "SA" ], "offsets": [ [ 0, 14 ], [ 16, 18 ] ] }, { "pmid": "11689471", "text": "Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions.", "type": "CHEMICAL", "entities": [ "Aspirin", "sodium salicylate", "salicylates" ], "offsets": [ [ 0, 7 ], [ 12, 29 ], [ 31, 42 ] ] }, { "pmid": "11689471", "text": "The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively.", "type": "CHEMICAL", "entities": [ "SA" ], "offsets": [ [ 17, 19 ] ] }, { "pmid": "11689471", "text": "BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 115, 118 ] ] }, { "pmid": "11689471", "text": "A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not.", "type": "CHEMICAL", "entities": [ "SA" ], "offsets": [ [ 52, 54 ] ] }, { "pmid": "11689471", "text": "Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression.", "type": "CHEMICAL", "entities": [ "Salicylates", "ATP" ], "offsets": [ [ 0, 11 ], [ 97, 100 ] ] }, { "pmid": "11689471", "text": "These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 28, 39 ] ] }, { "pmid": "11691635", "text": "Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice.\n", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "11691635", "text": "The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine-proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice.", "type": "CHEMICAL", "entities": [ "ornithine", "proline" ], "offsets": [ [ 87, 96 ], [ 97, 104 ] ] }, { "pmid": "11691635", "text": "The specific activity of only ornithine aminotransferase (OAT), the rate-limiting enzyme in the conversion of ornithine to proline, increased in 2 weeks of hypertrophy.", "type": "CHEMICAL", "entities": [ "ornithine", "ornithine", "proline" ], "offsets": [ [ 30, 39 ], [ 110, 119 ], [ 123, 130 ] ] }, { "pmid": "11695255", "text": "While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients.", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "11695255", "text": "A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac).", "type": "CHEMICAL", "entities": [ "celecoxib", "ketorolac" ], "offsets": [ [ 217, 226 ], [ 275, 284 ] ] }, { "pmid": "11695255", "text": "Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2", "thromboxane B2" ], "offsets": [ [ 135, 151 ], [ 153, 157 ], [ 198, 212 ] ] }, { "pmid": "11695255", "text": "The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 19, 23 ] ] }, { "pmid": "11695255", "text": "Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels.", "type": "CHEMICAL", "entities": [ "Ketorolac", "PGE2" ], "offsets": [ [ 0, 9 ], [ 66, 70 ] ] }, { "pmid": "11695255", "text": "Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels.", "type": "CHEMICAL", "entities": [ "Ketorolac", "PGE2" ], "offsets": [ [ 0, 9 ], [ 124, 128 ] ] }, { "pmid": "11695255", "text": "Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia.", "type": "CHEMICAL", "entities": [ "Celecoxib", "PGE2", "TxB2" ], "offsets": [ [ 0, 9 ], [ 33, 37 ], [ 46, 50 ] ] }, { "pmid": "11695255", "text": "These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 161, 165 ] ] }, { "pmid": "11698075", "text": "[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.\n", "type": "CHEMICAL", "entities": [ "[3H]dofetilide" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "11698075", "text": "The pharmacological characteristics of [3H]dofetilide binding were examined in membranes prepared from human embryonic kidney (HEK293) cells stably expressing human ether-a-go-go related gene (HERG) K+ channels.", "type": "CHEMICAL", "entities": [ "ether", "K+", "[3H]dofetilide" ], "offsets": [ [ 165, 170 ], [ 199, 201 ], [ 39, 53 ] ] }, { "pmid": "11698075", "text": "The classIII antiarrhythmic compounds dofetilide, clofilium, 4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl]carbonyl]methanesulfonanilide (E-4031), N-methyl-N-[2-[methyl-(1-methyl-1H-benzimidazol-2-yl)amino]ethyl]-4-[(methylsulfo nyl)amino]benzene-sulfonamide (WAY-123,398) and d-sotalol all inhibited [3H]dofetilide binding.", "type": "CHEMICAL", "entities": [ "d-sotalol", "[3H]dofetilide", "dofetilide", "clofilium", "4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl]carbonyl]methanesulfonanilide", "E-4031", "N-methyl-N-[2-[methyl-(1-methyl-1H-benzimidazol-2-yl)amino]ethyl]-4-[(methylsulfo nyl)amino]benzene-sulfonamide", "WAY-123,398" ], "offsets": [ [ 280, 289 ], [ 304, 318 ], [ 38, 48 ], [ 50, 59 ], [ 61, 139 ], [ 141, 147 ], [ 150, 261 ], [ 263, 274 ] ] }, { "pmid": "11698075", "text": "In addition, the structurally unrelated compounds pimozide, terfenadine and haloperidol, all of which prolong the QT interval in man, also inhibited binding.", "type": "CHEMICAL", "entities": [ "pimozide", "terfenadine", "haloperidol" ], "offsets": [ [ 50, 58 ], [ 60, 71 ], [ 76, 87 ] ] }, { "pmid": "11698075", "text": "These data indicate that a [3H]dofetilide binding assay using HERG membranes may help identify compounds that prolong the QT interval.", "type": "CHEMICAL", "entities": [ "[3H]dofetilide" ], "offsets": [ [ 27, 41 ] ] }, { "pmid": "11775064", "text": "Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain.\n", "type": "CHEMICAL", "entities": [ "phenelzine", "alanine", "alanine" ], "offsets": [ [ 45, 55 ], [ 59, 66 ], [ 71, 78 ] ] }, { "pmid": "11775064", "text": "Phenelzine (PLZ) is an antidepressant with anxiolytic properties.", "type": "CHEMICAL", "entities": [ "Phenelzine", "PLZ" ], "offsets": [ [ 0, 10 ], [ 12, 15 ] ] }, { "pmid": "11775064", "text": "Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T).", "type": "CHEMICAL", "entities": [ "GABA", "PLZ", "GABA", "GABA" ], "offsets": [ [ 164, 168 ], [ 18, 21 ], [ 52, 56 ], [ 138, 142 ] ] }, { "pmid": "11775064", "text": "2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain alanine levels.", "type": "CHEMICAL", "entities": [ "PLZ", "alanine" ], "offsets": [ [ 58, 61 ], [ 92, 99 ] ] }, { "pmid": "11775064", "text": "As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase.", "type": "CHEMICAL", "entities": [ "GABA", "alanine", "pyridoxal phosphate" ], "offsets": [ [ 8, 12 ], [ 32, 39 ], [ 51, 70 ] ] }, { "pmid": "11775064", "text": "In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain.", "type": "CHEMICAL", "entities": [ "PLZ", "amino acids", "pyridoxal phosphate" ], "offsets": [ [ 49, 52 ], [ 88, 99 ], [ 139, 158 ] ] }, { "pmid": "11775064", "text": "Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner).", "type": "CHEMICAL", "entities": [ "amino acids", "GABA", "alanine" ], "offsets": [ [ 9, 20 ], [ 40, 44 ], [ 49, 56 ] ] }, { "pmid": "11775064", "text": "The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on alanine transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced.", "type": "CHEMICAL", "entities": [ "alanine", "PLZ", "alanine", "ALA", "GABA" ], "offsets": [ [ 23, 30 ], [ 127, 130 ], [ 134, 141 ], [ 156, 159 ], [ 181, 185 ] ] }, { "pmid": "11775064", "text": "In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of alanine.", "type": "CHEMICAL", "entities": [ "alanine", "alanine", "PLZ", "PLZ", "alanine" ], "offsets": [ [ 50, 57 ], [ 87, 94 ], [ 151, 154 ], [ 175, 178 ], [ 233, 240 ] ] }, { "pmid": "11775064", "text": "These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ.", "type": "CHEMICAL", "entities": [ "PLZ" ], "offsets": [ [ 115, 118 ] ] }, { "pmid": "11811354", "text": "Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites.\n", "type": "CHEMICAL", "entities": [ "Nicotine", "oxygen" ], "offsets": [ [ 0, 8 ], [ 107, 113 ] ] }, { "pmid": "11811354", "text": "Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents.", "type": "CHEMICAL", "entities": [ "Nicotine", "Nomega-nitro-L-arginine methyl ester", "L-NAME", "arachidonic acid" ], "offsets": [ [ 0, 8 ], [ 76, 112 ], [ 114, 120 ], [ 126, 142 ] ] }, { "pmid": "11811354", "text": "The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "11811354", "text": "The contraction was abolished by chemical removal of endothelium saponin.", "type": "CHEMICAL", "entities": [ "saponin" ], "offsets": [ [ 65, 72 ] ] }, { "pmid": "11811354", "text": "Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction.", "type": "CHEMICAL", "entities": [ "Oxygen" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "11811354", "text": "Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction.", "type": "CHEMICAL", "entities": [ "flurbiprofen", "ketoprofen", "ketrolack", "nicotine", "nimesulide", "NS-389" ], "offsets": [ [ 37, 49 ], [ 51, 61 ], [ 66, 75 ], [ 92, 100 ], [ 222, 232 ], [ 237, 243 ] ] }, { "pmid": "11811354", "text": "A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations.", "type": "CHEMICAL", "entities": [ "TXA2", "OKY-046" ], "offsets": [ [ 2, 6 ], [ 29, 36 ] ] }, { "pmid": "11811354", "text": "A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "TXA2", "S-1452" ], "offsets": [ [ 2, 6 ], [ 28, 34 ] ] }, { "pmid": "11811354", "text": "A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction.", "type": "CHEMICAL", "entities": [ "hexamethonium", "prazosin" ], "offsets": [ [ 33, 46 ], [ 121, 129 ] ] }, { "pmid": "11811354", "text": "From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "nicotine", "L-NAME", "arachidonic acid", "oxygen" ], "offsets": [ [ 252, 268 ], [ 69, 77 ], [ 124, 130 ], [ 135, 151 ], [ 200, 206 ] ] }, { "pmid": "11811354", "text": "Part of the contraction is probably due to release of norepinephrine.", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 54, 68 ] ] }, { "pmid": "11858481", "text": "Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease.\n", "type": "CHEMICAL", "entities": [ "ristocetin" ], "offsets": [ [ 94, 104 ] ] }, { "pmid": "11858481", "text": "anti-hemophilic FVIII/VWF complex [human] dried, pasteurized) dosed in ristocetin cofactor units (VWF:RCo) in the treatment of von Willebrand disease (VWD) patients in Canada.", "type": "CHEMICAL", "entities": [ "ristocetin" ], "offsets": [ [ 71, 81 ] ] }, { "pmid": "11885959", "text": "Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid.", "type": "CHEMICAL", "entities": [ "prostaglandins", "thromboxanes", "arachidonic acid", "steroidal" ], "offsets": [ [ 140, 154 ], [ 159, 171 ], [ 177, 193 ], [ 4, 13 ] ] }, { "pmid": "11885959", "text": "Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program.", "type": "CHEMICAL", "entities": [ "zomepirac", "indomethacin", "diclofenac", "meclofenamic acid", "rofecoxib", "ketoprofen", "suprofen", "carprofen" ], "offsets": [ [ 141, 150 ], [ 152, 164 ], [ 166, 176 ], [ 181, 198 ], [ 97, 106 ], [ 108, 118 ], [ 120, 128 ], [ 130, 139 ] ] }, { "pmid": "11922402", "text": "Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions.", "type": "CHEMICAL", "entities": [ "Tamoxifen", "estrogen" ], "offsets": [ [ 0, 9 ], [ 89, 97 ] ] }, { "pmid": "11922402", "text": "Pure antiestrogens are devoid of any estrogen agonist effects.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "11922402", "text": "ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER).", "type": "CHEMICAL", "entities": [ "ICI 164,384", "estrogen", "estrogen", "ICI 182,780", "fulvestrant", "Faslodex" ], "offsets": [ [ 41, 52 ], [ 83, 91 ], [ 110, 118 ], [ 0, 11 ], [ 13, 24 ], [ 27, 35 ] ] }, { "pmid": "11922402", "text": "Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells.", "type": "CHEMICAL", "entities": [ "fulvestrant", "ICI 164,384", "tamoxifen" ], "offsets": [ [ 43, 54 ], [ 59, 70 ], [ 92, 101 ] ] }, { "pmid": "11922402", "text": "They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile.", "type": "CHEMICAL", "entities": [ "estrogen", "tamoxifen" ], "offsets": [ [ 23, 31 ], [ 107, 116 ] ] }, { "pmid": "11922402", "text": "Fulvestrant is the first pure antiestrogen to complete phase III clinical trials.", "type": "CHEMICAL", "entities": [ "Fulvestrant", "antiestrogen" ], "offsets": [ [ 0, 11 ], [ 30, 42 ] ] }, { "pmid": "11922402", "text": "Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy.", "type": "CHEMICAL", "entities": [ "fulvestrant", "anastrozole" ], "offsets": [ [ 29, 40 ], [ 64, 75 ] ] }, { "pmid": "11922402", "text": "EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER.", "type": "CHEMICAL", "entities": [ "EM-800", "EM-652", "EM-652" ], "offsets": [ [ 0, 6 ], [ 11, 17 ], [ 61, 67 ] ] }, { "pmid": "11922402", "text": "It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 83, 92 ] ] }, { "pmid": "12016548", "text": "Hepatotoxic adverse drug reactions have contributed to the decline of many promising therapies, even among mainstream medication classes (bromfenac and troglitazone are recent examples).", "type": "CHEMICAL", "entities": [ "bromfenac", "troglitazone" ], "offsets": [ [ 138, 147 ], [ 152, 164 ] ] }, { "pmid": "12016548", "text": "Of the antihypertensive agents, methyldopa is now rarely prescribed and adverse effects are reported infrequently, whereas cases of liver injury associated with the angiotensin receptor and converting enzyme inhibitors are increasingly reported.", "type": "CHEMICAL", "entities": [ "angiotensin" ], "offsets": [ [ 165, 176 ] ] }, { "pmid": "12016548", "text": "Of the antidiabetic agents, acarbose, gliclazide, metformin, and human insulin have been implicated in causing liver injury.", "type": "CHEMICAL", "entities": [ "acarbose", "gliclazide", "metformin" ], "offsets": [ [ 28, 36 ], [ 38, 48 ], [ 50, 59 ] ] }, { "pmid": "12016548", "text": "To date, the newer thiazolidinediones do not appear to share the hepatotoxic potential of troglitazone, although a few reports of acute hepatitis have accrued.", "type": "CHEMICAL", "entities": [ "thiazolidinediones", "troglitazone" ], "offsets": [ [ 19, 37 ], [ 90, 102 ] ] }, { "pmid": "12016548", "text": "Newer concepts in anticonvulsant hepatotoxicity have been the recognition of the reactive metabolite syndrome, delineation of the risk factors for valproic acid toxicity, the potential role of carnitine in preventing valproic acid hepatotoxicity, and the toxicity of second-line antiepileptic drugs.", "type": "CHEMICAL", "entities": [ "valproic acid", "carnitine", "valproic acid" ], "offsets": [ [ 147, 160 ], [ 193, 202 ], [ 217, 230 ] ] }, { "pmid": "12016548", "text": "Liver injury associated with newer psychotropic agents, particularly the selective serotonin reuptake inhibitors, is also discussed.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 83, 92 ] ] }, { "pmid": "12016548", "text": "Well-known causes of liver injury such as chlorpromazine, phenytoin, and methyldopa are not discussed.", "type": "CHEMICAL", "entities": [ "chlorpromazine", "phenytoin", "methyldopa" ], "offsets": [ [ 42, 56 ], [ 58, 67 ], [ 73, 83 ] ] }, { "pmid": "12046981", "text": "Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug.\n", "type": "CHEMICAL", "entities": [ "olopatadine hydrochloride" ], "offsets": [ [ 60, 85 ] ] }, { "pmid": "12046981", "text": "Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories.", "type": "CHEMICAL", "entities": [ "olopatadine", "11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride", "Olopatadine hydrochloride", "histamine" ], "offsets": [ [ 27, 38 ], [ 40, 139 ], [ 0, 25 ], [ 165, 174 ] ] }, { "pmid": "12046981", "text": "Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats.", "type": "CHEMICAL", "entities": [ "olopatadine" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "12046981", "text": "Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils.", "type": "CHEMICAL", "entities": [ "Olopatadine", "histamine", "leukotriene", "thromboxane" ], "offsets": [ [ 0, 11 ], [ 27, 36 ], [ 145, 156 ], [ 161, 172 ] ] }, { "pmid": "12046981", "text": "Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "Olopatadine was highly and rapidly absorbed in healthy human volunteers.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans.", "type": "CHEMICAL", "entities": [ "olopatadine", "olopatadine" ], "offsets": [ [ 25, 36 ], [ 145, 156 ] ] }, { "pmid": "12046981", "text": "Olopatadine is one of the few renal clearance drugs in antiallergic drugs.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000.", "type": "CHEMICAL", "entities": [ "Olopatadine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12046981", "text": "Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).", "type": "CHEMICAL", "entities": [ "olopatadine" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "12057823", "text": "Serotonin transporter polymorphisms and measures of impulsivity, aggression, and sensation seeking among African-American cocaine-dependent individuals.\n", "type": "CHEMICAL", "entities": [ "cocaine", "Serotonin" ], "offsets": [ [ 122, 129 ], [ 0, 9 ] ] }, { "pmid": "12057823", "text": "Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (5HTT), may mediate central effects of cocaine and may also be involved in impulsive and aggressive behavior.", "type": "CHEMICAL", "entities": [ "cocaine", "serotonin" ], "offsets": [ [ 140, 147 ], [ 79, 88 ] ] }, { "pmid": "12057823", "text": "We investigated whether polymorphisms in the 5HTT gene were related to traits of impulsivity, sensation seeking, and aggression among cocaine abusers.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 134, 141 ] ] }, { "pmid": "12057823", "text": "Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 101, 108 ] ] }, { "pmid": "12057823", "text": "Two polymorphisms of the 5HTT gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among cocaine patients.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 161, 168 ] ] }, { "pmid": "12057823", "text": "Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among cocaine patients.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 175, 182 ] ] }, { "pmid": "12057823", "text": "As expected, cocaine patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 13, 20 ] ] }, { "pmid": "12057823", "text": "The findings do not seem to support an association between these polymorphisms in the 5HTT gene and impulsive-aggressive traits among cocaine-dependent African-American individuals.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 134, 141 ] ] }, { "pmid": "12070353", "text": "A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression.\n", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "12070353", "text": "The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma.", "type": "CHEMICAL", "entities": [ "theophylline", "theophylline" ], "offsets": [ [ 108, 120 ], [ 60, 72 ] ] }, { "pmid": "12070353", "text": "Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription.", "type": "CHEMICAL", "entities": [ "Corticosteroids" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "12070353", "text": "We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages.", "type": "CHEMICAL", "entities": [ "theophylline" ], "offsets": [ [ 48, 60 ] ] }, { "pmid": "12070353", "text": "This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline.", "type": "CHEMICAL", "entities": [ "corticosteroid", "corticosteroids", "theophylline" ], "offsets": [ [ 51, 65 ], [ 125, 140 ], [ 145, 157 ] ] }, { "pmid": "12070353", "text": "This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects.", "type": "CHEMICAL", "entities": [ "theophylline", "adenosine" ], "offsets": [ [ 55, 67 ], [ 175, 184 ] ] }, { "pmid": "12070353", "text": "Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.", "type": "CHEMICAL", "entities": [ "theophylline", "corticosteroids" ], "offsets": [ [ 33, 45 ], [ 148, 163 ] ] }, { "pmid": "12085361", "text": "Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver.\n", "type": "CHEMICAL", "entities": [ "rifamycin SV", "rifampicin" ], "offsets": [ [ 16, 28 ], [ 33, 43 ] ] }, { "pmid": "12085361", "text": "The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans.", "type": "CHEMICAL", "entities": [ "rifampicin", "sulfobromophthalein", "BSP", "rifamycin SV" ], "offsets": [ [ 33, 43 ], [ 65, 84 ], [ 86, 89 ], [ 16, 28 ] ] }, { "pmid": "12085361", "text": "In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2.", "type": "CHEMICAL", "entities": [ "rifamycin SV", "rifampicin" ], "offsets": [ [ 9, 21 ], [ 26, 36 ] ] }, { "pmid": "12085361", "text": "Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers.", "type": "CHEMICAL", "entities": [ "rifamycin SV", "rifampicin", "rifampicin" ], "offsets": [ [ 42, 54 ], [ 59, 69 ], [ 121, 131 ] ] }, { "pmid": "12085361", "text": "In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes.", "type": "CHEMICAL", "entities": [ "rifamycin SV" ], "offsets": [ [ 61, 73 ] ] }, { "pmid": "12085361", "text": "In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished.", "type": "CHEMICAL", "entities": [ "rifamycin SV", "BSP" ], "offsets": [ [ 34, 46 ], [ 48, 51 ] ] }, { "pmid": "12085361", "text": "Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%.", "type": "CHEMICAL", "entities": [ "Rifampicin", "BSP", "BSP" ], "offsets": [ [ 132, 142 ], [ 184, 187 ], [ 263, 266 ] ] }, { "pmid": "12085361", "text": "100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively.", "type": "CHEMICAL", "entities": [ "rifampicin", "BSP" ], "offsets": [ [ 15, 25 ], [ 84, 87 ] ] }, { "pmid": "12085361", "text": "The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L).", "type": "CHEMICAL", "entities": [ "rifampicin" ], "offsets": [ [ 135, 145 ] ] }, { "pmid": "12085361", "text": "In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents.", "type": "CHEMICAL", "entities": [ "rifamycin SV", "rifampicin" ], "offsets": [ [ 39, 51 ], [ 56, 66 ] ] }, { "pmid": "12085361", "text": "Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination.", "type": "CHEMICAL", "entities": [ "rifamycin SV", "rifampicin" ], "offsets": [ [ 79, 91 ], [ 96, 106 ] ] }, { "pmid": "12086935", "text": "Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.\n", "type": "CHEMICAL", "entities": [ "Metformin", "AMP" ], "offsets": [ [ 0, 9 ], [ 20, 23 ] ] }, { "pmid": "12086935", "text": "Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood.", "type": "CHEMICAL", "entities": [ "glucose", "Metformin", "glucose", "glucose", "metformin" ], "offsets": [ [ 62, 69 ], [ 0, 9 ], [ 107, 114 ], [ 141, 148 ], [ 209, 218 ] ] }, { "pmid": "12086935", "text": "AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis.", "type": "CHEMICAL", "entities": [ "AMP", "glucose" ], "offsets": [ [ 0, 3 ], [ 165, 172 ] ] }, { "pmid": "12086935", "text": "We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production.", "type": "CHEMICAL", "entities": [ "metformin", "glucose" ], "offsets": [ [ 47, 56 ], [ 142, 149 ] ] }, { "pmid": "12086935", "text": "In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "12086935", "text": "Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity.", "type": "CHEMICAL", "entities": [ "Metformin", "acetyl-CoA" ], "offsets": [ [ 0, 9 ], [ 189, 199 ] ] }, { "pmid": "12086935", "text": "The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment.", "type": "CHEMICAL", "entities": [ "ATP", "phosphocreatine", "metformin" ], "offsets": [ [ 96, 99 ], [ 104, 119 ], [ 152, 161 ] ] }, { "pmid": "12086935", "text": "Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations.", "type": "CHEMICAL", "entities": [ "Metformin", "glucose" ], "offsets": [ [ 0, 9 ], [ 82, 89 ] ] }, { "pmid": "12105857", "text": "Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production.\n", "type": "CHEMICAL", "entities": [ "Thalidomide", "alcoholic" ], "offsets": [ [ 0, 11 ], [ 21, 30 ] ] }, { "pmid": "12105857", "text": "Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) alpha are critical for progression of alcoholic liver injury.", "type": "CHEMICAL", "entities": [ "alcoholic" ], "offsets": [ [ 153, 162 ] ] }, { "pmid": "12105857", "text": "Thalidomide has been shown to suppress TNF-alpha production from macrophages.", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "12105857", "text": "Accordingly, the purpose of this study was to determine whether thalidomide could prevent alcohol-induced liver injury.", "type": "CHEMICAL", "entities": [ "thalidomide", "alcohol" ], "offsets": [ [ 64, 75 ], [ 90, 97 ] ] }, { "pmid": "12105857", "text": "Rats were given ethanol (5 g/kg body wt) and thalidomide (5 mg/kg) once every 24 hours intragastrically.", "type": "CHEMICAL", "entities": [ "ethanol", "thalidomide" ], "offsets": [ [ 16, 23 ], [ 45, 56 ] ] }, { "pmid": "12105857", "text": "KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-alpha was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay.", "type": "CHEMICAL", "entities": [ "ethanol", "Ca2+", "Ca2+" ], "offsets": [ [ 35, 42 ], [ 71, 75 ], [ 78, 82 ] ] }, { "pmid": "12105857", "text": "Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "12105857", "text": "These pathologic parameters were diminished markedly by treatment with thalidomide.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 71, 82 ] ] }, { "pmid": "12105857", "text": "In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 14, 21 ] ] }, { "pmid": "12105857", "text": "Coadministration of thalidomide with ethanol prevented the KC sensitization completely.", "type": "CHEMICAL", "entities": [ "thalidomide", "ethanol" ], "offsets": [ [ 20, 31 ], [ 37, 44 ] ] }, { "pmid": "12105857", "text": "Furthermore, thalidomide abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs.", "type": "CHEMICAL", "entities": [ "thalidomide", "Ca2+" ], "offsets": [ [ 13, 24 ], [ 84, 88 ] ] }, { "pmid": "12105857", "text": "Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by thalidomide.", "type": "CHEMICAL", "entities": [ "ethanol", "thalidomide" ], "offsets": [ [ 62, 69 ], [ 106, 117 ] ] }, { "pmid": "12105857", "text": "Moreover, thalidomide reduced the LPS-induced TNF-alpha production by KCs by decreasing TNF-alpha messenger RNA.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "12105857", "text": "These results collectively indicate that thalidomide prevents alcoholic liver injury through suppression of TNF-alpha production and abolishment of KC sensitization.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "12141946", "text": "Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin.\n", "type": "CHEMICAL", "entities": [ "flavin", "spermine" ], "offsets": [ [ 47, 53 ], [ 65, 73 ] ] }, { "pmid": "12141946", "text": "During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively.", "type": "CHEMICAL", "entities": [ "spermidine", "putrescine", "spermine", "spermidine", "polyamine", "spermidine", "spermine", "N", "polyamine" ], "offsets": [ [ 191, 201 ], [ 206, 216 ], [ 29, 37 ], [ 42, 52 ], [ 7, 16 ], [ 77, 87 ], [ 88, 96 ], [ 97, 98 ], [ 156, 165 ] ] }, { "pmid": "12141946", "text": "In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT.", "type": "CHEMICAL", "entities": [ "spermine" ], "offsets": [ [ 127, 135 ] ] }, { "pmid": "12141946", "text": "A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 172, 183 ] ] }, { "pmid": "12141946", "text": "When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme.", "type": "CHEMICAL", "entities": [ "spermine", "spermidine", "N (1)-acetylspermidine", "spermine" ], "offsets": [ [ 79, 87 ], [ 117, 127 ], [ 132, 154 ], [ 188, 196 ] ] }, { "pmid": "12141946", "text": "Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine.", "type": "CHEMICAL", "entities": [ "N (1)-acetylspermidine", "spermine", "N (1)-acetylspermine", "spermidine", "N (1), N (12)-diacetylspermine" ], "offsets": [ [ 198, 220 ], [ 134, 142 ], [ 148, 168 ], [ 222, 232 ], [ 265, 295 ] ] }, { "pmid": "12141946", "text": "The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction.", "type": "CHEMICAL", "entities": [ "MDL-72,527", "spermine", "N (1)-( n -octanesulphonyl)spermine" ], "offsets": [ [ 19, 29 ], [ 67, 75 ], [ 119, 154 ] ] }, { "pmid": "12141946", "text": "Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion.", "type": "CHEMICAL", "entities": [ "spermine", "polyamine" ], "offsets": [ [ 145, 153 ], [ 214, 223 ] ] }, { "pmid": "12141946", "text": "The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors.", "type": "CHEMICAL", "entities": [ "spermine", "spermidine", "polyamine" ], "offsets": [ [ 62, 70 ], [ 74, 84 ], [ 230, 239 ] ] }, { "pmid": "12165285", "text": "The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and ADP (3 microM)-induced CD62P externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease.", "type": "CHEMICAL", "entities": [ "tirofiban", "eptifibatide", "ADP" ], "offsets": [ [ 43, 52 ], [ 67, 79 ], [ 111, 114 ] ] }, { "pmid": "12165285", "text": "Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced CD62P expression.", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 124, 127 ] ] }, { "pmid": "12165285", "text": "A moderate (twofold) stimulation of CD62P expression by abciximab but not by tirofiban or eptifibatide was observed in one patient.", "type": "CHEMICAL", "entities": [ "tirofiban", "eptifibatide" ], "offsets": [ [ 77, 86 ], [ 90, 102 ] ] }, { "pmid": "12165285", "text": "In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated CD62P expression.", "type": "CHEMICAL", "entities": [ "ADP" ], "offsets": [ [ 233, 236 ] ] }, { "pmid": "12167474", "text": "Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism.\n", "type": "CHEMICAL", "entities": [ "cysteine S-conjugates" ], "offsets": [ [ 19, 40 ] ] }, { "pmid": "12167474", "text": "Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively.", "type": "CHEMICAL", "entities": [ "S-(1,2-dichlorovinyl)-L-cysteine", "DCVC", "S-(1,1,2,2-tetrafluoroethyl)-L-cysteine", "TFEC", "cysteine S-conjugates", "haloalkenes", "trichloroethylene", "tetrafluoroethylene" ], "offsets": [ [ 154, 186 ], [ 188, 192 ], [ 198, 237 ], [ 239, 243 ], [ 59, 80 ], [ 8, 19 ], [ 95, 112 ], [ 117, 136 ] ] }, { "pmid": "12167474", "text": "Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently.", "type": "CHEMICAL", "entities": [ "DCVC", "TFEC", "haloalkene-derived cysteine S-conjugates" ], "offsets": [ [ 9, 13 ], [ 86, 90 ], [ 101, 141 ] ] }, { "pmid": "12167474", "text": "Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace.", "type": "CHEMICAL", "entities": [ "haloalkenes" ], "offsets": [ [ 50, 61 ] ] }, { "pmid": "12167474", "text": "Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate beta-lyases to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins.", "type": "CHEMICAL", "entities": [ "cysteine S-conjugates", "cysteine S-conjugate", "pyruvate", "ammonia", "alpha-chloroenethiolate", "DCVC", "alpha-difluoroalkylthiolate", "TFEC", "halide", "thioacyl halide", "epsilon-amino", "lysine" ], "offsets": [ [ 17, 38 ], [ 58, 78 ], [ 94, 102 ], [ 104, 111 ], [ 120, 143 ], [ 150, 154 ], [ 162, 189 ], [ 196, 200 ], [ 221, 227 ], [ 238, 253 ], [ 273, 286 ], [ 297, 303 ] ] }, { "pmid": "12167474", "text": "Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)).", "type": "CHEMICAL", "entities": [ "cysteine S-conjugate", "aspartate", "pyridoxal 5'-phosphate", "PLP", "branched-chain amino acid" ], "offsets": [ [ 72, 92 ], [ 139, 148 ], [ 15, 37 ], [ 39, 42 ], [ 196, 221 ] ] }, { "pmid": "12167474", "text": "Most of the cysteine S-conjugate beta-lyases are syncatalytically inactivated.", "type": "CHEMICAL", "entities": [ "cysteine S-conjugate" ], "offsets": [ [ 12, 32 ] ] }, { "pmid": "12167474", "text": "TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism.", "type": "CHEMICAL", "entities": [ "TFEC" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "12167474", "text": "Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation.", "type": "CHEMICAL", "entities": [ "alpha-ketoglutarate", "branched-chain alpha-keto acid", "pyruvate" ], "offsets": [ [ 19, 38 ], [ 44, 74 ], [ 130, 138 ] ] }, { "pmid": "12167474", "text": "mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC.", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 84, 87 ] ] }, { "pmid": "12175785", "text": "The juvenile visceral steatosis (jvs) mouse, having a mutation in the carnitine transporter gene Octn2, is a model of primary systemic carnitine deficiency in humans (SCD, OMIM 212140).", "type": "CHEMICAL", "entities": [ "carnitine", "carnitine" ], "offsets": [ [ 70, 79 ], [ 135, 144 ] ] }, { "pmid": "12175785", "text": "Like humans with SCD, homozygous jvs -/- mice have hepatic and cardiac steatoses, reduced plasma and tissue carnitines, and increased urinary carnitine clearance.", "type": "CHEMICAL", "entities": [ "carnitines", "carnitine" ], "offsets": [ [ 108, 118 ], [ 142, 151 ] ] }, { "pmid": "12175785", "text": "Because symptomatic heterozygotes have been reported for some fatty acid oxidation disorders, including SCD, we compared the jvs heterozygotes to normal control mice.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "12175785", "text": "We measured the free and esterified carnitine, total cholesterol, and triglycerides in adult liver samples, myocardium, and skeletal muscle.", "type": "CHEMICAL", "entities": [ "carnitine", "cholesterol", "triglycerides" ], "offsets": [ [ 36, 45 ], [ 53, 64 ], [ 70, 83 ] ] }, { "pmid": "12175785", "text": "+/- SEM, p < 0.01) for the following parameters: free carnitine, 2.28 +/- 0.36 nmol/mg protein vs 0.41 +/- 0.13; total carnitine, 3.48 +/- 0.36 vs 1.27 +/- 0.25; triglycerides, 0.14 +/- 0.04 vs 0.39 +/- 0.02; and total cholesterol, 0.21 +/- 0.02 vs 0.39 +/- 0.04, but not for esterified carnitine, 1.18 +/- 0.17 vs 0.90 +/- 0.17 (p > 0.05).", "type": "CHEMICAL", "entities": [ "carnitine", "carnitine", "triglycerides", "cholesterol", "carnitine" ], "offsets": [ [ 54, 63 ], [ 119, 128 ], [ 162, 175 ], [ 219, 230 ], [ 287, 296 ] ] }, { "pmid": "12175785", "text": "There is also a negative correlation between hepatic free carnitine and triglycerides from jvs heterozygotes (p < 0.05).", "type": "CHEMICAL", "entities": [ "carnitine", "triglycerides" ], "offsets": [ [ 58, 67 ], [ 72, 85 ] ] }, { "pmid": "12175785", "text": "We conclude that free and total carnitine levels are significantly lower in the heterozygote mouse liver and heart while triglyceride and total cholesterol levels are significantly higher.", "type": "CHEMICAL", "entities": [ "carnitine", "triglyceride", "cholesterol" ], "offsets": [ [ 32, 41 ], [ 121, 133 ], [ 144, 155 ] ] }, { "pmid": "12175785", "text": "We speculate that in situations of lipolytic stress, some SCD heterozygotes might develop clinical symptoms of carnitine deficiency.", "type": "CHEMICAL", "entities": [ "carnitine" ], "offsets": [ [ 111, 120 ] ] }, { "pmid": "12181285", "text": "Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1).", "type": "CHEMICAL", "entities": [ "noradrenaline", "NA", "noradrenaline" ], "offsets": [ [ 26, 39 ], [ 41, 43 ], [ 120, 133 ] ] }, { "pmid": "12181285", "text": "Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones.", "type": "CHEMICAL", "entities": [ "[3H]-N-methyl-4-phenylpyridinium", "[3H]-MPP+" ], "offsets": [ [ 83, 115 ], [ 117, 126 ] ] }, { "pmid": "12181285", "text": "The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone.", "type": "CHEMICAL", "entities": [ "desipramine", "reserpine", "desipramine", "oestradiol", "corticosterone" ], "offsets": [ [ 68, 79 ], [ 84, 93 ], [ 127, 138 ], [ 176, 186 ], [ 191, 205 ] ] }, { "pmid": "12181285", "text": "In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA.", "type": "CHEMICAL", "entities": [ "[3H]-NA" ], "offsets": [ [ 87, 94 ] ] }, { "pmid": "12181285", "text": "Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863.", "type": "CHEMICAL", "entities": [ "[3H]-NA", "[3H]-DHPG" ], "offsets": [ [ 203, 210 ], [ 230, 239 ] ] }, { "pmid": "12181285", "text": "The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters.", "type": "CHEMICAL", "entities": [ "[3H]-MPP+", "MPP+", "guanidine", "choline", "amantadine" ], "offsets": [ [ 15, 24 ], [ 55, 59 ], [ 61, 70 ], [ 72, 79 ], [ 84, 94 ] ] }, { "pmid": "12181285", "text": "However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action.", "type": "CHEMICAL", "entities": [ "MPP+", "desipramine" ], "offsets": [ [ 145, 149 ], [ 9, 20 ] ] }, { "pmid": "12181285", "text": "The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863.", "type": "CHEMICAL", "entities": [ "MPP+", "[3H]-MPP+", "desipramine" ], "offsets": [ [ 4, 8 ], [ 28, 37 ], [ 87, 98 ] ] }, { "pmid": "12181285", "text": "No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM.", "type": "CHEMICAL", "entities": [ "[3H]-MPP+" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "12181285", "text": "Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+.", "type": "CHEMICAL", "entities": [ "[3H]-MPP+" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "12181285", "text": "Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release.", "type": "CHEMICAL", "entities": [ "[3H]-MPP+" ], "offsets": [ [ 170, 179 ] ] }, { "pmid": "12200198", "text": "Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes.\n", "type": "CHEMICAL", "entities": [ "propargylamines" ], "offsets": [ [ 19, 34 ] ] }, { "pmid": "12200198", "text": "In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 107, 115 ] ] }, { "pmid": "12200198", "text": "An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it.", "type": "CHEMICAL", "entities": [ "(-)deprenyl", "selegiline", "monoamine" ], "offsets": [ [ 50, 61 ], [ 63, 73 ], [ 23, 32 ] ] }, { "pmid": "12200198", "text": "However, the animal and cellular models of PD proved that selegiline protects neurons from cell death.", "type": "CHEMICAL", "entities": [ "selegiline" ], "offsets": [ [ 58, 68 ] ] }, { "pmid": "12200198", "text": "Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments.", "type": "CHEMICAL", "entities": [ "selegiline", "propargylamines", "(R)(+)-N-propargyl-1-aminoindan", "rasagiline" ], "offsets": [ [ 6, 16 ], [ 25, 40 ], [ 42, 73 ], [ 75, 85 ] ] }, { "pmid": "12200198", "text": "In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal).", "type": "CHEMICAL", "entities": [ "rasagiline", "N-methyl(R)salsolinol", "NM(R)Sal" ], "offsets": [ [ 55, 65 ], [ 186, 207 ], [ 209, 217 ] ] }, { "pmid": "12200198", "text": "NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions.", "type": "CHEMICAL", "entities": [ "NM(R)Sal" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "12200198", "text": "Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF).", "type": "CHEMICAL", "entities": [ "Rasagiline" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12200198", "text": "Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons.", "type": "CHEMICAL", "entities": [ "propargylamines", "superoxide", "dopamine" ], "offsets": [ [ 28, 43 ], [ 102, 112 ], [ 174, 182 ] ] }, { "pmid": "12200198", "text": "Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.", "type": "CHEMICAL", "entities": [ "Rasagiline", "propargylamines", "dopamine" ], "offsets": [ [ 0, 10 ], [ 23, 38 ], [ 63, 71 ] ] }, { "pmid": "12213119", "text": "Pharmacodynamics and pharmacokinetics of phenylbutazone in calves.\n", "type": "CHEMICAL", "entities": [ "phenylbutazone" ], "offsets": [ [ 41, 55 ] ] }, { "pmid": "12213119", "text": "Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.)", "type": "CHEMICAL", "entities": [ "Phenylbutazone", "PBZ" ], "offsets": [ [ 0, 14 ], [ 16, 19 ] ] }, { "pmid": "12213119", "text": "PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle.", "type": "CHEMICAL", "entities": [ "PBZ", "oxyphenbutazone", "OPBZ" ], "offsets": [ [ 0, 3 ], [ 212, 227 ], [ 229, 233 ] ] }, { "pmid": "12213119", "text": "Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ).", "type": "CHEMICAL", "entities": [ "PBZ" ], "offsets": [ [ 463, 466 ] ] }, { "pmid": "12213119", "text": "The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2", "leukotriene B4", "LTB4", "thromboxane B2", "TxB2" ], "offsets": [ [ 87, 103 ], [ 105, 109 ], [ 112, 126 ], [ 128, 132 ], [ 209, 223 ], [ 225, 229 ] ] }, { "pmid": "12213119", "text": "These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors.", "type": "CHEMICAL", "entities": [ "PBZ", "OPBZ", "PBZ", "PBZ" ], "offsets": [ [ 156, 159 ], [ 172, 176 ], [ 213, 216 ], [ 292, 295 ] ] }, { "pmid": "12213119", "text": "To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.", "type": "CHEMICAL", "entities": [ "PBZ" ], "offsets": [ [ 50, 53 ] ] }, { "pmid": "12227806", "text": "Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction.\n", "type": "CHEMICAL", "entities": [ "aprepitant" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "12227806", "text": "A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described.", "type": "CHEMICAL", "entities": [ "aprepitant", "substance P", "SP" ], "offsets": [ [ 45, 55 ], [ 70, 81 ], [ 83, 85 ] ] }, { "pmid": "12227806", "text": "The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process.", "type": "CHEMICAL", "entities": [ "oxazinone" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "12227806", "text": "Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring.", "type": "CHEMICAL", "entities": [ "cis-sec-amine", "chiral alcohol", "trichloroacetimidate", "morpholine" ], "offsets": [ [ 49, 62 ], [ 143, 157 ], [ 165, 185 ], [ 248, 258 ] ] }, { "pmid": "12297509", "text": "Redundancy and specificity in the regulation of adenylyl cyclase and other effectors.\n", "type": "CHEMICAL", "entities": [ "adenylyl" ], "offsets": [ [ 48, 56 ] ] }, { "pmid": "12297509", "text": "Platelet responses at sites of vascular injury are regulated by intracellular cAMP levels, which rise rapidly when prostacyclin (PGI(2)) is released from endothelial cells.", "type": "CHEMICAL", "entities": [ "prostacyclin", "cAMP", "PGI(2)" ], "offsets": [ [ 115, 127 ], [ 78, 82 ], [ 129, 135 ] ] }, { "pmid": "12297509", "text": "Platelet agonists such as ADP and epinephrine suppress PGI(2)-stimulated cAMP formation by activating receptors coupled to G(i) family members, four of which are present in platelets.", "type": "CHEMICAL", "entities": [ "ADP", "PGI(2)", "cAMP" ], "offsets": [ [ 26, 29 ], [ 55, 61 ], [ 73, 77 ] ] }, { "pmid": "12297509", "text": "To address questions about the specificity of receptor:G protein coupling, the regulation of cAMP formation in vivo and the contribution of G(i)-mediated pathways that do not involve adenylyl cyclase, we studied platelets from mice that lacked the alpha subunits of one or more of the three most abundantly expressed G(i) family members and compared the results with platelets from mice that lacked the PGI(2) receptor, IP.", "type": "CHEMICAL", "entities": [ "cAMP", "adenylyl", "PGI(2)" ], "offsets": [ [ 93, 97 ], [ 183, 191 ], [ 403, 409 ] ] }, { "pmid": "12297509", "text": "As reported previously, loss of G(i2)alpha or G(z)alpha inhibited aggregation in response to ADP and epinephrine, respectively, producing defects that could not be reversed by adding an adenylyl cyclase inhibitor.", "type": "CHEMICAL", "entities": [ "ADP", "epinephrine", "adenylyl" ], "offsets": [ [ 93, 96 ], [ 101, 112 ], [ 186, 194 ] ] }, { "pmid": "12297509", "text": "Loss of either G(z)alpha or G(i2)alpha impaired the ability of ADP and epinephrine to inhibit PGI(2)-stimulated adenylyl cyclase activity and caused a 40%-50% rise in basal cAMP levels, whereas loss of G(i3)alpha did not.", "type": "CHEMICAL", "entities": [ "ADP", "epinephrine", "PGI(2)", "adenylyl", "cAMP" ], "offsets": [ [ 63, 66 ], [ 71, 82 ], [ 94, 100 ], [ 112, 120 ], [ 173, 177 ] ] }, { "pmid": "12297509", "text": "Conversely, deletion of IP abolished responses to PGI(2) and caused cAMP levels to fall by 30%, effects that did not translate into enhanced responsiveness to agonists ex vivo.", "type": "CHEMICAL", "entities": [ "PGI(2)", "cAMP" ], "offsets": [ [ 50, 56 ], [ 68, 72 ] ] }, { "pmid": "12297509", "text": "From these results we conclude that 1) cAMP levels in circulating platelets reflect ongoing signaling through G(i2), G(z), and IP, but not G(i3); 2) platelet epinephrine (alpha(2A)-adrenergic) and ADP (P2Y12) receptors display strong preferences among G(i) family members with little evidence of redundancy; and 3) these receptor preferences do not extend to G(i3).", "type": "CHEMICAL", "entities": [ "cAMP", "epinephrine", "ADP" ], "offsets": [ [ 39, 43 ], [ 158, 169 ], [ 197, 200 ] ] }, { "pmid": "12297509", "text": "Finally, the failure of ADP and epinephrine to inhibit basal, as opposed to PGI(2)-stimulated, cAMP formation highlights the need during platelet activation for G(i) signaling pathways that involve effectors other than adenylyl cyclase.", "type": "CHEMICAL", "entities": [ "ADP", "epinephrine", "PGI(2)", "cAMP", "adenylyl" ], "offsets": [ [ 24, 27 ], [ 32, 43 ], [ 76, 82 ], [ 95, 99 ], [ 219, 227 ] ] }, { "pmid": "12375053", "text": "Effects of pentosan polysulfate sodium on the estrogen-induced pituitary prolactinoma in Fischer 344 rats.\n", "type": "CHEMICAL", "entities": [ "sodium", "estrogen" ], "offsets": [ [ 32, 38 ], [ 46, 54 ] ] }, { "pmid": "12375053", "text": "The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 19, 27 ] ] }, { "pmid": "12375053", "text": "Pentosan polysulfate sodium (PPS) has been shown to exert antitumor activity by antagonizing the binding of bFGF to cell surface receptors.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 21, 27 ] ] }, { "pmid": "12375053", "text": "We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats.", "type": "CHEMICAL", "entities": [ "diethylstilbestrol" ], "offsets": [ [ 97, 115 ] ] }, { "pmid": "12388412", "text": "Localization of the ammonium transporter proteins RhBG and RhCG in mouse kidney.\n", "type": "CHEMICAL", "entities": [ "ammonium" ], "offsets": [ [ 20, 28 ] ] }, { "pmid": "12388412", "text": "Ammonia is both produced and transported by renal epithelial cells, and it regulates renal ion transport.", "type": "CHEMICAL", "entities": [ "Ammonia" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "12388412", "text": "Recent studies have identified a family of putative ammonium transporters; mRNA for two members of this family, Rh B-glycoprotein (RhBG) and Rh C-glycoprotein (RhCG), is expressed in the kidney.", "type": "CHEMICAL", "entities": [ "ammonium" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "12388412", "text": "Colocalization of RhBG with carbonic anhydrase II, the thiazide-sensitive transporter, and the anion exchangers AE1 and pendrin demonstrated RhBG immunoreactivity in all CNT cells and all CCD and ICT principal cells.", "type": "CHEMICAL", "entities": [ "thiazide" ], "offsets": [ [ 55, 63 ] ] }, { "pmid": "12388412", "text": "Immunoreactivity for a second putative ammonium transporter, RhCG, was present in the apical region of cells with almost the same distribution as RhBG.", "type": "CHEMICAL", "entities": [ "ammonium" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "12388412", "text": "These findings suggest that RhBG and RhCG may play important and cell-specific roles in ammonium transport and signaling in these regions of the kidney.", "type": "CHEMICAL", "entities": [ "ammonium" ], "offsets": [ [ 88, 96 ] ] }, { "pmid": "12414329", "text": "Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on PDE5 inhibition using sildenafil as the model for pharmacologic PDE5 inhibition are assessed.", "type": "CHEMICAL", "entities": [ "nitric oxide", "cyclic guanosine monophosphate", "cGMP" ], "offsets": [ [ 28, 40 ], [ 41, 71 ], [ 73, 77 ] ] }, { "pmid": "12414329", "text": "PDE5 is the predominant PDE in the corpus cavernosum, and cGMP is its primary substrate.", "type": "CHEMICAL", "entities": [ "cGMP" ], "offsets": [ [ 58, 62 ] ] }, { "pmid": "12414329", "text": "Therefore, in men with ED, elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP-specific PDE5 is a means of improving erectile function at minimal risk of adverse events.", "type": "CHEMICAL", "entities": [ "cGMP", "cGMP" ], "offsets": [ [ 40, 44 ], [ 101, 105 ] ] }, { "pmid": "12414329", "text": "This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "12414329", "text": "Sildenafil exhibits inhibitory potency against PDE5 and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant PDE in the phototransduction cascade in rods.", "type": "CHEMICAL", "entities": [ "Sildenafil" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12414329", "text": "Clinically, sildenafil improves erectile function in a large percentage of men with ED.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "12414329", "text": "As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 8, 18 ] ] }, { "pmid": "12414329", "text": "Selective inhibition of PDE5 is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 108, 118 ] ] }, { "pmid": "12421359", "text": "Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin.\n", "type": "CHEMICAL", "entities": [ "GABA", "ivermectin" ], "offsets": [ [ 31, 35 ], [ 89, 99 ] ] }, { "pmid": "12421359", "text": "Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 54, 58 ] ] }, { "pmid": "12421359", "text": "These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively.", "type": "CHEMICAL", "entities": [ "ivermectin" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "12421359", "text": "Sequence analysis indicates that they differ in four amino acids.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "12421359", "text": "To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 137, 141 ] ] }, { "pmid": "12421359", "text": "When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed.", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid", "GABA" ], "offsets": [ [ 94, 117 ], [ 119, 123 ] ] }, { "pmid": "12421359", "text": "The effects of ivermectin on the hetero-oligomeric receptors were determined.", "type": "CHEMICAL", "entities": [ "ivermectin" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "12421359", "text": "Application of ivermectin alone had no effect on the receptors.", "type": "CHEMICAL", "entities": [ "ivermectin" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "12421359", "text": "However, when coapplied with 10 micro m GABA, ivermectin potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor.", "type": "CHEMICAL", "entities": [ "GABA", "ivermectin", "GABA", "GABA" ], "offsets": [ [ 40, 44 ], [ 46, 56 ], [ 73, 77 ], [ 140, 144 ] ] }, { "pmid": "12421359", "text": "We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of ivermectin resistance.", "type": "CHEMICAL", "entities": [ "GABA", "GABA", "ivermectin" ], "offsets": [ [ 65, 69 ], [ 135, 139 ], [ 170, 180 ] ] }, { "pmid": "12438517", "text": "Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype.\n", "type": "CHEMICAL", "entities": [ "Yohimbine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "12438517", "text": "Yohimbine is a potent and selective alpha2- versus alpha1-adrenoceptor antagonist.", "type": "CHEMICAL", "entities": [ "Yohimbine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "12438517", "text": "Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human alpha2C-adrenoceptor in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively.", "type": "CHEMICAL", "entities": [ "yohimbine" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "12438517", "text": "To improve on this alpha2-adrenoceptor subtype selectivity, a series of yohimbine dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells.", "type": "CHEMICAL", "entities": [ "yohimbine" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "12438517", "text": "Each dimeric analog showed higher affinities for alpha2A- and alpha2C-adrenoceptor versus the alpha2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the alpha2C-adrenoceptor.", "type": "CHEMICAL", "entities": [ "yohimbine" ], "offsets": [ [ 120, 129 ] ] }, { "pmid": "12438517", "text": "The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold.", "type": "CHEMICAL", "entities": [ "yohimbine" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "12438517", "text": "respectively) for the alpha2C-adrenoceptor in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 131, 135 ] ] }, { "pmid": "12438517", "text": "These findings demonstrate that the addition of spacer linkages to bivalent yohimbine molecules provides a successful approach to the development of ligands that are potent and highly selective for the alpha2C-adrenoceptor.", "type": "CHEMICAL", "entities": [ "yohimbine" ], "offsets": [ [ 76, 85 ] ] }, { "pmid": "12470615", "text": "Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod.\n", "type": "CHEMICAL", "entities": [ "resiquimod", "imiquimod" ], "offsets": [ [ 106, 116 ], [ 92, 101 ] ] }, { "pmid": "12470615", "text": "The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans.", "type": "CHEMICAL", "entities": [ "imiquimod", "resiquimod" ], "offsets": [ [ 31, 40 ], [ 45, 55 ] ] }, { "pmid": "12470615", "text": "Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod.", "type": "CHEMICAL", "entities": [ "imiquimod", "resiquimod" ], "offsets": [ [ 73, 82 ], [ 87, 97 ] ] }, { "pmid": "12470615", "text": "Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood.", "type": "CHEMICAL", "entities": [ "imiquimod", "resiquimod" ], "offsets": [ [ 22, 31 ], [ 36, 46 ] ] }, { "pmid": "12470615", "text": "Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10.", "type": "CHEMICAL", "entities": [ "Resiquimod" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12470615", "text": "Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability.", "type": "CHEMICAL", "entities": [ "Resiquimod" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12470615", "text": "Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone.", "type": "CHEMICAL", "entities": [ "resiquimod", "Resiquimod" ], "offsets": [ [ 94, 104 ], [ 0, 10 ] ] }, { "pmid": "12470615", "text": "These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability.", "type": "CHEMICAL", "entities": [ "imidazoquinoline" ], "offsets": [ [ 31, 47 ] ] }, { "pmid": "12472888", "text": "Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death.\n", "type": "CHEMICAL", "entities": [ "sodium arsenite", "hydrogen peroxide" ], "offsets": [ [ 43, 58 ], [ 99, 116 ] ] }, { "pmid": "12472888", "text": "Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points.", "type": "CHEMICAL", "entities": [ "sodium arsenite", "H2O2" ], "offsets": [ [ 29, 44 ], [ 144, 148 ] ] }, { "pmid": "12472888", "text": "Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH).", "type": "CHEMICAL", "entities": [ "cycloheximide", "CXH", "Arsenite" ], "offsets": [ [ 81, 94 ], [ 96, 99 ], [ 0, 8 ] ] }, { "pmid": "12472888", "text": "H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "12472888", "text": "These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells.", "type": "CHEMICAL", "entities": [ "arsenite" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "12472888", "text": "The protective effect of arsenite was not detected in the presence of CHX.", "type": "CHEMICAL", "entities": [ "arsenite", "CHX" ], "offsets": [ [ 25, 33 ], [ 70, 73 ] ] }, { "pmid": "12472888", "text": "Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 138, 142 ] ] }, { "pmid": "12472888", "text": "However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX.", "type": "CHEMICAL", "entities": [ "CHX" ], "offsets": [ [ 104, 107 ] ] }, { "pmid": "12472888", "text": "The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2.", "type": "CHEMICAL", "entities": [ "arsenite", "H2O2", "H2O2" ], "offsets": [ [ 32, 40 ], [ 118, 122 ], [ 200, 204 ] ] }, { "pmid": "12472888", "text": "It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 51, 55 ] ] }, { "pmid": "12487427", "text": "Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and omapatrilat.\n", "type": "CHEMICAL", "entities": [ "GW660511X", "omapatrilat", "bradykinin" ], "offsets": [ [ 110, 119 ], [ 124, 135 ], [ 17, 27 ] ] }, { "pmid": "12487427", "text": "Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi.", "type": "CHEMICAL", "entities": [ "bradykinin" ], "offsets": [ [ 56, 66 ] ] }, { "pmid": "12487427", "text": "In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial.", "type": "CHEMICAL", "entities": [ "BK", "Br-Phe5", "BrBK", "GW660511X", "omapatrilat" ], "offsets": [ [ 158, 160 ], [ 168, 175 ], [ 177, 181 ], [ 234, 243 ], [ 248, 259 ] ] }, { "pmid": "12487427", "text": "In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe.", "type": "CHEMICAL", "entities": [ "BrBK", "GW660511X", "omapatrilat", "BrBK", "BrBK1-8", "BrBK1-7", "BrBK1-5", "Br-Phe" ], "offsets": [ [ 20, 24 ], [ 79, 88 ], [ 105, 116 ], [ 197, 201 ], [ 220, 227 ], [ 229, 236 ], [ 238, 245 ], [ 250, 256 ] ] }, { "pmid": "12487427", "text": "Unlike GW660511X, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found.", "type": "CHEMICAL", "entities": [ "GW660511X", "omapatrilat", "BrBK1-5", "BrBK1-7", "GW660511X" ], "offsets": [ [ 7, 16 ], [ 18, 29 ], [ 58, 65 ], [ 70, 77 ], [ 126, 135 ] ] }, { "pmid": "12487427", "text": "In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat.", "type": "CHEMICAL", "entities": [ "BrBK1-8", "omapatrilat" ], "offsets": [ [ 30, 37 ], [ 135, 146 ] ] }, { "pmid": "12487427", "text": "The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with omapatrilat after 4 h of incubation.", "type": "CHEMICAL", "entities": [ "Br-Phe5", "GW660511X", "omapatrilat" ], "offsets": [ [ 18, 25 ], [ 43, 52 ], [ 99, 110 ] ] }, { "pmid": "12487427", "text": "In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma.", "type": "CHEMICAL", "entities": [ "BrBK1-8", "BrBK1-7", "BrBK1-5", "Br-Phe5", "BrBK2-9", "BrBK4-8", "BrBK2-8", "BrBK", "GW660511X", "omapatrilat", "BrBK" ], "offsets": [ [ 214, 221 ], [ 223, 230 ], [ 232, 239 ], [ 244, 251 ], [ 257, 264 ], [ 266, 273 ], [ 278, 285 ], [ 18, 22 ], [ 77, 86 ], [ 99, 110 ], [ 191, 195 ] ] }, { "pmid": "12487427", "text": "GW660511X and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat.", "type": "CHEMICAL", "entities": [ "GW660511X", "omapatrilat", "BrBK1-5", "BrBK1-7", "omapatrilat" ], "offsets": [ [ 0, 9 ], [ 14, 25 ], [ 52, 59 ], [ 64, 71 ], [ 109, 120 ] ] }, { "pmid": "12487427", "text": "GW660511X and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8.", "type": "CHEMICAL", "entities": [ "GW660511X", "omapatrilat", "BrBK1-8", "Br-Phe5", "BrBK4-8", "BrBK2-8" ], "offsets": [ [ 0, 9 ], [ 14, 25 ], [ 59, 66 ], [ 71, 78 ], [ 95, 102 ], [ 107, 114 ] ] }, { "pmid": "12487427", "text": "This study shows that the potency of GW660511X in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans.", "type": "CHEMICAL", "entities": [ "GW660511X", "omapatrilat" ], "offsets": [ [ 37, 46 ], [ 66, 77 ] ] }, { "pmid": "12513698", "text": "Receptor activation was assessed by measuring the inhibition of forskolin-stimulated cyclic adenosine mono phosphate (cAMP) production.", "type": "CHEMICAL", "entities": [ "forskolin", "cyclic adenosine mono phosphate", "cAMP" ], "offsets": [ [ 64, 73 ], [ 85, 116 ], [ 118, 122 ] ] }, { "pmid": "12513698", "text": "Efficacies and potencies of these ligands were determined relative to the endogenous ligand beta-endorphin and the common mu agonist, morphine.", "type": "CHEMICAL", "entities": [ "morphine" ], "offsets": [ [ 134, 142 ] ] }, { "pmid": "12513698", "text": "Among the ligands studied naltrexone, WIN 44,441 and SKF 10047, were classified as antagonists, while the remaining ligands were agonists.", "type": "CHEMICAL", "entities": [ "naltrexone", "WIN 44,441", "SKF 10047" ], "offsets": [ [ 26, 36 ], [ 38, 48 ], [ 53, 62 ] ] }, { "pmid": "12513698", "text": "Agonist efficacy was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production.", "type": "CHEMICAL", "entities": [ "forskolin", "cAMP" ], "offsets": [ [ 73, 82 ], [ 94, 98 ] ] }, { "pmid": "12513698", "text": "The rank order of efficacy of the agonists was fentanyl = hydromorphone = beta-endorphin > etorphine = lofentanil = butorphanol = morphine", "type": "CHEMICAL", "entities": [ "fentanyl", "hydromorphone", "etorphine", "lofentanil", "butorphanol", "morphine" ], "offsets": [ [ 47, 55 ], [ 58, 71 ], [ 91, 100 ], [ 103, 113 ], [ 116, 127 ], [ 130, 138 ] ] }, { "pmid": "12513698", "text": "= nalbuphine = nalorphine > cyclazocine = dezocine = metazocine >or= xorphanol.", "type": "CHEMICAL", "entities": [ "nalbuphine", "nalorphine", "cyclazocine", "dezocine", "metazocine", "xorphanol" ], "offsets": [ [ 2, 12 ], [ 15, 25 ], [ 28, 39 ], [ 42, 50 ], [ 53, 63 ], [ 69, 78 ] ] }, { "pmid": "12513698", "text": "The rank order of potency of these ligands was different from that of their efficacies; etorphine > hydromorphone > dezocine > xorphanol = nalorphine = butorphanol = lofentanil > metazocine >", "type": "CHEMICAL", "entities": [ "etorphine", "hydromorphone", "dezocine", "xorphanol", "nalorphine", "butorphanol", "lofentanil", "metazocine" ], "offsets": [ [ 88, 97 ], [ 100, 113 ], [ 116, 124 ], [ 127, 136 ], [ 139, 149 ], [ 152, 163 ], [ 166, 176 ], [ 179, 189 ] ] }, { "pmid": "12513698", "text": "nalbuphine > cyclazocine > fentanyl > morphine >>>> beta-endorphin.", "type": "CHEMICAL", "entities": [ "cyclazocine", "fentanyl", "morphine", "nalbuphine" ], "offsets": [ [ 13, 24 ], [ 27, 35 ], [ 38, 46 ], [ 0, 10 ] ] }, { "pmid": "12604879", "text": "Ventricular tachyarrhythmias in a canine model of LQT3: arrhythmogenic effects of sympathetic activity and therapeutic effects of mexiletine.\n", "type": "CHEMICAL", "entities": [ "mexiletine" ], "offsets": [ [ 130, 140 ] ] }, { "pmid": "12604879", "text": "The VSP was performed 8 times before and 5 times after administration of mexiletine in each experiment.", "type": "CHEMICAL", "entities": [ "mexiletine" ], "offsets": [ [ 73, 83 ] ] }, { "pmid": "12604879", "text": "Before mexiletine, vagal stimulation slowed the heart rate and created large transmural ARI dispersion because of a greater ARI prolongation at Mid rather than Epi/Endo sites.", "type": "CHEMICAL", "entities": [ "mexiletine" ], "offsets": [ [ 7, 17 ] ] }, { "pmid": "12604879", "text": "Mexiletine attenuated transmural ARI dispersion, and neither ARI alternans nor ventricular tachyarrhythmias was observed during all 35 trials of the VSP after mexiletine administration.", "type": "CHEMICAL", "entities": [ "Mexiletine", "mexiletine" ], "offsets": [ [ 0, 10 ], [ 159, 169 ] ] }, { "pmid": "12604879", "text": "Mexiletine homogenizes ventricular repolarization, suppresses premature complexes and was antiarrhythmic during ventricular tachyarrhythmias induced by the VSP.", "type": "CHEMICAL", "entities": [ "Mexiletine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "12636181", "text": "Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels.", "type": "CHEMICAL", "entities": [ "acetylcholine", "ACh" ], "offsets": [ [ 150, 163 ], [ 165, 168 ] ] }, { "pmid": "12636181", "text": "Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias.", "type": "CHEMICAL", "entities": [ "cymserine", "MF-8622", "rivastigmine" ], "offsets": [ [ 82, 91 ], [ 103, 110 ], [ 159, 171 ] ] }, { "pmid": "12636181", "text": "The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options.", "type": "CHEMICAL", "entities": [ "rivastigmine" ], "offsets": [ [ 99, 111 ] ] }, { "pmid": "12710892", "text": "A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess cyclin D1 levels.\n", "type": "CHEMICAL", "entities": [ "eicosapentaenoic acid" ], "offsets": [ [ 41, 62 ] ] }, { "pmid": "12710892", "text": "Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab.", "type": "CHEMICAL", "entities": [ "prednisone", "cyclophosphamide", "doxorubicin", "vincristine" ], "offsets": [ [ 148, 158 ], [ 101, 117 ], [ 119, 130 ], [ 132, 143 ] ] }, { "pmid": "12710892", "text": "Agents which have recently been shown to block cyclin D1 translation by regulating calcium levels are the unsaturated essential fatty acid, eicosapentaenoic acid (EPA), the antidiabetic thiazolidinediones, and the antifungal agent, clotrimazole.", "type": "CHEMICAL", "entities": [ "unsaturated essential fatty acid", "eicosapentaenoic acid", "EPA", "thiazolidinediones", "clotrimazole" ], "offsets": [ [ 106, 138 ], [ 140, 161 ], [ 163, 166 ], [ 186, 204 ], [ 232, 244 ] ] }, { "pmid": "12710892", "text": "Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2).", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 84, 95 ] ] }, { "pmid": "12710892", "text": "Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis.", "type": "CHEMICAL", "entities": [ "Retinoids", "EPA" ], "offsets": [ [ 0, 9 ], [ 41, 44 ] ] }, { "pmid": "12719755", "text": "Angiotensin AT1 receptor antagonist losartan and the defence reaction in the anaesthetised rat.", "type": "CHEMICAL", "entities": [ "Angiotensin", "losartan" ], "offsets": [ [ 0, 11 ], [ 36, 44 ] ] }, { "pmid": "12719755", "text": "Angiotensin II acting on angiotensin AT1 receptors at the central nervous system appears to have an important role in these modulatory processes.", "type": "CHEMICAL", "entities": [ "Angiotensin II", "angiotensin" ], "offsets": [ [ 0, 14 ], [ 25, 36 ] ] }, { "pmid": "12719755", "text": "The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 90, 104 ] ] }, { "pmid": "12719755", "text": "We investigated the effect of AT1 receptor blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent pancuronium bromide.", "type": "CHEMICAL", "entities": [ "pancuronium bromide" ], "offsets": [ [ 169, 188 ] ] }, { "pmid": "12720300", "text": "Defective processing of the transforming growth factor-beta1 in azoxymethane-induced mouse colon tumors.\n", "type": "CHEMICAL", "entities": [ "azoxymethane" ], "offsets": [ [ 64, 76 ] ] }, { "pmid": "12720300", "text": "To determine the expression and activation status of TGF-beta1 in chemically induced tumors, 6-wk-old A/J mice were injected intraperitoneally with either azoxymethane (AOM) (10 mg/kg body weight, once a week for 6 wk) or normal saline solution, and colon tumors were isolated 24 wk following the last injection.", "type": "CHEMICAL", "entities": [ "azoxymethane", "AOM" ], "offsets": [ [ 155, 167 ], [ 169, 172 ] ] }, { "pmid": "12720300", "text": "With a fluorogenic peptide substrate for serine proteases, a deficiency in plasmin activity was found in the tumors.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 41, 47 ] ] }, { "pmid": "12720300", "text": "To gain further insight into the functionality of the TGF-beta1 pathway, cDNA microarrays were performed and the expression levels of a panel of 21 TGF-beta1-specific target genes were determined in AOM-induced tumors that overexpress the ligand.", "type": "CHEMICAL", "entities": [ "AOM" ], "offsets": [ [ 199, 202 ] ] }, { "pmid": "12842269", "text": "Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors.\n", "type": "CHEMICAL", "entities": [ "GTPgammaS" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "12842269", "text": "Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain.", "type": "CHEMICAL", "entities": [ "[35S]-GTPgammaS", "GTPgammaS" ], "offsets": [ [ 131, 146 ], [ 29, 38 ] ] }, { "pmid": "12842269", "text": "Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor.", "type": "CHEMICAL", "entities": [ "[35S]-GTPgammaS", "125I" ], "offsets": [ [ 29, 44 ], [ 97, 101 ] ] }, { "pmid": "12842269", "text": "Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone.", "type": "CHEMICAL", "entities": [ "C", "[35S]-GTPgammaS", "naloxone" ], "offsets": [ [ 48, 49 ], [ 95, 110 ], [ 196, 204 ] ] }, { "pmid": "12842269", "text": "Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor.", "type": "CHEMICAL", "entities": [ "[35S]-GTPgammaS" ], "offsets": [ [ 181, 196 ] ] }, { "pmid": "12852767", "text": "Tethered dimers as NAD synthetase inhibitors with antibacterial activity.\n", "type": "CHEMICAL", "entities": [ "NAD" ], "offsets": [ [ 19, 22 ] ] }, { "pmid": "12852767", "text": "The solution-phase parallel synthesis of tethered dimers was employed to identify lead inhibitors of bacterial NAD synthetase.", "type": "CHEMICAL", "entities": [ "NAD" ], "offsets": [ [ 111, 114 ] ] }, { "pmid": "12852767", "text": "Effective inhibitors of NAD synthetase also inhibited the growth of Gram-positive (but not Gram-negative) bacteria, including antibiotic-resistant strains.", "type": "CHEMICAL", "entities": [ "NAD" ], "offsets": [ [ 24, 27 ] ] }, { "pmid": "12852767", "text": "Similarly, a close structural analogue of the most active inhibitors contained two additional ether oxygens in the tether and was inactive in both assays.", "type": "CHEMICAL", "entities": [ "oxygens" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "12852767", "text": "These results are consistent with the premise that NAD synthetase inhibition is responsible for the antibacterial actions and support further studies on NAD synthetase as a new target for antibacterial agents.", "type": "CHEMICAL", "entities": [ "NAD", "NAD" ], "offsets": [ [ 51, 54 ], [ 153, 156 ] ] }, { "pmid": "12897749", "text": "Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils.\n", "type": "CHEMICAL", "entities": [ "PDE4", "LTC4", "salmeterol" ], "offsets": [ [ 111, 115 ], [ 12, 16 ], [ 96, 106 ] ] }, { "pmid": "12897749", "text": "However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells.", "type": "CHEMICAL", "entities": [ "cAMP", "PDE4" ], "offsets": [ [ 38, 42 ], [ 52, 56 ] ] }, { "pmid": "12897749", "text": "We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)).", "type": "CHEMICAL", "entities": [ "PDE4" ], "offsets": [ [ 41, 45 ] ] }, { "pmid": "12897749", "text": "To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP.", "type": "CHEMICAL", "entities": [ "cAMP", "PDE4", "rolipram", "arachidonic acid", "AA", "leukotriene C(4)", "LTC(4)", "AA", "formyl-met-leu-phe", "cytochalasin B", "PDE4", "LTC(4)", "cAMP" ], "offsets": [ [ 332, 336 ], [ 25, 29 ], [ 52, 60 ], [ 83, 99 ], [ 101, 103 ], [ 109, 125 ], [ 127, 133 ], [ 419, 421 ], [ 176, 194 ], [ 200, 214 ], [ 245, 249 ], [ 426, 432 ], [ 459, 463 ] ] }, { "pmid": "12897749", "text": "Human eosinophils were pretreated with buffer, salmeterol or rolipram (singly or combination) before FMLP/B activation.", "type": "CHEMICAL", "entities": [ "salmeterol", "rolipram" ], "offsets": [ [ 47, 57 ], [ 61, 69 ] ] }, { "pmid": "12897749", "text": "Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined.", "type": "CHEMICAL", "entities": [ "AA", "LTC(4)", "cAMP" ], "offsets": [ [ 11, 13 ], [ 18, 24 ], [ 40, 44 ] ] }, { "pmid": "12897749", "text": "Rolipram unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4).", "type": "CHEMICAL", "entities": [ "Rolipram", "salmeterol", "AA", "LTC(4)" ], "offsets": [ [ 0, 8 ], [ 81, 91 ], [ 147, 149 ], [ 165, 171 ] ] }, { "pmid": "12897749", "text": "Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils.", "type": "CHEMICAL", "entities": [ "cAMP", "rolipram", "rolipram", "salmeterol" ], "offsets": [ [ 37, 41 ], [ 63, 71 ], [ 81, 89 ], [ 95, 105 ] ] }, { "pmid": "12897749", "text": "CONCLUSIONS: Inhibition of PDE4 by rolipram unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B.", "type": "CHEMICAL", "entities": [ "PDE4", "rolipram", "LTC(4)" ], "offsets": [ [ 27, 31 ], [ 35, 43 ], [ 83, 89 ] ] }, { "pmid": "12942109", "text": "A phase 1 study of tazarotene in adults with advanced cancer.\n", "type": "CHEMICAL", "entities": [ "tazarotene" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "12942109", "text": "Tazarotene is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and RARgamma.", "type": "CHEMICAL", "entities": [ "tazarotenic acid", "Tazarotene", "retinoid", "acetylenic retinoid" ], "offsets": [ [ 61, 77 ], [ 0, 10 ], [ 113, 121 ], [ 17, 36 ] ] }, { "pmid": "12942109", "text": "The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer.", "type": "CHEMICAL", "entities": [ "tazarotene" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "12942109", "text": "The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1).", "type": "CHEMICAL", "entities": [ "tazarotene" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "12942109", "text": "Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly.", "type": "CHEMICAL", "entities": [ "tazarotenic acid" ], "offsets": [ [ 25, 41 ] ] }, { "pmid": "12942109", "text": "No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)).", "type": "CHEMICAL", "entities": [ "tazarotene" ], "offsets": [ [ 149, 159 ] ] }, { "pmid": "12942109", "text": "We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.", "type": "CHEMICAL", "entities": [ "tazarotene", "retinoids" ], "offsets": [ [ 22, 32 ], [ 143, 152 ] ] }, { "pmid": "1322047", "text": "Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation.\n", "type": "CHEMICAL", "entities": [ "clenbuterol" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "1322047", "text": "The potent anabolic effects of the beta 2-adrenoceptor agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors.", "type": "CHEMICAL", "entities": [ "clenbuterol" ], "offsets": [ [ 63, 74 ] ] }, { "pmid": "1322047", "text": "In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass.", "type": "CHEMICAL", "entities": [ "clenbuterol" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "1322047", "text": "These effects were not mimicked by oral administration of the beta 2-adrenoceptor agonist salbutamol even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of DL-propranolol (200 mg/kg diet).", "type": "CHEMICAL", "entities": [ "salbutamol", "clenbuterol", "DL-propranolol" ], "offsets": [ [ 90, 100 ], [ 155, 166 ], [ 201, 215 ] ] }, { "pmid": "1322047", "text": "However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of clenbuterol.", "type": "CHEMICAL", "entities": [ "clenbuterol", "ICI-118,551", "clenbuterol", "DL-propranolol" ], "offsets": [ [ 201, 212 ], [ 41, 52 ], [ 103, 114 ], [ 135, 149 ] ] }, { "pmid": "1322047", "text": "Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content.", "type": "CHEMICAL", "entities": [ "salbutamol" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "1322047", "text": "These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the beta 2-adrenoceptor.", "type": "CHEMICAL", "entities": [ "clenbuterol" ], "offsets": [ [ 52, 63 ] ] }, { "pmid": "1356794", "text": "In the hot-plate test in mice, the antinociceptive action of the alpha 2-adrenoceptor agonist, UK 14,304, was abolished by the alpha 2-adrenoceptor antagonist, idazoxan, the potent alpha 2A-adrenoceptor antagonist, RX 821002 and the preferential alpha 2A-adrenoceptor antagonist, BRL 44408.", "type": "CHEMICAL", "entities": [ "UK 14,304", "idazoxan", "RX 821002", "BRL 44408" ], "offsets": [ [ 95, 104 ], [ 160, 168 ], [ 215, 224 ], [ 280, 289 ] ] }, { "pmid": "1356794", "text": "In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive.", "type": "CHEMICAL", "entities": [ "ARC-239", "BRL 41992", "prazosin" ], "offsets": [ [ 93, 100 ], [ 102, 111 ], [ 116, 124 ] ] }, { "pmid": "1356794", "text": "The preferential alpha 2A-adrenoceptor partial agonist, guanfacine, partially inhibited UK 14,304-induced antinociception.", "type": "CHEMICAL", "entities": [ "guanfacine", "UK 14,304" ], "offsets": [ [ 56, 66 ], [ 88, 97 ] ] }, { "pmid": "1356794", "text": "Further, guanfacine BRL 44408 reversibly elicited submaximal antinociception.", "type": "CHEMICAL", "entities": [ "BRL 44408", "guanfacine" ], "offsets": [ [ 20, 29 ], [ 9, 19 ] ] }, { "pmid": "14596599", "text": "Crystal structure of serine dehydratase from rat liver.\n", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 21, 27 ] ] }, { "pmid": "14596599", "text": "SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia.", "type": "CHEMICAL", "entities": [ "L-serine", "L-serine", "pyridoxal 5'-phosphate", "pyruvate", "PLP", "ammonia" ], "offsets": [ [ 108, 116 ], [ 5, 13 ], [ 54, 76 ], [ 126, 134 ], [ 78, 81 ], [ 139, 146 ] ] }, { "pmid": "14596599", "text": "Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate.", "type": "CHEMICAL", "entities": [ "pyruvate", "hydroxyl", "serine", "aminoacrylate", "aminoacrylate", "pyruvate" ], "offsets": [ [ 13, 21 ], [ 65, 73 ], [ 83, 89 ], [ 112, 125 ], [ 140, 153 ], [ 206, 214 ] ] }, { "pmid": "14596599", "text": "The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement.", "type": "CHEMICAL", "entities": [ "O-methylserine", "OMS" ], "offsets": [ [ 31, 45 ], [ 47, 50 ] ] }, { "pmid": "14596599", "text": "The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur.", "type": "CHEMICAL", "entities": [ "aldimine", "OMS", "Schiff base", "PLP" ], "offsets": [ [ 31, 39 ], [ 76, 79 ], [ 93, 104 ], [ 118, 121 ] ] }, { "pmid": "14596599", "text": "The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated.", "type": "CHEMICAL", "entities": [ "PLP", "GGGGL", "hydrogen", "amide", "amino acid", "phosphate" ], "offsets": [ [ 23, 26 ], [ 83, 88 ], [ 105, 113 ], [ 129, 134 ], [ 151, 161 ], [ 192, 201 ] ] }, { "pmid": "14596599", "text": "N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes.", "type": "CHEMICAL", "entities": [ "PLP", "hydrogen", "hydrogen" ], "offsets": [ [ 8, 11 ], [ 30, 38 ], [ 69, 77 ] ] }, { "pmid": "14596599", "text": "These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure.", "type": "CHEMICAL", "entities": [ "hydrogen", "pyridine", "quinone" ], "offsets": [ [ 6, 14 ], [ 83, 91 ], [ 111, 118 ] ] }, { "pmid": "14596599", "text": "These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases.", "type": "CHEMICAL", "entities": [ "PLP", "PLP-Ser aldimine" ], "offsets": [ [ 35, 38 ], [ 138, 154 ] ] }, { "pmid": "14596599", "text": "A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine.", "type": "CHEMICAL", "entities": [ "phosphate", "hydroxyl", "serine" ], "offsets": [ [ 44, 53 ], [ 163, 171 ], [ 181, 187 ] ] }, { "pmid": "14633707", "text": "Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 189, 209 ] ] }, { "pmid": "14633707", "text": "Blocking EGFR signaling with the EGFR/HER-2 kinase inhibitor (KI) GW572016 decreased the postradiation survival of irradiated Ras-transformed cells and normal cells but had no effect on the survival of unirradiated cells.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "14633707", "text": "Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by GW572016.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 141, 149 ] ] }, { "pmid": "14633707", "text": "Thus, Ras utilizes autocrine signaling through EGFR to increase radioresistance, and the EGFR KI GW572016 acts as a radiosensitizer.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 97, 105 ] ] }, { "pmid": "14633707", "text": "The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with GW572016 demonstrates that EGFR KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through EGFR.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 99, 107 ] ] }, { "pmid": "14660028", "text": "(-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations.", "type": "CHEMICAL", "entities": [ "(-)-Isoprenaline", "(+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride", "(+/-)-CGP12177A", "(-)-phenylephrine" ], "offsets": [ [ 0, 16 ], [ 69, 175 ], [ 177, 192 ], [ 241, 258 ] ] }, { "pmid": "14660028", "text": "Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors.", "type": "CHEMICAL", "entities": [ "(+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate", "CGP20712A", "(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride", "ICI-118,5511", "(-)-isoprenaline", "(+/-)-CGP12177A" ], "offsets": [ [ 35, 176 ], [ 178, 187 ], [ 238, 337 ], [ 339, 351 ], [ 495, 511 ], [ 552, 567 ] ] }, { "pmid": "14660028", "text": "In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM).", "type": "CHEMICAL", "entities": [ "CGP20712A", "ICI-118,551", "(-)-isoprenaline", "(+/-)-CGP12177A", "(+/-)-bupranolol" ], "offsets": [ [ 19, 28 ], [ 33, 44 ], [ 106, 122 ], [ 127, 142 ], [ 243, 259 ] ] }, { "pmid": "14716684", "text": "Use of the norepinephrine transporter as a reporter gene for non-invasive imaging of genetically modified cells.\n", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 11, 25 ] ] }, { "pmid": "14716684", "text": "The norepinephrine transporter (NET) is a high-affinity transporter for catecholamines.", "type": "CHEMICAL", "entities": [ "norepinephrine", "catecholamines" ], "offsets": [ [ 4, 18 ], [ 72, 86 ] ] }, { "pmid": "14716684", "text": "Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG).", "type": "CHEMICAL", "entities": [ "[(131)I]meta-iodobenzylguanidine", "[(131)I]MIBG" ], "offsets": [ [ 59, 91 ], [ 93, 105 ] ] }, { "pmid": "14716684", "text": "The specificity of tracer uptake was determined by adding the NET inhibitor imipramine.", "type": "CHEMICAL", "entities": [ "imipramine" ], "offsets": [ [ 76, 86 ] ] }, { "pmid": "14716684", "text": "Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of [(123)I]MIBG in vivo was determined after tracer administration.", "type": "CHEMICAL", "entities": [ "[(123)I]MIBG" ], "offsets": [ [ 84, 96 ] ] }, { "pmid": "14716684", "text": "In vitro stably transduced cells showed a 66- to 120-fold higher [(131)I]MIBG uptake than parental cells.", "type": "CHEMICAL", "entities": [ "[(131)I]MIBG" ], "offsets": [ [ 65, 77 ] ] }, { "pmid": "14716684", "text": "Incubation with imipramine reduced [(131)I]MIBG uptake of transduced cells to the level found in parental cells.", "type": "CHEMICAL", "entities": [ "imipramine", "[(131)I]MIBG" ], "offsets": [ [ 16, 26 ], [ 35, 47 ] ] }, { "pmid": "14716684", "text": "[(131)I]MIBG uptake in PC12 cells, which express the NET endogenously, was 20- to 28-fold lower than in transduced cells.", "type": "CHEMICAL", "entities": [ "[(131)I]MIBG" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "14716684", "text": "In vivo, A431NET tumors demonstrated a 33-fold higher [(123)I]MIBG uptake than parental tumors.", "type": "CHEMICAL", "entities": [ "[(123)I]MIBG" ], "offsets": [ [ 54, 66 ] ] }, { "pmid": "14716684", "text": "CONCLUSIONS: Transduction of tumor cells with NET cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "catecholamine" ], "offsets": [ [ 114, 127 ] ] }, { "pmid": "14730417", "text": "The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of human beta-adrenergic receptors in an identical cellular background.", "type": "CHEMICAL", "entities": [ "formoterol", "broxaterol", "propranolol", "alprenolol", "atenolol", "metoprolol", "bisoprolol", "carvedilol", "pindolol", "BRL 37344", "CGP 20712", "SR 59230A", "CGP 12177", "ICI 118551", "epinephrine", "norepinephrine", "isoproterenol", "fenoterol", "salbutamol", "salmeterol", "terbutalin" ], "offsets": [ [ 189, 199 ], [ 201, 211 ], [ 230, 241 ], [ 243, 253 ], [ 255, 263 ], [ 265, 275 ], [ 277, 287 ], [ 289, 299 ], [ 301, 309 ], [ 311, 320 ], [ 322, 331 ], [ 333, 342 ], [ 344, 353 ], [ 355, 365 ], [ 98, 109 ], [ 111, 125 ], [ 127, 140 ], [ 142, 151 ], [ 153, 163 ], [ 165, 175 ], [ 177, 187 ] ] }, { "pmid": "14730417", "text": "We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand.", "type": "CHEMICAL", "entities": [ "125I-cyanopindolol" ], "offsets": [ [ 192, 210 ] ] }, { "pmid": "14730417", "text": "Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines.", "type": "CHEMICAL", "entities": [ "adenylyl" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "14733708", "text": "Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells.\n", "type": "CHEMICAL", "entities": [ "PG", "prostaglandin", "PG", "PG" ], "offsets": [ [ 146, 148 ], [ 22, 35 ], [ 37, 39 ], [ 50, 52 ] ] }, { "pmid": "14733708", "text": "Natural prostaglandins (PGs) such as PGD2, PGE2, PGF2(2alpha), and PGI2 exhibited the highest affinity for their respective cognate receptors, but were the least selective agents when tested in receptor binding assays.", "type": "CHEMICAL", "entities": [ "PGs", "PGD2", "PGE2", "PGF2(2alpha)", "PGI2", "prostaglandins" ], "offsets": [ [ 24, 27 ], [ 37, 41 ], [ 43, 47 ], [ 49, 61 ], [ 67, 71 ], [ 8, 22 ] ] }, { "pmid": "14733708", "text": "Travoprost acid ([+]-fluprostenol) was the most FP-receptor-selective compound, exhibiting a high affinity (Ki = 35 +/- 5 nM) for the FP receptor, and minimal affinity for DP (Ki = 52,000 nM), EP1 (Ki = 9540 nM), EP3 (Ki = 3501 nM), EP4 (Ki = 41,000 nM), IP (Ki > 90,000 nM), and TP (Ki = 121,000 nM) receptors.", "type": "CHEMICAL", "entities": [ "Travoprost acid", "[+]-fluprostenol" ], "offsets": [ [ 0, 15 ], [ 17, 33 ] ] }, { "pmid": "14733708", "text": "Travoprost acid was the most potent PG analog tested in FP receptor functional phosphoinositide turnover assays in the following cell types: human ciliary muscle (EC50 = 1.4 nM), human trabecular meshwork (EC50 = 3.6 nM), and mouse fibroblasts and rat aortic smooth muscle cells (EC50 = 2.6 nM).", "type": "CHEMICAL", "entities": [ "Travoprost acid", "PG", "phosphoinositide" ], "offsets": [ [ 0, 15 ], [ 36, 38 ], [ 79, 95 ] ] }, { "pmid": "14733708", "text": "Although latanoprost acid exhibited a relatively high affinity for the FP receptor (Ki = 98 nM), it had significant functional activity at FP (EC50 = 32-124 nM) and EP1 (EC50 = 119 nM) receptors.", "type": "CHEMICAL", "entities": [ "latanoprost acid" ], "offsets": [ [ 9, 25 ] ] }, { "pmid": "14733708", "text": "Bimatoprost acid was less selective, exhibiting a relatively high affinity for the FP (Ki = 83 nM), EP1 (Ki = 95 nM), and EP3 (Ki = 387 nM) receptors.", "type": "CHEMICAL", "entities": [ "Bimatoprost acid" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "14733708", "text": "Bimatoprost acid exhibited functional activity at the EP1 (EC50 = 2.7 nM) and FP (EC50 = 2.8-3.8 nM in most cells) receptors.", "type": "CHEMICAL", "entities": [ "Bimatoprost acid" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "14733708", "text": "Bimatoprost (nonhydrolyzed amide) also behaved as an FP agonist at the cloned human FP receptor (EC50 = 681 nM), in h-TM (EC50 = 3245 nM) and other cell types.", "type": "CHEMICAL", "entities": [ "Bimatoprost" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "14733708", "text": "Unoprostone and S-1033 bound with low affinity (Ki = 5.9 microM to > 22 microM) to the FP receptor, were not selective, but activated the FP receptor.", "type": "CHEMICAL", "entities": [ "Unoprostone", "S-1033" ], "offsets": [ [ 0, 11 ], [ 16, 22 ] ] }, { "pmid": "14733708", "text": "In conclusion, travoprost acid has the highest affinity, the highest FP-receptor-selectivity, and the highest potency at the FP receptor as compared to the other ocular hypotensive PG analogs known so far, including free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester.", "type": "CHEMICAL", "entities": [ "travoprost acid", "free acids of latanoprost, bimatoprost, and unoprostone isopropyl ester" ], "offsets": [ [ 15, 30 ], [ 216, 287 ] ] }, { "pmid": "14734046", "text": "Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger.\nIncreased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart.", "type": "CHEMICAL", "entities": [ "Na+", "Ca(2+)", "Na+", "Ca(2+)" ], "offsets": [ [ 98, 101 ], [ 102, 108 ], [ 66, 69 ], [ 70, 76 ] ] }, { "pmid": "14734046", "text": "Responses to isoproterenol were largely mediated through the beta1AR in control myocytes.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 13, 26 ] ] }, { "pmid": "14734046", "text": "Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the isoproterenol concentration-response curve.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 130, 143 ] ] }, { "pmid": "14734046", "text": "Responses to isoproterenol could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 13, 26 ] ] }, { "pmid": "14734046", "text": "Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that beta2AR effects were mediated by Gi.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 27, 40 ] ] }, { "pmid": "14741265", "text": "Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors.\n", "type": "CHEMICAL", "entities": [ "2-aryl propionic acid" ], "offsets": [ [ 36, 57 ] ] }, { "pmid": "14741265", "text": "The nonsteroidal anti-inflammatory drugs flurbiprofen and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by COX-1.", "type": "CHEMICAL", "entities": [ "flurbiprofen", "ibuprofen" ], "offsets": [ [ 41, 53 ], [ 58, 67 ] ] }, { "pmid": "14741265", "text": "Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior.", "type": "CHEMICAL", "entities": [ "halogen" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "14741265", "text": "Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state.", "type": "CHEMICAL", "entities": [ "carboxylate", "flurbiprofen", "ester", "amide" ], "offsets": [ [ 18, 29 ], [ 40, 52 ], [ 59, 64 ], [ 68, 73 ] ] }, { "pmid": "14751502", "text": "Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance.\n", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 42, 50 ] ] }, { "pmid": "14751502", "text": "To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 185, 193 ] ] }, { "pmid": "14751502", "text": "Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 187, 195 ] ] }, { "pmid": "14751502", "text": "GW572016 inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line.", "type": "CHEMICAL", "entities": [ "tyrosine", "GW572016" ], "offsets": [ [ 67, 75 ], [ 0, 8 ] ] }, { "pmid": "14751502", "text": "GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization.", "type": "CHEMICAL", "entities": [ "GW572016", "GW572016" ], "offsets": [ [ 0, 8 ], [ 140, 148 ] ] }, { "pmid": "14751502", "text": "One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 85, 93 ] ] }, { "pmid": "14751502", "text": "Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 86, 94 ] ] }, { "pmid": "14751502", "text": "GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "14751502", "text": "Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation.", "type": "CHEMICAL", "entities": [ "GW572016" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "14753499", "text": "+/- 0.04 microl/min (control), 0.16 +/- 0.03 microl/min (acetazolamide-treated) and 1.14 +/- 0.15 microl/min (forskolin-treated), and reduced by up to 25% in AQP1 null mice.", "type": "CHEMICAL", "entities": [ "acetazolamide", "forskolin" ], "offsets": [ [ 57, 70 ], [ 110, 119 ] ] }, { "pmid": "14871885", "text": "Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion.\n", "type": "CHEMICAL", "entities": [ "Metformin", "AMP", "glucose" ], "offsets": [ [ 0, 9 ], [ 37, 40 ], [ 98, 105 ] ] }, { "pmid": "14871885", "text": "Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK).", "type": "CHEMICAL", "entities": [ "Metformin", "AMP" ], "offsets": [ [ 0, 9 ], [ 161, 164 ] ] }, { "pmid": "14871885", "text": "Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "14871885", "text": "Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets.", "type": "CHEMICAL", "entities": [ "glucose", "metformin" ], "offsets": [ [ 28, 35 ], [ 37, 46 ] ] }, { "pmid": "14871885", "text": "Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 13, 20 ] ] }, { "pmid": "14871885", "text": "Incubation with metformin (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "14871885", "text": "These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal beta-cells.", "type": "CHEMICAL", "entities": [ "glucose", "metformin" ], "offsets": [ [ 78, 85 ], [ 90, 99 ] ] }, { "pmid": "14871885", "text": "The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "14993281", "text": "A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression.\n", "type": "CHEMICAL", "entities": [ "retinoic acid", "retinoic acid" ], "offsets": [ [ 51, 64 ], [ 8, 21 ] ] }, { "pmid": "14993281", "text": "The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy.", "type": "CHEMICAL", "entities": [ "retinoic acid", "RA" ], "offsets": [ [ 27, 40 ], [ 42, 44 ] ] }, { "pmid": "14993281", "text": "RA is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by RA.", "type": "CHEMICAL", "entities": [ "RA", "RA", "RA" ], "offsets": [ [ 273, 275 ], [ 0, 2 ], [ 96, 98 ] ] }, { "pmid": "14993281", "text": "The RA-treated HL-60 cells used here expressed all RA receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma.", "type": "CHEMICAL", "entities": [ "RA", "RA", "retinoid" ], "offsets": [ [ 4, 6 ], [ 51, 53 ], [ 73, 81 ] ] }, { "pmid": "14993281", "text": "A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by RA.", "type": "CHEMICAL", "entities": [ "RA", "RA" ], "offsets": [ [ 43, 45 ], [ 199, 201 ] ] }, { "pmid": "14993281", "text": "Within this sequence DNase I footprinting revealed that RA induced binding of a nuclear protein complex to an element containing two GT boxes.", "type": "CHEMICAL", "entities": [ "RA" ], "offsets": [ [ 56, 58 ] ] }, { "pmid": "14993281", "text": "Without RA there was neither complex binding nor transcriptional activation.", "type": "CHEMICAL", "entities": [ "RA" ], "offsets": [ [ 8, 10 ] ] }, { "pmid": "14993281", "text": "Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by RA.", "type": "CHEMICAL", "entities": [ "RA" ], "offsets": [ [ 130, 132 ] ] }, { "pmid": "14993281", "text": "The ability of this cis-acting RAR-RXR binding element to activate transcription in response to RA also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary.", "type": "CHEMICAL", "entities": [ "RA", "cyclic AMP" ], "offsets": [ [ 96, 98 ], [ 309, 319 ] ] }, { "pmid": "14993281", "text": "A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex.", "type": "CHEMICAL", "entities": [ "RA" ], "offsets": [ [ 90, 92 ] ] }, { "pmid": "14993281", "text": "RA upregulated expression of these three factors.", "type": "CHEMICAL", "entities": [ "RA" ], "offsets": [ [ 0, 2 ] ] }, { "pmid": "14993281", "text": "In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel RA response element.", "type": "CHEMICAL", "entities": [ "RA", "RA" ], "offsets": [ [ 114, 116 ], [ 54, 56 ] ] }, { "pmid": "15002740", "text": "The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function.\n", "type": "CHEMICAL", "entities": [ "desipramine", "norepinephrine" ], "offsets": [ [ 37, 48 ], [ 78, 92 ] ] }, { "pmid": "15002740", "text": "The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake.", "type": "CHEMICAL", "entities": [ "DMI", "DMI", "[3H]NE", "desipramine" ], "offsets": [ [ 76, 79 ], [ 122, 125 ], [ 145, 151 ], [ 63, 74 ] ] }, { "pmid": "15002740", "text": "Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium.", "type": "CHEMICAL", "entities": [ "DMI", "[3H]NE" ], "offsets": [ [ 32, 35 ], [ 90, 96 ] ] }, { "pmid": "15002740", "text": "Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI.", "type": "CHEMICAL", "entities": [ "DMI", "[3H]DMI" ], "offsets": [ [ 60, 63 ], [ 146, 153 ] ] }, { "pmid": "15002740", "text": "[3H]DMI trapped in membranes was displaceable by the structurally unrelated NET inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the NET.", "type": "CHEMICAL", "entities": [ "[3H]DMI", "[3H]DMI", "nisoxetine" ], "offsets": [ [ 173, 180 ], [ 0, 7 ], [ 91, 101 ] ] }, { "pmid": "15002740", "text": "A similar cellular retention was observed following incubation of cells with nisoxetine.", "type": "CHEMICAL", "entities": [ "nisoxetine" ], "offsets": [ [ 77, 87 ] ] }, { "pmid": "15002740", "text": "The results demonstrate that DMI and nisoxetine are persistently retained in cell membranes, at least partly in association with the NET.", "type": "CHEMICAL", "entities": [ "DMI", "nisoxetine" ], "offsets": [ [ 29, 32 ], [ 37, 47 ] ] }, { "pmid": "15002740", "text": "The retention and slow diffusion of DMI and nisoxetine from membranes may contribute to their pharmacological and modulatory action on NET.", "type": "CHEMICAL", "entities": [ "DMI", "nisoxetine" ], "offsets": [ [ 36, 39 ], [ 44, 54 ] ] }, { "pmid": "15030294", "text": "AT1-receptor antagonism in hypertension: what has been learned with irbesartan?\n", "type": "CHEMICAL", "entities": [ "irbesartan" ], "offsets": [ [ 68, 78 ] ] }, { "pmid": "15030294", "text": "Irbesartan is a long-acting angiotensin II antagonist acting specifically at the level of the Type 1-receptor subtype (AT1-receptor).", "type": "CHEMICAL", "entities": [ "Irbesartan", "angiotensin II" ], "offsets": [ [ 0, 10 ], [ 28, 42 ] ] }, { "pmid": "15030294", "text": "The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available.", "type": "CHEMICAL", "entities": [ "irbesartan", "irbesartan", "hydrochlorothiazide" ], "offsets": [ [ 33, 43 ], [ 134, 144 ], [ 149, 168 ] ] }, { "pmid": "15030294", "text": "Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy.", "type": "CHEMICAL", "entities": [ "Irbesartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15030294", "text": "In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure.", "type": "CHEMICAL", "entities": [ "irbesartan" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "15030294", "text": "Irbesartan may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of angiotensin II.", "type": "CHEMICAL", "entities": [ "Irbesartan", "angiotensin II" ], "offsets": [ [ 0, 10 ], [ 240, 254 ] ] }, { "pmid": "15060759", "text": "Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers.\n", "type": "CHEMICAL", "entities": [ "(-)-[3H]-CGP12177" ], "offsets": [ [ 11, 28 ] ] }, { "pmid": "15060759", "text": "To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two beta(1)-adrenoceptor sites, human beta(1)-adrenoceptors, expressed in CHO cells, were labelled with (-)-[(3)H]-CGP12177.", "type": "CHEMICAL", "entities": [ "(-)-[(3)H]-CGP12177", "(-)-CGP12177" ], "offsets": [ [ 193, 212 ], [ 67, 79 ] ] }, { "pmid": "15060759", "text": "We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM).", "type": "CHEMICAL", "entities": [ "cyclic AMP", "(-)-isoprenaline", "(-)-CGP12177", "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 104, 114 ], [ 136, 152 ], [ 157, 169 ], [ 170, 189 ] ] }, { "pmid": "15060759", "text": "(-)-[(3)H]-CGP12177 dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site.", "type": "CHEMICAL", "entities": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 0, 19 ] ] }, { "pmid": "15060759", "text": "(-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6.", "type": "CHEMICAL", "entities": [ "(-)-Isoprenaline", "(-)-CGP12177", "cyclic AMP" ], "offsets": [ [ 0, 16 ], [ 21, 33 ], [ 82, 92 ] ] }, { "pmid": "15060759", "text": "(-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9.", "type": "CHEMICAL", "entities": [ "(-)-CGP12177", "(-)-isoprenaline" ], "offsets": [ [ 0, 12 ], [ 40, 56 ] ] }, { "pmid": "15060759", "text": "The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56.", "type": "CHEMICAL", "entities": [ "(+/-)-bisoprolol", "(+/-)-alprenolol", "(+/-)-nadolol", "(-)-bupranolol", "(-)-CGP12177", "(-)-atenolol", "(-)-isoprenaline", "(+/-)-metropolol", "(-)-pindolol", "(-)-timolol", "(+/-)-carvedilol", "(+/-)-oxprenolol", "(+/-)-sotalol", "(-)-propranolol" ], "offsets": [ [ 282, 298 ], [ 303, 319 ], [ 324, 337 ], [ 345, 359 ], [ 87, 99 ], [ 121, 133 ], [ 45, 61 ], [ 141, 157 ], [ 163, 175 ], [ 181, 192 ], [ 198, 214 ], [ 220, 236 ], [ 242, 255 ], [ 261, 276 ] ] }, { "pmid": "15060759", "text": "In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM (-)-[(3)H]-CGP12177 (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects.", "type": "CHEMICAL", "entities": [ "(-)-[(3)H]-CGP12177", "(-)-isoprenaline" ], "offsets": [ [ 95, 114 ], [ 218, 234 ] ] }, { "pmid": "15060759", "text": "We conclude that (-)-[(3)H]-CGP12177 binds at two sites in the recombinant beta(1)-adrenoceptor.", "type": "CHEMICAL", "entities": [ "(-)-[(3)H]-CGP12177" ], "offsets": [ [ 17, 36 ] ] }, { "pmid": "15060759", "text": "(-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site.", "type": "CHEMICAL", "entities": [ "(-)-CGP12177", "catecholamine" ], "offsets": [ [ 0, 12 ], [ 33, 46 ] ] }, { "pmid": "15072849", "text": "Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro.\n", "type": "CHEMICAL", "entities": [ "Imiquimod" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15072849", "text": "Imiquimod (IMQ), an activator of Toll-like receptor-7 (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo.", "type": "CHEMICAL", "entities": [ "Imiquimod", "IMQ" ], "offsets": [ [ 0, 9 ], [ 11, 14 ] ] }, { "pmid": "15072849", "text": "This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce perforin in CTLs in vitro.", "type": "CHEMICAL", "entities": [ "IMQ" ], "offsets": [ [ 91, 94 ] ] }, { "pmid": "15072849", "text": "In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed.", "type": "CHEMICAL", "entities": [ "IMQ" ], "offsets": [ [ 60, 63 ] ] }, { "pmid": "15072849", "text": "[corrected] IMQ.", "type": "CHEMICAL", "entities": [ "IMQ" ], "offsets": [ [ 12, 15 ] ] }, { "pmid": "15072849", "text": "Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ.", "type": "CHEMICAL", "entities": [ "IMQ" ], "offsets": [ [ 112, 115 ] ] }, { "pmid": "15072849", "text": "Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system.", "type": "CHEMICAL", "entities": [ "IMQ" ], "offsets": [ [ 33, 36 ] ] }, { "pmid": "15095008", "text": "Caffeine as a psychomotor stimulant: mechanism of action.\n", "type": "CHEMICAL", "entities": [ "Caffeine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15095008", "text": "The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain.", "type": "CHEMICAL", "entities": [ "adenosine", "caffeine" ], "offsets": [ [ 124, 133 ], [ 18, 26 ] ] }, { "pmid": "15095008", "text": "Adenosine A(1) and A(2A) receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control.", "type": "CHEMICAL", "entities": [ "Adenosine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15095008", "text": "Caffeine acts as an antagonist to both types of receptors.", "type": "CHEMICAL", "entities": [ "Caffeine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15095008", "text": "Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia.", "type": "CHEMICAL", "entities": [ "caffeine" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "15095008", "text": "These cells express high levels of adenosine A(2A) receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32.", "type": "CHEMICAL", "entities": [ "adenosine", "dopamine", "cyclic AMP" ], "offsets": [ [ 35, 44 ], [ 189, 197 ], [ 203, 213 ] ] }, { "pmid": "15095008", "text": "The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.", "type": "CHEMICAL", "entities": [ "caffeine", "caffeine" ], "offsets": [ [ 114, 122 ], [ 45, 53 ] ] }, { "pmid": "15133856", "text": "Mesenteric artery remodeling and effects of imidapril and irbesartan on it in spontaneously hypertensive rats.\n", "type": "CHEMICAL", "entities": [ "imidapril", "irbesartan" ], "offsets": [ [ 44, 53 ], [ 58, 68 ] ] }, { "pmid": "15133856", "text": "AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, c-Jun in mesenteric artery and effects of imidapril and irbesartan on the remodeling in spontaneously hypertensive rats (SHR).", "type": "CHEMICAL", "entities": [ "imidapril", "irbesartan" ], "offsets": [ [ 131, 140 ], [ 145, 155 ] ] }, { "pmid": "15133856", "text": "Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3", "type": "CHEMICAL", "entities": [ "imidapril", "imidapril" ], "offsets": [ [ 135, 144 ], [ 152, 161 ] ] }, { "pmid": "15133856", "text": "mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk).", "type": "CHEMICAL", "entities": [ "irbesartan", "irbesartan" ], "offsets": [ [ 52, 62 ], [ 70, 80 ] ] }, { "pmid": "15133856", "text": "Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay.", "type": "CHEMICAL", "entities": [ "Angiotensin II", "Ang II" ], "offsets": [ [ 0, 14 ], [ 16, 22 ] ] }, { "pmid": "15133856", "text": "Compared with imidapril group and irbesartan group, the blood pressure was remarkably increased in SHR group.", "type": "CHEMICAL", "entities": [ "imidapril", "irbesartan" ], "offsets": [ [ 14, 23 ], [ 34, 44 ] ] }, { "pmid": "15133856", "text": "Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in imidapril group.", "type": "CHEMICAL", "entities": [ "Ang II", "irbesartan", "imidapril" ], "offsets": [ [ 0, 6 ], [ 124, 134 ], [ 154, 163 ] ] }, { "pmid": "15133856", "text": "The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01).", "type": "CHEMICAL", "entities": [ "imidapril", "irbesartan" ], "offsets": [ [ 165, 174 ], [ 186, 196 ] ] }, { "pmid": "15133856", "text": "Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in irbesartan group (P<0.05).", "type": "CHEMICAL", "entities": [ "Ang II", "imidapril", "irbesartan" ], "offsets": [ [ 0, 6 ], [ 50, 59 ], [ 103, 113 ] ] }, { "pmid": "15133856", "text": "The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in irbesartan group (P<0.05).", "type": "CHEMICAL", "entities": [ "imidapril", "irbesartan", "imidapril", "irbesartan" ], "offsets": [ [ 170, 179 ], [ 185, 195 ], [ 307, 316 ], [ 331, 341 ] ] }, { "pmid": "15133856", "text": "Imidapril and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, c-Jun in SHR.", "type": "CHEMICAL", "entities": [ "Imidapril", "irbesartan" ], "offsets": [ [ 0, 9 ], [ 14, 24 ] ] }, { "pmid": "15133856", "text": "Imidapril is more effective than irbesartan.", "type": "CHEMICAL", "entities": [ "Imidapril", "irbesartan" ], "offsets": [ [ 0, 9 ], [ 33, 43 ] ] }, { "pmid": "15184278", "text": "Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles.\n", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 23, 37 ] ] }, { "pmid": "15184278", "text": "BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process.", "type": "CHEMICAL", "entities": [ "NE", "duloxetine", "(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine", "NE", "norepinephrine" ], "offsets": [ [ 127, 129 ], [ 213, 223 ], [ 225, 282 ], [ 302, 304 ], [ 111, 125 ] ] }, { "pmid": "15184278", "text": "Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers.", "type": "CHEMICAL", "entities": [ "Duloxetine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15184278", "text": "Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02).", "type": "CHEMICAL", "entities": [ "duloxetine" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "15184278", "text": "The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001).", "type": "CHEMICAL", "entities": [ "dihydoxyphenylglycol", "NE", "DHPG", "NE", "duloxetine" ], "offsets": [ [ 11, 31 ], [ 35, 37 ], [ 39, 43 ], [ 44, 46 ], [ 117, 127 ] ] }, { "pmid": "15184278", "text": "Plasma NE was significantly increased starting at 120 mg/d duloxetine.", "type": "CHEMICAL", "entities": [ "duloxetine", "NE" ], "offsets": [ [ 59, 69 ], [ 7, 9 ] ] }, { "pmid": "15184278", "text": "Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio.", "type": "CHEMICAL", "entities": [ "creatinine", "NE", "DHPG", "DHPG", "NE" ], "offsets": [ [ 37, 47 ], [ 130, 132 ], [ 134, 138 ], [ 148, 152 ], [ 153, 155 ] ] }, { "pmid": "15184278", "text": "The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose.", "type": "CHEMICAL", "entities": [ "DHPG", "NE" ], "offsets": [ [ 32, 36 ], [ 37, 39 ] ] }, { "pmid": "15184278", "text": "Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study.", "type": "CHEMICAL", "entities": [ "NE", "duloxetine" ], "offsets": [ [ 8, 10 ], [ 86, 96 ] ] }, { "pmid": "15184278", "text": "These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine.", "type": "CHEMICAL", "entities": [ "DHPG", "NE" ], "offsets": [ [ 96, 100 ], [ 101, 103 ] ] }, { "pmid": "15184278", "text": "Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.", "type": "CHEMICAL", "entities": [ "DHPG", "NE" ], "offsets": [ [ 10, 14 ], [ 15, 17 ] ] }, { "pmid": "15191400", "text": "Auranofin increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart.\n", "type": "CHEMICAL", "entities": [ "Auranofin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15191400", "text": "Auranofin, an antirheumatic gold compound, is an inhibitor of selenocysteine enzymes, such as thioredoxin reductase and glutathione peroxidase.", "type": "CHEMICAL", "entities": [ "Auranofin", "glutathione", "selenocysteine" ], "offsets": [ [ 0, 9 ], [ 120, 131 ], [ 62, 76 ] ] }, { "pmid": "15191400", "text": "Auranofin (100 mg/kg) was administered to rats and their hearts were subjected to an in vitro model of ischaemia-reperfusion.", "type": "CHEMICAL", "entities": [ "Auranofin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15191400", "text": "The activity of thioredoxin reductase and glutathione peroxidase was determined in liver and heart tissues in an attempt to correlate enzymatic activity with heart recovery after ischaemia-reperfusion.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 42, 53 ] ] }, { "pmid": "15191400", "text": "There was significantly less thioredoxin reductase activity in rat liver extracts, whereas the level of glutathione activity remained unchanged, demonstrating that the dose of auranofin used was able to selectively inhibit one of these enzyme systems.", "type": "CHEMICAL", "entities": [ "glutathione", "auranofin" ], "offsets": [ [ 104, 115 ], [ 176, 185 ] ] }, { "pmid": "15191400", "text": "Rats administered auranofin displayed significantly impaired recovery from ischaemic insult.", "type": "CHEMICAL", "entities": [ "auranofin" ], "offsets": [ [ 18, 27 ] ] }, { "pmid": "15191400", "text": "Auranofin significantly increased the degree of postischaemic apoptosis, leading to poor postischaemic recovery.", "type": "CHEMICAL", "entities": [ "Auranofin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15206110", "text": "Gallium and other main group metal compounds as antitumor agents.\n", "type": "CHEMICAL", "entities": [ "Gallium" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "15206110", "text": "Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice.", "type": "CHEMICAL", "entities": [ "Gallium", "platinum" ], "offsets": [ [ 0, 7 ], [ 118, 126 ] ] }, { "pmid": "15206110", "text": "It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron.", "type": "CHEMICAL", "entities": [ "ferric iron" ], "offsets": [ [ 117, 128 ] ] }, { "pmid": "15206110", "text": "Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis.", "type": "CHEMICAL", "entities": [ "gallium", "iron" ], "offsets": [ [ 103, 110 ], [ 125, 129 ] ] }, { "pmid": "15206110", "text": "Furthermore, gallium also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases.", "type": "CHEMICAL", "entities": [ "gallium", "iron", "H(+)" ], "offsets": [ [ 13, 20 ], [ 72, 76 ], [ 169, 173 ] ] }, { "pmid": "15206110", "text": "Apart from the consequences of iron deprivation, gallium exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis.", "type": "CHEMICAL", "entities": [ "iron", "gallium", "iron", "ribonucleotide" ], "offsets": [ [ 31, 35 ], [ 49, 56 ], [ 113, 117 ], [ 135, 149 ] ] }, { "pmid": "15206110", "text": "Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity.", "type": "CHEMICAL", "entities": [ "ribonucleotide", "gallium" ], "offsets": [ [ 64, 78 ], [ 118, 125 ] ] }, { "pmid": "15206110", "text": "However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization.", "type": "CHEMICAL", "entities": [ "iron", "gallium" ], "offsets": [ [ 96, 100 ], [ 125, 132 ] ] }, { "pmid": "15206110", "text": "The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting.", "type": "CHEMICAL", "entities": [ "gallium", "gallium", "tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III)", "gallium maltolate", "tris(8-quinolinolato)gallium(III)", "KP46", "gallium", "gallium nitrate", "gallium chloride", "gallium" ], "offsets": [ [ 198, 205 ], [ 282, 289 ], [ 308, 361 ], [ 363, 380 ], [ 385, 418 ], [ 420, 424 ], [ 524, 531 ], [ 33, 48 ], [ 53, 69 ], [ 127, 134 ] ] }, { "pmid": "15206110", "text": "These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects.", "type": "CHEMICAL", "entities": [ "gallium" ], "offsets": [ [ 135, 142 ] ] }, { "pmid": "15206110", "text": "Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored.", "type": "CHEMICAL", "entities": [ "Gallium" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "15206110", "text": "With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun.", "type": "CHEMICAL", "entities": [ "trioxide", "arsenic" ], "offsets": [ [ 36, 44 ], [ 132, 139 ] ] }, { "pmid": "15206110", "text": "Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well.", "type": "CHEMICAL", "entities": [ "arsenic trioxide", "arsenic" ], "offsets": [ [ 51, 67 ], [ 157, 164 ] ] }, { "pmid": "15210974", "text": "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.\n", "type": "CHEMICAL", "entities": [ "levetiracetam" ], "offsets": [ [ 81, 94 ] ] }, { "pmid": "15210974", "text": "Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy.", "type": "CHEMICAL", "entities": [ "levetiracetam", "LEV" ], "offsets": [ [ 82, 95 ], [ 97, 100 ] ] }, { "pmid": "15210974", "text": "The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa.", "type": "CHEMICAL", "entities": [ "LEV" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "15210974", "text": "Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding.", "type": "CHEMICAL", "entities": [ "LEV", "LEV" ], "offsets": [ [ 94, 97 ], [ 148, 151 ] ] }, { "pmid": "15210974", "text": "LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding.", "type": "CHEMICAL", "entities": [ "LEV", "LEV" ], "offsets": [ [ 0, 3 ], [ 104, 107 ] ] }, { "pmid": "15210974", "text": "Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain.", "type": "CHEMICAL", "entities": [ "LEV", "LEV" ], "offsets": [ [ 143, 146 ], [ 93, 96 ] ] }, { "pmid": "15210974", "text": "These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs.", "type": "CHEMICAL", "entities": [ "LEV", "LEV", "LEV" ], "offsets": [ [ 68, 71 ], [ 94, 97 ], [ 176, 179 ] ] }, { "pmid": "15240758", "text": "GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "15240758", "text": "Extracellular application of GABA induced inward currents carried by chloride ions.", "type": "CHEMICAL", "entities": [ "chloride", "GABA" ], "offsets": [ [ 69, 77 ], [ 29, 33 ] ] }, { "pmid": "15240758", "text": "GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors.", "type": "CHEMICAL", "entities": [ "GABA", "bicuculline" ], "offsets": [ [ 0, 4 ], [ 105, 116 ] ] }, { "pmid": "15240758", "text": "Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites.", "type": "CHEMICAL", "entities": [ "GABA", "GABA" ], "offsets": [ [ 19, 23 ], [ 112, 116 ] ] }, { "pmid": "15240758", "text": "GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values.", "type": "CHEMICAL", "entities": [ "GABA", "picrotoxin" ], "offsets": [ [ 0, 4 ], [ 41, 51 ] ] }, { "pmid": "15240758", "text": "Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner.", "type": "CHEMICAL", "entities": [ "Zinc", "GABA" ], "offsets": [ [ 0, 4 ], [ 17, 21 ] ] }, { "pmid": "15240758", "text": "Furthermore, GABA receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors.", "type": "CHEMICAL", "entities": [ "GABA", "diazepam", "zolpidem", "methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate", "pentobarbital", "alphaxalone" ], "offsets": [ [ 13, 17 ], [ 95, 103 ], [ 105, 113 ], [ 115, 160 ], [ 162, 175 ], [ 181, 192 ] ] }, { "pmid": "15240758", "text": "GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively).", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "15255990", "text": "Decreased histamine H1 receptor binding in the brain of depressed patients.\n", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "15255990", "text": "Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 51, 60 ] ] }, { "pmid": "15255990", "text": "In this study, we examined, using positron emission tomography (PET) and [(11)C]-doxepin, whether the histaminergic neuron system is involved in human depression.", "type": "CHEMICAL", "entities": [ "[(11)C]-doxepin" ], "offsets": [ [ 73, 88 ] ] }, { "pmid": "15255990", "text": "Cerebral histamine H1 receptor (H(1)R) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and [(11)C]-doxepin.", "type": "CHEMICAL", "entities": [ "histamine", "[(11)C]-doxepin" ], "offsets": [ [ 9, 18 ], [ 149, 164 ] ] }, { "pmid": "15255990", "text": "Binding potential (BP) values for [(11)C]-doxepin binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects.", "type": "CHEMICAL", "entities": [ "[(11)C]-doxepin" ], "offsets": [ [ 34, 49 ] ] }, { "pmid": "15255990", "text": "There was no area of the brain where [(11)C]-doxepin binding was significantly higher in the depressed patients than in the controls.", "type": "CHEMICAL", "entities": [ "[(11)C]-doxepin" ], "offsets": [ [ 37, 52 ] ] }, { "pmid": "15255990", "text": "ROI-based analysis also revealed that BP values for [(11)C]-doxepin binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores.", "type": "CHEMICAL", "entities": [ "[(11)C]-doxepin" ], "offsets": [ [ 52, 67 ] ] }, { "pmid": "15286093", "text": "Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography.\n", "type": "CHEMICAL", "entities": [ "histamine", "11C-doxepin", "fexofenadine", "cetirizine" ], "offsets": [ [ 121, 130 ], [ 159, 170 ], [ 19, 31 ], [ 36, 46 ] ] }, { "pmid": "15286093", "text": "Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders.", "type": "CHEMICAL", "entities": [ "antihistamines", "Histamine" ], "offsets": [ [ 44, 58 ], [ 0, 9 ] ] }, { "pmid": "15286093", "text": "This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain.", "type": "CHEMICAL", "entities": [ "antihistamines", "fexofenadine", "cetirizine", "histamine" ], "offsets": [ [ 67, 81 ], [ 83, 95 ], [ 100, 110 ], [ 360, 369 ] ] }, { "pmid": "15286093", "text": "Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study.", "type": "CHEMICAL", "entities": [ "fexofenadine", "cetirizine" ], "offsets": [ [ 145, 157 ], [ 168, 178 ] ] }, { "pmid": "15286093", "text": "Hydroxyzine 30 mg was included as a positive control.", "type": "CHEMICAL", "entities": [ "Hydroxyzine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15286093", "text": "H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls.", "type": "CHEMICAL", "entities": [ "(11)C-doxepin" ], "offsets": [ [ 64, 77 ] ] }, { "pmid": "15286093", "text": "In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks.", "type": "CHEMICAL", "entities": [ "fexofenadine", "cetirizine", "hydroxyzine" ], "offsets": [ [ 22, 34 ], [ 118, 128 ], [ 189, 200 ] ] }, { "pmid": "15286093", "text": "For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo.", "type": "CHEMICAL", "entities": [ "fexofenadine", "cetirizine", "fexofenadine" ], "offsets": [ [ 27, 39 ], [ 94, 104 ], [ 162, 174 ] ] }, { "pmid": "15286093", "text": "H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%).", "type": "CHEMICAL", "entities": [ "fexofenadine", "cetirizine" ], "offsets": [ [ 25, 37 ], [ 71, 81 ] ] }, { "pmid": "15286093", "text": "In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing.", "type": "CHEMICAL", "entities": [ "fexofenadine", "cetirizine" ], "offsets": [ [ 15, 27 ], [ 59, 69 ] ] }, { "pmid": "15352500", "text": "A novel membrane sensor for histamine H1-receptor antagonist \"fexofenadine\".\n", "type": "CHEMICAL", "entities": [ "histamine", "fexofenadine" ], "offsets": [ [ 28, 37 ], [ 62, 74 ] ] }, { "pmid": "15352500", "text": "The construction and general performance of thirteen new polymeric membrane sensors for the determination of fexofenadine hydrochloride based on its ion exchange with reineckate, tetraphenylborate and tetraiodomercurate have been studied.", "type": "CHEMICAL", "entities": [ "fexofenadine hydrochloride", "tetraphenylborate", "tetraiodomercurate" ], "offsets": [ [ 109, 135 ], [ 179, 196 ], [ 201, 219 ] ] }, { "pmid": "15352500", "text": "The novel sensor based on reineckate exchanger shows a stable, potentiometric response for fexofenadine in the concentration range of 1 x 10(-2) - 2.5 x 10(-6)", "type": "CHEMICAL", "entities": [ "fexofenadine" ], "offsets": [ [ 91, 103 ] ] }, { "pmid": "15352500", "text": "M with a fast response time of 20 - 40 s. Selectivity coefficients for a number of interfering ions and excipients relative to fexofenadine were investigated.", "type": "CHEMICAL", "entities": [ "fexofenadine" ], "offsets": [ [ 127, 139 ] ] }, { "pmid": "15352500", "text": "There is negligible interference from almost all studied cations, anions, and pharmaceutical excipients, however, citrizine that has a structure homologous to that of fexofenadine was found to interfere.", "type": "CHEMICAL", "entities": [ "citrizine", "fexofenadine" ], "offsets": [ [ 114, 123 ], [ 167, 179 ] ] }, { "pmid": "15352500", "text": "The determination of fexofenadine in aqueous solution shows an average recovery of 99.83% with a mean relative standard deviation (RSD) of 0.5%.", "type": "CHEMICAL", "entities": [ "fexofenadine" ], "offsets": [ [ 21, 33 ] ] }, { "pmid": "15352500", "text": "Direct potentiometric determination of fexofenadine in tablets gave results that compare favorably with those obtained by standard spectrophotometric methods.", "type": "CHEMICAL", "entities": [ "fexofenadine" ], "offsets": [ [ 39, 51 ] ] }, { "pmid": "15352500", "text": "Potentiometric titration of fexofenadine with phosphomolybdic acid as a titrant has been monitored with the proposed sensor as an end point indicator electrode.", "type": "CHEMICAL", "entities": [ "fexofenadine", "phosphomolybdic acid" ], "offsets": [ [ 28, 40 ], [ 46, 66 ] ] }, { "pmid": "15353299", "text": "Thymidylate synthase: a critical target in cancer therapy?\n", "type": "CHEMICAL", "entities": [ "Thymidylate" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15353299", "text": "Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis.", "type": "CHEMICAL", "entities": [ "Thymidylate", "5-fluorouracil", "5-FU", "UFT", "LV", "Orzel", "capecitabine", "Xeloda", "S-1", "2-deoxythymidine-5-monophosphate" ], "offsets": [ [ 0, 11 ], [ 64, 78 ], [ 80, 84 ], [ 104, 107 ], [ 108, 110 ], [ 112, 117 ], [ 120, 132 ], [ 134, 140 ], [ 147, 150 ], [ 216, 248 ] ] }, { "pmid": "15353299", "text": "While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors.", "type": "CHEMICAL", "entities": [ "fluoropyrimidine", "ZD1694", "raltitrexed", "Tomudex", "AG337", "Thymitag" ], "offsets": [ [ 6, 22 ], [ 79, 85 ], [ 87, 98 ], [ 100, 107 ], [ 113, 118 ], [ 120, 128 ] ] }, { "pmid": "15353299", "text": "Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex.", "type": "CHEMICAL", "entities": [ "fluoropyrimidine", "Tomudex" ], "offsets": [ [ 201, 217 ], [ 221, 228 ] ] }, { "pmid": "15353299", "text": "The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts.", "type": "CHEMICAL", "entities": [ "thymidine", "5-FU", "5-FU" ], "offsets": [ [ 128, 137 ], [ 179, 183 ], [ 24, 28 ] ] }, { "pmid": "15382615", "text": "Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis.", "type": "CHEMICAL", "entities": [ "Sibutramine", "norepinephrine", "dopamine" ], "offsets": [ [ 0, 11 ], [ 31, 45 ], [ 47, 55 ] ] }, { "pmid": "15382615", "text": "Sibutramine administration for a year can induce a weight loss of 4-7%.", "type": "CHEMICAL", "entities": [ "Sibutramine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15382615", "text": "Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat.", "type": "CHEMICAL", "entities": [ "Orlistat" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15465654", "text": "Troglitazone, bosentan and glibenclamide inhibit the bile salt export pump (Bsep) which transports taurocholate into bile.", "type": "CHEMICAL", "entities": [ "taurocholate", "Troglitazone", "bosentan", "glibenclamide" ], "offsets": [ [ 99, 111 ], [ 0, 12 ], [ 14, 22 ], [ 27, 40 ] ] }, { "pmid": "15465654", "text": "Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL).", "type": "CHEMICAL", "entities": [ "sodium taurocholate" ], "offsets": [ [ 54, 73 ] ] }, { "pmid": "15465654", "text": "The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system.", "type": "CHEMICAL", "entities": [ "lactate", "alamar blue", "3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide", "MTT", "propidium iodide" ], "offsets": [ [ 96, 103 ], [ 125, 136 ], [ 138, 198 ], [ 200, 203 ], [ 209, 225 ] ] }, { "pmid": "15465654", "text": "Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay.", "type": "CHEMICAL", "entities": [ "Troglitazone", "Bosentan", "MTT", "propidium iodide", "alamar blue" ], "offsets": [ [ 0, 12 ], [ 97, 105 ], [ 155, 158 ], [ 163, 179 ], [ 298, 309 ] ] }, { "pmid": "15465654", "text": "Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study.", "type": "CHEMICAL", "entities": [ "Glibenclamide" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "15465654", "text": "Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure.", "type": "CHEMICAL", "entities": [ "propidium iodide" ], "offsets": [ [ 47, 63 ] ] }, { "pmid": "15494548", "text": "Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity.\n", "type": "CHEMICAL", "entities": [ "Valdecoxib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15494548", "text": "The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1.", "type": "CHEMICAL", "entities": [ "prostaglandin" ], "offsets": [ [ 151, 164 ] ] }, { "pmid": "15494548", "text": "Celecoxib and rofecoxib were among the molecules developed from these efforts.", "type": "CHEMICAL", "entities": [ "Celecoxib", "rofecoxib" ], "offsets": [ [ 0, 9 ], [ 14, 23 ] ] }, { "pmid": "15494548", "text": "We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied.", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 84, 94 ] ] }, { "pmid": "15494548", "text": "Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib.", "type": "CHEMICAL", "entities": [ "Valdecoxib", "celecoxib", "rofecoxib", "etoricoxib" ], "offsets": [ [ 0, 10 ], [ 128, 137 ], [ 154, 163 ], [ 182, 192 ] ] }, { "pmid": "15494548", "text": "Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib).", "type": "CHEMICAL", "entities": [ "rofecoxib", "valdecoxib", "etoricoxib" ], "offsets": [ [ 145, 154 ], [ 31, 41 ], [ 170, 180 ] ] }, { "pmid": "15494548", "text": "The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min).", "type": "CHEMICAL", "entities": [ "valdecoxib", "celecoxib", "rofecoxib", "etoricoxib" ], "offsets": [ [ 53, 63 ], [ 100, 109 ], [ 121, 130 ], [ 147, 157 ] ] }, { "pmid": "15494548", "text": "Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM).", "type": "CHEMICAL", "entities": [ "Valdecoxib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15494548", "text": "Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2.", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 97, 107 ] ] }, { "pmid": "15494548", "text": "Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50)", "type": "CHEMICAL", "entities": [ "Valdecoxib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15494548", "text": "In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50)", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 9, 19 ] ] }, { "pmid": "15494548", "text": "These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans.", "type": "CHEMICAL", "entities": [ "valdecoxib" ], "offsets": [ [ 81, 91 ] ] }, { "pmid": "15498586", "text": "An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.\n", "type": "CHEMICAL", "entities": [ "telmisartan", "glucose", "angiotensin II" ], "offsets": [ [ 43, 54 ], [ 64, 71 ], [ 3, 17 ] ] }, { "pmid": "15498586", "text": "Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 42, 56 ] ] }, { "pmid": "15498586", "text": "We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "15498586", "text": "With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 57, 68 ] ] }, { "pmid": "15498586", "text": "Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 86, 97 ] ] }, { "pmid": "15498586", "text": "By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes.", "type": "CHEMICAL", "entities": [ "telmisartan", "11beta-hydroxysteroid" ], "offsets": [ [ 13, 24 ], [ 36, 57 ] ] }, { "pmid": "15498586", "text": "Of note, we demonstrated for the first time that telmisartan augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability.", "type": "CHEMICAL", "entities": [ "telmisartan", "2-deoxy glucose" ], "offsets": [ [ 49, 60 ], [ 100, 115 ] ] }, { "pmid": "15557128", "text": "Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma.\n", "type": "CHEMICAL", "entities": [ "albuterol" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "15557128", "text": "Genetic variants at the beta(2)-adrenergic receptor (beta(2)AR) may modify asthma severity and albuterol responsiveness.", "type": "CHEMICAL", "entities": [ "albuterol" ], "offsets": [ [ 95, 104 ] ] }, { "pmid": "15557128", "text": "We tested the association of beta(2)AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma.", "type": "CHEMICAL", "entities": [ "albuterol" ], "offsets": [ [ 101, 110 ] ] }, { "pmid": "15557128", "text": "We used both family-based and cross-sectional tests of association with 8 beta(2)AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 91, 101 ] ] }, { "pmid": "15557128", "text": "Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01).", "type": "CHEMICAL", "entities": [ "arginine", "Arg" ], "offsets": [ [ 37, 45 ], [ 47, 50 ] ] }, { "pmid": "15557128", "text": "We found a strong interaction of baseline FEV(1) with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response.", "type": "CHEMICAL", "entities": [ "Gly" ], "offsets": [ [ 72, 75 ] ] }, { "pmid": "15577244", "text": "A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences.", "type": "CHEMICAL", "entities": [ "8'-epi-cleomiscosin A", "coumarinolignoid", "8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one" ], "offsets": [ [ 23, 44 ], [ 6, 22 ], [ 81, 148 ] ] }, { "pmid": "15577244", "text": "Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme tyrosinase, as compared to the standard tyrosinase inhibitors kojic acid (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes.", "type": "CHEMICAL", "entities": [ "kojic acid", "L-mimosine" ], "offsets": [ [ 152, 162 ], [ 187, 197 ] ] }, { "pmid": "15646817", "text": "In vivo activity of the potent oxytocin antagonist on uterine activity in the rat.\nOxytocin antagonist (OTA), TT-235, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates.", "type": "CHEMICAL", "entities": [ "Oxytocin", "TT-235", "oxytocin", "oxytocin" ], "offsets": [ [ 83, 91 ], [ 110, 116 ], [ 31, 39 ], [ 188, 196 ] ] }, { "pmid": "15646817", "text": "The purpose of the present study was to confirm the duration of TT-235 to block oxytocin-induced uterine contractions in estrous rats.", "type": "CHEMICAL", "entities": [ "TT-235", "oxytocin" ], "offsets": [ [ 64, 70 ], [ 80, 88 ] ] }, { "pmid": "15646817", "text": "The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, Antag II and TT-235.", "type": "CHEMICAL", "entities": [ "Antag I", "Antag II", "TT-235" ], "offsets": [ [ 111, 118 ], [ 120, 128 ], [ 133, 139 ] ] }, { "pmid": "15646817", "text": "Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of oxytocin 5 minutes later, also done as a single bolus.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 89, 97 ] ] }, { "pmid": "15646817", "text": "Oxytocin injection of the same dosage was repeated every hour for 5 hours.", "type": "CHEMICAL", "entities": [ "Oxytocin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15646817", "text": "Experiment 2 determined the effect of the three OTAs on uterine oxytocin receptor number (Rn) and binding affinity (Kd).", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 64, 72 ] ] }, { "pmid": "15646817", "text": "In Experiment 1, Antag I, Antag II and TT-235 inhibited the integrated uterine response to oxytocin at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05).", "type": "CHEMICAL", "entities": [ "Antag I", "Antag II", "TT-235", "oxytocin" ], "offsets": [ [ 17, 24 ], [ 26, 34 ], [ 39, 45 ], [ 91, 99 ] ] }, { "pmid": "15646817", "text": "Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05).", "type": "CHEMICAL", "entities": [ "Antag I" ], "offsets": [ [ 26, 33 ] ] }, { "pmid": "15646817", "text": "At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls.", "type": "CHEMICAL", "entities": [ "Antag I" ], "offsets": [ [ 78, 85 ] ] }, { "pmid": "15646817", "text": "The suppressive uterine activity with Antag II continued up to 3 hours.", "type": "CHEMICAL", "entities": [ "Antag II" ], "offsets": [ [ 38, 46 ] ] }, { "pmid": "15646817", "text": "However, uterine contractility remained lower (53%) in rats treated with TT-235 5 hours later.", "type": "CHEMICAL", "entities": [ "TT-235" ], "offsets": [ [ 73, 79 ] ] }, { "pmid": "15646817", "text": "In Experiment 2, TT-235 induced a significant decrease (p<0.05) in oxytocin receptor number and binding affinity at both 0.5 and 4 hours compared with controls.", "type": "CHEMICAL", "entities": [ "TT-235", "oxytocin" ], "offsets": [ [ 17, 23 ], [ 67, 75 ] ] }, { "pmid": "15646817", "text": "Antag I and Antag II did not alter oxytocin receptor number or binding affinity significantly at each time point studied compared with controls.", "type": "CHEMICAL", "entities": [ "Antag I", "Antag II", "oxytocin" ], "offsets": [ [ 0, 7 ], [ 12, 20 ], [ 35, 43 ] ] }, { "pmid": "15646817", "text": "In conclusion, TT-235 may inhibit the uterine response to oxytocin by decreasing oxytocin receptor numbers and oxytocin binding affinity, which might explain the prolonged oxytocin antagonist activity of TT-235.", "type": "CHEMICAL", "entities": [ "TT-235", "oxytocin", "oxytocin", "oxytocin", "oxytocin", "TT-235" ], "offsets": [ [ 15, 21 ], [ 58, 66 ], [ 81, 89 ], [ 111, 119 ], [ 172, 180 ], [ 204, 210 ] ] }, { "pmid": "15655513", "text": "Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2.\n1.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 28, 39 ] ] }, { "pmid": "15655513", "text": "This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor.", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 52, 63 ] ] }, { "pmid": "15655513", "text": "2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively.", "type": "CHEMICAL", "entities": [ "Lumiracoxib" ], "offsets": [ [ 3, 14 ] ] }, { "pmid": "15655513", "text": "In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1).", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "15655513", "text": "In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515).", "type": "CHEMICAL", "entities": [ "lumiracoxib" ], "offsets": [ [ 48, 59 ] ] }, { "pmid": "15655513", "text": "4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5.", "type": "CHEMICAL", "entities": [ "Lumiracoxib" ], "offsets": [ [ 3, 14 ] ] }, { "pmid": "15655513", "text": "Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2))", "type": "CHEMICAL", "entities": [ "lumiracoxib", "thromboxane B(2)", "TxB(2)" ], "offsets": [ [ 9, 20 ], [ 45, 61 ], [ 63, 69 ] ] }, { "pmid": "15655513", "text": "generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1).", "type": "CHEMICAL", "entities": [ "prostaglandin E(2)", "PGE(2)" ], "offsets": [ [ 79, 97 ], [ 99, 105 ] ] }, { "pmid": "15655513", "text": "6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac.", "type": "CHEMICAL", "entities": [ "lumiracoxib", "diclofenac" ], "offsets": [ [ 15, 26 ], [ 122, 132 ] ] }, { "pmid": "15655513", "text": "However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05).", "type": "CHEMICAL", "entities": [ "lumiracoxib", "diclofenac" ], "offsets": [ [ 60, 71 ], [ 167, 177 ] ] }, { "pmid": "15655513", "text": "7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.", "type": "CHEMICAL", "entities": [ "Lumiracoxib", "diclofenac" ], "offsets": [ [ 3, 14 ], [ 130, 140 ] ] }, { "pmid": "15664409", "text": "Cloning, sequencing, structural and molecular biological characterization of placental protein 20 (PP20)/human thiamin pyrophosphokinase (hTPK).\n", "type": "CHEMICAL", "entities": [ "thiamin" ], "offsets": [ [ 111, 118 ] ] }, { "pmid": "15664409", "text": "Full-length cDNAs of placental protein 20 (PP20) were cloned by screening a human placental cDNA library, which encode a 243 amino acid protein, identical to human thiamin pyrophosphokinase (hTPK) as confirmed by protein sequence analysis.", "type": "CHEMICAL", "entities": [ "thiamin" ], "offsets": [ [ 164, 171 ] ] }, { "pmid": "15664409", "text": "As thiamine metabolism deficiencies have been seen in placental infarcts previously, these indicate that PP20/hTPK may have a role in placental diseases.", "type": "CHEMICAL", "entities": [ "thiamine" ], "offsets": [ [ 3, 11 ] ] }, { "pmid": "15664409", "text": "A high degree of structural homology showed that the thiamin binding site was highly similar to that of the mouse enzyme, but highly different from the bacterial ones.", "type": "CHEMICAL", "entities": [ "thiamin" ], "offsets": [ [ 53, 60 ] ] }, { "pmid": "15704203", "text": "Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.\n", "type": "CHEMICAL", "entities": [ "denufosol tetrasodium" ], "offsets": [ [ 27, 48 ] ] }, { "pmid": "15704203", "text": "Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF.", "type": "CHEMICAL", "entities": [ "Denufosol tetrasodium", "Cl(-)", "INS37217" ], "offsets": [ [ 0, 21 ], [ 106, 111 ], [ 23, 31 ] ] }, { "pmid": "15704203", "text": "The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport.", "type": "CHEMICAL", "entities": [ "Cl(-)", "Cl(-)", "Na(+)" ], "offsets": [ [ 4, 9 ], [ 91, 96 ], [ 181, 186 ] ] }, { "pmid": "15704203", "text": "Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists.", "type": "CHEMICAL", "entities": [ "Denufosol" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "15704203", "text": "The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 125, 134 ] ] }, { "pmid": "15704203", "text": "The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days.", "type": "CHEMICAL", "entities": [ "denufosol", "denufosol" ], "offsets": [ [ 102, 111 ], [ 318, 327 ] ] }, { "pmid": "15704203", "text": "Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "15704203", "text": "The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 76, 85 ] ] }, { "pmid": "15704203", "text": "The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%).", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 52, 61 ] ] }, { "pmid": "15704203", "text": "Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "15704203", "text": "In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "15704203", "text": "Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.", "type": "CHEMICAL", "entities": [ "denufosol" ], "offsets": [ [ 258, 267 ] ] }, { "pmid": "15723099", "text": "The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan.\n", "type": "CHEMICAL", "entities": [ "dextromethorphan", "dimemorfan", "dextromethorphan" ], "offsets": [ [ 138, 154 ], [ 28, 38 ], [ 4, 20 ] ] }, { "pmid": "15723099", "text": "In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects.", "type": "CHEMICAL", "entities": [ "dextromethorphan", "dimemorfan" ], "offsets": [ [ 44, 60 ], [ 69, 79 ] ] }, { "pmid": "15723099", "text": "Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors.", "type": "CHEMICAL", "entities": [ "Dextromethorphan", "dimemorfan" ], "offsets": [ [ 0, 16 ], [ 21, 31 ] ] }, { "pmid": "15723099", "text": "Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan.", "type": "CHEMICAL", "entities": [ "Dextromethorphan", "phencyclidine", "dimemorfan", "dimemorfan" ], "offsets": [ [ 0, 16 ], [ 45, 58 ], [ 72, 82 ], [ 203, 213 ] ] }, { "pmid": "15723099", "text": "Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats.", "type": "CHEMICAL", "entities": [ "Kainate", "KA" ], "offsets": [ [ 0, 7 ], [ 9, 11 ] ] }, { "pmid": "15723099", "text": "Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "dimemorfan" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "15723099", "text": "Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus.", "type": "CHEMICAL", "entities": [ "Dimemorfan", "KA" ], "offsets": [ [ 0, 10 ], [ 45, 47 ] ] }, { "pmid": "15723099", "text": "These effects of dimemorfan were comparable to those of dextromethorphan.", "type": "CHEMICAL", "entities": [ "dimemorfan", "dextromethorphan" ], "offsets": [ [ 17, 27 ], [ 56, 72 ] ] }, { "pmid": "15723099", "text": "The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors.", "type": "CHEMICAL", "entities": [ "BD 1047", "dextromethorphan", "dextromethorphan", "dimemorfan", "dimemorfan" ], "offsets": [ [ 133, 140 ], [ 187, 203 ], [ 29, 45 ], [ 49, 59 ], [ 207, 217 ] ] }, { "pmid": "15723099", "text": "We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan).", "type": "CHEMICAL", "entities": [ "dextromethorphan", "dimemorfan", "dextromethorphan", "dextrorphan", "phencyclidine" ], "offsets": [ [ 143, 159 ], [ 17, 27 ], [ 75, 91 ], [ 95, 106 ], [ 110, 123 ] ] }, { "pmid": "15723099", "text": "Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects.", "type": "CHEMICAL", "entities": [ "phencyclidine", "dextrorphan", "dextromethorphan" ], "offsets": [ [ 102, 115 ], [ 117, 128 ], [ 132, 148 ] ] }, { "pmid": "15723099", "text": "Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.", "type": "CHEMICAL", "entities": [ "dimemorfan", "dextromethorphan", "KA" ], "offsets": [ [ 25, 35 ], [ 53, 69 ], [ 84, 86 ] ] }, { "pmid": "15740719", "text": "Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and carbetocin.\n", "type": "CHEMICAL", "entities": [ "oxytocin", "carbetocin", "oxytocin", "oxytocin", "barusiban" ], "offsets": [ [ 128, 136 ], [ 141, 151 ], [ 23, 31 ], [ 59, 67 ], [ 88, 97 ] ] }, { "pmid": "15740719", "text": "We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin.", "type": "CHEMICAL", "entities": [ "vasopressin", "atosiban", "oxytocin", "carbetocin", "oxytocin", "barusiban", "oxytocin" ], "offsets": [ [ 152, 163 ], [ 197, 205 ], [ 223, 231 ], [ 236, 246 ], [ 40, 48 ], [ 62, 71 ], [ 92, 100 ] ] }, { "pmid": "15740719", "text": "For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells.", "type": "CHEMICAL", "entities": [ "oxytocin", "vasopressin" ], "offsets": [ [ 46, 54 ], [ 55, 66 ] ] }, { "pmid": "15740719", "text": "These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996.", "type": "CHEMICAL", "entities": [ "oxytocin", "vasopressin", "oxytocin" ], "offsets": [ [ 79, 87 ], [ 114, 125 ], [ 238, 246 ] ] }, { "pmid": "15740719", "text": "Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor.", "type": "CHEMICAL", "entities": [ "oxytocin", "vasopressin" ], "offsets": [ [ 61, 69 ], [ 117, 128 ] ] }, { "pmid": "15740719", "text": "In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban.", "type": "CHEMICAL", "entities": [ "carbetocin", "atosiban", "barusiban", "oxytocin", "[Arg8]vasopressin" ], "offsets": [ [ 178, 188 ], [ 194, 202 ], [ 85, 94 ], [ 149, 157 ], [ 159, 176 ] ] }, { "pmid": "15740719", "text": "The binding profiles for the agonists oxytocin and carbetocin were found to be similar.", "type": "CHEMICAL", "entities": [ "oxytocin", "carbetocin" ], "offsets": [ [ 38, 46 ], [ 51, 61 ] ] }, { "pmid": "15740719", "text": "For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor.", "type": "CHEMICAL", "entities": [ "N", "oxytocin" ], "offsets": [ [ 68, 69 ], [ 132, 140 ] ] }, { "pmid": "15740719", "text": "For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor.", "type": "CHEMICAL", "entities": [ "vasopressin", "vasopressin", "oxytocin", "atosiban" ], "offsets": [ [ 165, 176 ], [ 8, 19 ], [ 24, 32 ], [ 53, 61 ] ] }, { "pmid": "15740719", "text": "In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the vasopressin V2 receptor.", "type": "CHEMICAL", "entities": [ "barusiban", "oxytocin", "vasopressin" ], "offsets": [ [ 28, 37 ], [ 130, 138 ], [ 155, 166 ] ] }, { "pmid": "15740719", "text": "The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies.", "type": "CHEMICAL", "entities": [ "barusiban", "oxytocin", "d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin" ], "offsets": [ [ 22, 31 ], [ 101, 109 ], [ 130, 172 ] ] }, { "pmid": "15740719", "text": "Overall, the data supported the concept of a central pocket site within the oxytocin receptor.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 76, 84 ] ] }, { "pmid": "15772097", "text": "Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase.\n", "type": "CHEMICAL", "entities": [ "pyridox(am)ine 5'-phosphate" ], "offsets": [ [ 80, 107 ] ] }, { "pmid": "15772097", "text": "In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy.", "type": "CHEMICAL", "entities": [ "pyridoxal phosphate", "PLP", "pyridoxal 5'-phosphate" ], "offsets": [ [ 140, 159 ], [ 161, 164 ], [ 93, 115 ] ] }, { "pmid": "15772097", "text": "Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes.", "type": "CHEMICAL", "entities": [ "aromatic L-amino acid", "PLP" ], "offsets": [ [ 69, 90 ], [ 115, 118 ] ] }, { "pmid": "15772097", "text": "Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO).", "type": "CHEMICAL", "entities": [ "PLP", "pyridox(am)ine 5'-phosphate" ], "offsets": [ [ 43, 46 ], [ 123, 150 ] ] }, { "pmid": "15772097", "text": "Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity.", "type": "CHEMICAL", "entities": [ "pyridox(am)ine phosphate" ], "offsets": [ [ 208, 232 ] ] }, { "pmid": "15772097", "text": "Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).", "type": "CHEMICAL", "entities": [ "PLP" ], "offsets": [ [ 23, 26 ] ] }, { "pmid": "15795105", "text": "Effect of 5-azacytidine and procainamide on CD3-zeta chain expression in Jurkat T cells.\n", "type": "CHEMICAL", "entities": [ "procainamide", "5-azacytidine" ], "offsets": [ [ 28, 40 ], [ 10, 23 ] ] }, { "pmid": "15795105", "text": "The compounds 5'-azacytidine (AZC) and procainamide (PCA) belong to inhibitors of DNMT1, whose low activity correlates with increase in transcription of various genes.", "type": "CHEMICAL", "entities": [ "5'-azacytidine", "AZC", "procainamide", "PCA" ], "offsets": [ [ 14, 28 ], [ 30, 33 ], [ 39, 51 ], [ 53, 56 ] ] }, { "pmid": "15795105", "text": "Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and PCA did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1.", "type": "CHEMICAL", "entities": [ "AZC", "PCA" ], "offsets": [ [ 100, 103 ], [ 108, 111 ] ] }, { "pmid": "15795105", "text": "However, the flowcytometric analysis revealed that AZC and PCA decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner.", "type": "CHEMICAL", "entities": [ "AZC", "PCA" ], "offsets": [ [ 51, 54 ], [ 59, 62 ] ] }, { "pmid": "15805545", "text": "Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts.\n", "type": "CHEMICAL", "entities": [ "sterol" ], "offsets": [ [ 73, 79 ] ] }, { "pmid": "15805545", "text": "Seven human disorders of postsqualene cholesterol biosynthesis have been described.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "15805545", "text": "One of these, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, results from mutations in the X-linked gene NADH sterol dehydrogenase-like (NSDHL) encoding a sterol dehydrogenase.", "type": "CHEMICAL", "entities": [ "NADH", "sterol", "sterol" ], "offsets": [ [ 143, 147 ], [ 148, 154 ], [ 193, 199 ] ] }, { "pmid": "15805545", "text": "To investigate the molecular basis of defects associated with perturbations in cholesterol biosynthesis, microarray analysis was performed comparing gene expression in embryonic fibroblasts expressing the Bpa(1H) allele versus wild-type (wt) cells.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 79, 90 ] ] }, { "pmid": "15805545", "text": "Among 44 genes that showed higher expression in the Bpa(1H) versus wt cells grown in LDS, 11 function in cholesterol biosynthesis, 7 are involved in fatty acid synthesis, 3 (Srebp2, Insig1, and Orf11) encode sterol-regulatory proteins, and 2 (Ldlr and StarD4) are lipid transporters.", "type": "CHEMICAL", "entities": [ "cholesterol", "fatty acid", "sterol" ], "offsets": [ [ 105, 116 ], [ 149, 159 ], [ 208, 214 ] ] }, { "pmid": "15805545", "text": "Of the 21 remaining genes, 16 are known genes, some of which have been implicated previously in cholesterol homeostasis or lipid-mediated signaling, and 5 are uncharacterized cDNA clones.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 96, 107 ] ] }, { "pmid": "15866500", "text": "Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients.\n", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine" ], "offsets": [ [ 29, 44 ] ] }, { "pmid": "15866500", "text": "A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR).", "type": "CHEMICAL", "entities": [ "UdR", "2'-deoxyuridine" ], "offsets": [ [ 170, 173 ], [ 153, 168 ] ] }, { "pmid": "15866500", "text": "The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct", "type": "CHEMICAL", "entities": [ "formate" ], "offsets": [ [ 105, 112 ] ] }, { "pmid": "15866500", "text": "[M+HCOO]- at m/z 273.", "type": "CHEMICAL", "entities": [ "HCOO" ], "offsets": [ [ 3, 7 ] ] }, { "pmid": "15866500", "text": "Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively.", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine", "5-iodo-2'-deoxyuridine" ], "offsets": [ [ 42, 57 ], [ 62, 84 ] ] }, { "pmid": "15866500", "text": "Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve.", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine" ], "offsets": [ [ 20, 35 ] ] }, { "pmid": "15866500", "text": "The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively.", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine", "5-iodo-deoxyuridine" ], "offsets": [ [ 45, 60 ], [ 65, 84 ] ] }, { "pmid": "15866500", "text": "The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (TS).", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine", "fluoropyrimidine", "capecitabine", "N4-pentoxycarbonyl-5'-5-fluorocytidine", "2'-deoxyuridine", "thymidylate" ], "offsets": [ [ 117, 132 ], [ 262, 278 ], [ 288, 300 ], [ 302, 340 ], [ 365, 380 ], [ 465, 476 ] ] }, { "pmid": "15866500", "text": "These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP).", "type": "CHEMICAL", "entities": [ "FdUMP", "capecitabine", "5-fluoro-2'-deoxyuridine monophosphate" ], "offsets": [ [ 202, 207 ], [ 75, 87 ], [ 162, 200 ] ] }, { "pmid": "15866500", "text": "Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials.", "type": "CHEMICAL", "entities": [ "UdR", "capecitabine" ], "offsets": [ [ 21, 24 ], [ 101, 113 ] ] }, { "pmid": "15866500", "text": "Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed.", "type": "CHEMICAL", "entities": [ "2'-deoxyuridine" ], "offsets": [ [ 29, 44 ] ] }, { "pmid": "15887238", "text": "Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells.\n", "type": "CHEMICAL", "entities": [ "imatinib mesylate" ], "offsets": [ [ 86, 103 ] ] }, { "pmid": "15887238", "text": "Imatinib mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases.", "type": "CHEMICAL", "entities": [ "Imatinib mesylate", "tyrosine" ], "offsets": [ [ 0, 17 ], [ 23, 31 ] ] }, { "pmid": "15887238", "text": "In this report, we describe other cellular targets for imatinib.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 55, 63 ] ] }, { "pmid": "15887238", "text": "Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "15887238", "text": "Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process.", "type": "CHEMICAL", "entities": [ "Imatinib" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15887238", "text": "Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 46, 54 ] ] }, { "pmid": "15887238", "text": "An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "15887238", "text": "Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 181, 189 ] ] }, { "pmid": "15887238", "text": "Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation.", "type": "CHEMICAL", "entities": [ "Imatinib" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15887238", "text": "Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "15887238", "text": "Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors.", "type": "CHEMICAL", "entities": [ "imatinib", "tyrosine" ], "offsets": [ [ 10, 18 ], [ 96, 104 ] ] }, { "pmid": "15894928", "text": "STI 571 (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and c-kit oncoproteins.", "type": "CHEMICAL", "entities": [ "STI 571", "imatinib mesylate", "Gleevec", "Gleevec" ], "offsets": [ [ 0, 7 ], [ 9, 26 ], [ 28, 35 ], [ 88, 95 ] ] }, { "pmid": "1590750", "text": "Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity.\n", "type": "CHEMICAL", "entities": [ "ethanol", "alcohol", "aldehyde" ], "offsets": [ [ 104, 111 ], [ 50, 57 ], [ 62, 70 ] ] }, { "pmid": "1590750", "text": "Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity.", "type": "CHEMICAL", "entities": [ "Alcohol", "aldehyde" ], "offsets": [ [ 0, 7 ], [ 32, 40 ] ] }, { "pmid": "1590750", "text": "The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline.", "type": "CHEMICAL", "entities": [ "ethanol", "ethanol", "4-methylpyrazole", "1,10-phenanthroline" ], "offsets": [ [ 109, 116 ], [ 150, 157 ], [ 177, 193 ], [ 197, 216 ] ] }, { "pmid": "1590750", "text": "The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied.", "type": "CHEMICAL", "entities": [ "polypeptide" ], "offsets": [ [ 37, 48 ] ] }, { "pmid": "1590750", "text": "These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 45, 52 ] ] }, { "pmid": "1590750", "text": "The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite.", "type": "CHEMICAL", "entities": [ "acetaldehyde", "alcohol" ], "offsets": [ [ 184, 196 ], [ 217, 224 ] ] }, { "pmid": "15936988", "text": "Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells.\n", "type": "CHEMICAL", "entities": [ "Simvastatin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "15936988", "text": "The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. Simvastatin, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC).", "type": "CHEMICAL", "entities": [ "HMG-CoA", "Simvastatin", "HMG-CoA", "3-hydroxy-3-methylglutaryl coenzyme-A" ], "offsets": [ [ 109, 116 ], [ 242, 253 ], [ 258, 265 ], [ 70, 107 ] ] }, { "pmid": "15936988", "text": "The IL-18 production is located upstream of the cytokine cascade activated by simvastatin.", "type": "CHEMICAL", "entities": [ "simvastatin" ], "offsets": [ [ 78, 89 ] ] }, { "pmid": "15936988", "text": "Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes.", "type": "CHEMICAL", "entities": [ "simvastatin" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "15936988", "text": "In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin.", "type": "CHEMICAL", "entities": [ "simvastatin", "simvastatin" ], "offsets": [ [ 26, 37 ], [ 200, 211 ] ] }, { "pmid": "15936988", "text": "The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin.", "type": "CHEMICAL", "entities": [ "simvastatin", "HMG-CoA", "mevalonate", "HMG-CoA", "simvastatin" ], "offsets": [ [ 15, 26 ], [ 80, 87 ], [ 99, 109 ], [ 141, 148 ], [ 176, 187 ] ] }, { "pmid": "15939622", "text": "COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis.\n", "type": "CHEMICAL", "entities": [ "phenylbutazone", "flunixin", "carprofen", "meloxicam" ], "offsets": [ [ 45, 59 ], [ 61, 69 ], [ 71, 80 ], [ 85, 94 ] ] }, { "pmid": "15939622", "text": "We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays.", "type": "CHEMICAL", "entities": [ "carprofen", "phenylbutazone", "flunixin", "meloxicam" ], "offsets": [ [ 62, 71 ], [ 73, 87 ], [ 92, 100 ], [ 51, 60 ] ] }, { "pmid": "15939622", "text": "As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined.", "type": "CHEMICAL", "entities": [ "meloxicam", "carprofen", "phenylbutazone", "flunixin", "meloxicam" ], "offsets": [ [ 47, 56 ], [ 61, 70 ], [ 115, 129 ], [ 134, 142 ], [ 144, 153 ] ] }, { "pmid": "15939622", "text": "However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50.", "type": "CHEMICAL", "entities": [ "carprofen", "phenylbutazone", "flunixin", "meloxicam" ], "offsets": [ [ 135, 144 ], [ 17, 31 ], [ 46, 54 ], [ 112, 121 ] ] }, { "pmid": "15942707", "text": "Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart.\n", "type": "CHEMICAL", "entities": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15942707", "text": "To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "15942707", "text": "Carvedilol at 50 mg/kg body weight per day after surgery was given.", "type": "CHEMICAL", "entities": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "15942707", "text": "Mean arterial pressure decreased after treatment with carvedilol.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "15942707", "text": "The increased wall thickness and heart weight was reversed to normal by carvedilol.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 72, 82 ] ] }, { "pmid": "15942707", "text": "Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups.", "type": "CHEMICAL", "entities": [ "valsartan", "doxazosin", "N-acetylcysteine" ], "offsets": [ [ 15, 24 ], [ 26, 35 ], [ 40, 56 ] ] }, { "pmid": "15942707", "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": "15942707", "text": "Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 136, 146 ] ] }, { "pmid": "15942707", "text": "Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and NGF-beta in the hypertrophic myocardium.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "15946589", "text": "Imatinib resistance in gastrointestinal stromal tumors.\n", "type": "CHEMICAL", "entities": [ "Imatinib" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15946589", "text": "Imatinib (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs.", "type": "CHEMICAL", "entities": [ "Imatinib", "STI571", "Gleevec", "Glivec" ], "offsets": [ [ 0, 8 ], [ 10, 16 ], [ 18, 25 ], [ 27, 33 ] ] }, { "pmid": "15946589", "text": "Unfortunately, imatinib resistance has emerged.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "15946589", "text": "The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala.", "type": "CHEMICAL", "entities": [ "imatinib" ], "offsets": [ [ 26, 34 ] ] }, { "pmid": "15946589", "text": "The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed.", "type": "CHEMICAL", "entities": [ "imatinib", "imatinib", "imatinib" ], "offsets": [ [ 55, 63 ], [ 140, 148 ], [ 183, 191 ] ] }, { "pmid": "15947036", "text": "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist.\n", "type": "CHEMICAL", "entities": [ "4-methylhistamine", "histamine", "histamine" ], "offsets": [ [ 112, 129 ], [ 14, 23 ], [ 71, 80 ] ] }, { "pmid": "15947036", "text": "The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "15947036", "text": "Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM.", "type": "CHEMICAL", "entities": [ "[(3)H]histamine" ], "offsets": [ [ 132, 147 ] ] }, { "pmid": "15947036", "text": "Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists.", "type": "CHEMICAL", "entities": [ "imidazole" ], "offsets": [ [ 38, 47 ] ] }, { "pmid": "15947036", "text": "Interestingly, we identified 4-methylhistamine as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes.", "type": "CHEMICAL", "entities": [ "4-methylhistamine", "histamine" ], "offsets": [ [ 29, 46 ], [ 157, 166 ] ] }, { "pmid": "15947036", "text": "Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120", "type": "CHEMICAL", "entities": [ "4-methylhistamine", "JNJ 7777120" ], "offsets": [ [ 10, 27 ], [ 176, 187 ] ] }, { "pmid": "15947036", "text": "[1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8).", "type": "CHEMICAL", "entities": [ "1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine" ], "offsets": [ [ 1, 57 ] ] }, { "pmid": "15947036", "text": "The identification of 4-methylhistamine as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R.", "type": "CHEMICAL", "entities": [ "4-methylhistamine" ], "offsets": [ [ 22, 39 ] ] }, { "pmid": "15975002", "text": "Novel agents that potentially inhibit irinotecan-induced diarrhea.\n", "type": "CHEMICAL", "entities": [ "irinotecan" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "15975002", "text": "Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I).", "type": "CHEMICAL", "entities": [ "7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin", "Irinotecan", "CPT-11" ], "offsets": [ [ 20, 86 ], [ 0, 10 ], [ 12, 18 ] ] }, { "pmid": "15975002", "text": "The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively.", "type": "CHEMICAL", "entities": [ "CPT-11" ], "offsets": [ [ 99, 105 ] ] }, { "pmid": "15975002", "text": "This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms.", "type": "CHEMICAL", "entities": [ "CPT-11" ], "offsets": [ [ 59, 65 ] ] }, { "pmid": "15975002", "text": "Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine.", "type": "CHEMICAL", "entities": [ "CPT-11", "atropine" ], "offsets": [ [ 51, 57 ], [ 181, 189 ] ] }, { "pmid": "15975002", "text": "Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa.", "type": "CHEMICAL", "entities": [ "SN-38", "7-ethyl-10-hydroxycamptothecin", "CPT-11" ], "offsets": [ [ 73, 78 ], [ 80, 110 ], [ 144, 150 ] ] }, { "pmid": "15975002", "text": "CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-).", "type": "CHEMICAL", "entities": [ "CPT-11", "SN-38", "prostaglandins", "PGs", "Na(+)", "Cl(-)" ], "offsets": [ [ 0, 6 ], [ 11, 16 ], [ 85, 99 ], [ 101, 104 ], [ 138, 143 ], [ 148, 153 ] ] }, { "pmid": "15975002", "text": "Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity.", "type": "CHEMICAL", "entities": [ "loperamide" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "15975002", "text": "These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38.", "type": "CHEMICAL", "entities": [ "SN-38" ], "offsets": [ [ 237, 242 ] ] }, { "pmid": "15975002", "text": "Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.", "type": "CHEMICAL", "entities": [ "CPT-11", "CPT-11" ], "offsets": [ [ 77, 83 ], [ 139, 145 ] ] }, { "pmid": "15985434", "text": "Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives.\n", "type": "CHEMICAL", "entities": [ "pyridoxal", "roscovitine" ], "offsets": [ [ 21, 30 ], [ 54, 65 ] ] }, { "pmid": "15985434", "text": "Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+.", "type": "CHEMICAL", "entities": [ "pyridoxal", "pyridoxamine", "Pyridoxal", "pyridoxine", "ATP", "Zn2+" ], "offsets": [ [ 57, 66 ], [ 68, 80 ], [ 0, 9 ], [ 86, 96 ], [ 116, 119 ], [ 124, 128 ] ] }, { "pmid": "15985434", "text": "This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes.", "type": "CHEMICAL", "entities": [ "vitamin B6", "pyridoxal 5'-phosphate", "PLP" ], "offsets": [ [ 104, 114 ], [ 55, 77 ], [ 79, 82 ] ] }, { "pmid": "15985434", "text": "(R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections.", "type": "CHEMICAL", "entities": [ "(R)-Roscovitine", "CYC202", "Seliciclib" ], "offsets": [ [ 0, 15 ], [ 17, 23 ], [ 25, 35 ] ] }, { "pmid": "15985434", "text": "Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK.", "type": "CHEMICAL", "entities": [ "(R)-roscovitine" ], "offsets": [ [ 55, 70 ] ] }, { "pmid": "15985434", "text": "To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs.", "type": "CHEMICAL", "entities": [ "(R)-roscovitine", "N6-methyl-(R)-roscovitine", "O6-(R)-roscovitine" ], "offsets": [ [ 92, 107 ], [ 109, 134 ], [ 140, 158 ] ] }, { "pmid": "15985434", "text": "Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site.", "type": "CHEMICAL", "entities": [ "roscovitines", "pyridoxal", "ATP" ], "offsets": [ [ 46, 58 ], [ 81, 90 ], [ 143, 146 ] ] }, { "pmid": "15985434", "text": "The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal.", "type": "CHEMICAL", "entities": [ "pyridoxal", "pyridoxal" ], "offsets": [ [ 4, 13 ], [ 108, 117 ] ] }, { "pmid": "15985434", "text": "This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs.", "type": "CHEMICAL", "entities": [ "roscovitine" ], "offsets": [ [ 88, 99 ] ] }, { "pmid": "15985434", "text": "It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs.", "type": "CHEMICAL", "entities": [ "roscovitine" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "15985706", "text": "In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 196, 204 ] ] }, { "pmid": "15985706", "text": "Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin.", "type": "CHEMICAL", "entities": [ "forskolin", "[(3)H]glucosamine", "PD153035", "wortmannin", "cAMP", "adenylate" ], "offsets": [ [ 417, 426 ], [ 6, 23 ], [ 189, 197 ], [ 210, 220 ], [ 372, 376 ], [ 388, 397 ] ] }, { "pmid": "15985706", "text": "The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059.", "type": "CHEMICAL", "entities": [ "isoproterenol", "PP2", "tyrosine", "PD98059" ], "offsets": [ [ 41, 54 ], [ 87, 90 ], [ 117, 125 ], [ 224, 231 ] ] }, { "pmid": "15985706", "text": "The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin.", "type": "CHEMICAL", "entities": [ "cAMP", "forskolin" ], "offsets": [ [ 93, 97 ], [ 102, 111 ] ] }, { "pmid": "15991937", "text": "Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure.\n", "type": "CHEMICAL", "entities": [ "Losartan", "angiotensin II" ], "offsets": [ [ 0, 8 ], [ 22, 36 ] ] }, { "pmid": "15991937", "text": "Losartan (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1))", "type": "CHEMICAL", "entities": [ "angiotensin II", "AII", "Losartan", "COZAAR" ], "offsets": [ [ 74, 88 ], [ 90, 93 ], [ 0, 8 ], [ 10, 16 ] ] }, { "pmid": "15991937", "text": "Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects.", "type": "CHEMICAL", "entities": [ "AII" ], "offsets": [ [ 17, 20 ] ] }, { "pmid": "15991937", "text": "Losartan (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition).", "type": "CHEMICAL", "entities": [ "Losartan" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15991937", "text": "Losartan is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition).", "type": "CHEMICAL", "entities": [ "Losartan" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "15991937", "text": "Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population.", "type": "CHEMICAL", "entities": [ "losartan", "captopril", "angiotensin" ], "offsets": [ [ 99, 107 ], [ 115, 124 ], [ 142, 153 ] ] }, { "pmid": "15991937", "text": "The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The Losartan Heart Failure Survival Study - ELITE II, 2) The Losartan Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The Losartan Hypertension Survival Study - LIFE and 4) The Losartan Renal Protection Study - RENAAL.", "type": "CHEMICAL", "entities": [ "Losartan", "Losartan", "losartan", "losartan", "Losartan", "Losartan" ], "offsets": [ [ 373, 381 ], [ 428, 436 ], [ 26, 34 ], [ 200, 208 ], [ 246, 254 ], [ 303, 311 ] ] }, { "pmid": "1611705", "text": "Effect of amrinone on tumor necrosis factor production in endotoxic shock.\n", "type": "CHEMICAL", "entities": [ "amrinone" ], "offsets": [ [ 10, 18 ] ] }, { "pmid": "1611705", "text": "We now demonstrate that amrinone, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced TNF production at concentrations readily achieved in vivo.", "type": "CHEMICAL", "entities": [ "amrinone" ], "offsets": [ [ 24, 32 ] ] }, { "pmid": "1611705", "text": "Inhibition by amrinone (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by dexamethasone.", "type": "CHEMICAL", "entities": [ "amrinone", "pentoxifylline", "dexamethasone" ], "offsets": [ [ 14, 22 ], [ 43, 57 ], [ 144, 157 ] ] }, { "pmid": "1611705", "text": "Combined application of dexamethasone and amrinone caused additive inhibition of TNF biosynthesis in vitro.", "type": "CHEMICAL", "entities": [ "dexamethasone", "amrinone" ], "offsets": [ [ 24, 37 ], [ 42, 50 ] ] }, { "pmid": "1611705", "text": "Furthermore, treatment of mice with amrinone immediately prior to endotoxin challenge led to significantly improved survival.", "type": "CHEMICAL", "entities": [ "amrinone" ], "offsets": [ [ 36, 44 ] ] }, { "pmid": "1611705", "text": "These findings suggest that amrinone possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections.", "type": "CHEMICAL", "entities": [ "amrinone" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "1611705", "text": "Abrupt removal of amrinone or pentoxifylline from the culture medium prior to LPS stimulation, however, caused significantly augmented TNF production.", "type": "CHEMICAL", "entities": [ "amrinone", "pentoxifylline" ], "offsets": [ [ 18, 26 ], [ 30, 44 ] ] }, { "pmid": "1611705", "text": "Therefore, amrinone and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy.", "type": "CHEMICAL", "entities": [ "amrinone" ], "offsets": [ [ 11, 19 ] ] }, { "pmid": "16207494", "text": "Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region.\n", "type": "CHEMICAL", "entities": [ "pyridoxal phosphate" ], "offsets": [ [ 25, 44 ] ] }, { "pmid": "16207494", "text": "In the present study, age-related changes of pyridoxal 5'-phosphate (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper.", "type": "CHEMICAL", "entities": [ "pyridoxine 5'-phosphate", "pyridoxal 5'-phosphate", "PLP", "pyridoxal" ], "offsets": [ [ 123, 146 ], [ 45, 67 ], [ 69, 72 ], [ 96, 105 ] ] }, { "pmid": "16207494", "text": "Therefore, decreases of PLK and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function.", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid", "GABA" ], "offsets": [ [ 130, 153 ], [ 155, 159 ] ] }, { "pmid": "16213084", "text": "Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex.\n", "type": "CHEMICAL", "entities": [ "H+", "nicotinate" ], "offsets": [ [ 30, 32 ], [ 44, 54 ] ] }, { "pmid": "16213084", "text": "In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex.", "type": "CHEMICAL", "entities": [ "H(+)", "nicotinate" ], "offsets": [ [ 55, 59 ], [ 68, 78 ] ] }, { "pmid": "16213084", "text": "The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5.", "type": "CHEMICAL", "entities": [ "[(3)H]nicotinate" ], "offsets": [ [ 4, 20 ] ] }, { "pmid": "16213084", "text": "The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min.", "type": "CHEMICAL", "entities": [ "nicotinic acid" ], "offsets": [ [ 4, 18 ] ] }, { "pmid": "16213084", "text": "This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that nicotinate uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system.", "type": "CHEMICAL", "entities": [ "carbonylcyanide p-trifluoromethoxyphenylhydrazone", "monocarboxylate", "alpha-cyano-4-hydroxycinnamic acid", "nicotinate", "H(+)", "monocarboxylate" ], "offsets": [ [ 44, 93 ], [ 109, 124 ], [ 154, 188 ], [ 206, 216 ], [ 257, 261 ], [ 270, 285 ] ] }, { "pmid": "16213084", "text": "[(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM).", "type": "CHEMICAL", "entities": [ "[(3)H]Nicotinate", "monocarboxylic acids", "l-lactic acid", "pyruvic acid" ], "offsets": [ [ 0, 16 ], [ 84, 104 ], [ 113, 126 ], [ 131, 143 ] ] }, { "pmid": "16213084", "text": "On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM).", "type": "CHEMICAL", "entities": [ "l-lactic acid" ], "offsets": [ [ 41, 54 ] ] }, { "pmid": "16213084", "text": "Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2.", "type": "CHEMICAL", "entities": [ "l-lactate", "nicotinate", "nicotinate" ], "offsets": [ [ 8, 17 ], [ 40, 50 ], [ 92, 102 ] ] }, { "pmid": "16213084", "text": "These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for nicotinate in rat cerebrocortical astrocytes.", "type": "CHEMICAL", "entities": [ "H(+)", "monocarboxylate", "H(+)", "monocarboxylate", "nicotinate" ], "offsets": [ [ 48, 52 ], [ 123, 138 ], [ 173, 177 ], [ 186, 201 ], [ 224, 234 ] ] }, { "pmid": "16220064", "text": "A review of the structural and functional features of olmesartan medoxomil, an angiotensin receptor blocker.\n", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil" ], "offsets": [ [ 54, 74 ] ] }, { "pmid": "16220064", "text": "The angiotensin II (A-II) type 1 (AT1) receptor-mediated effects of A-II play a key role in the pathophysiology of hypertension.", "type": "CHEMICAL", "entities": [ "A-II", "angiotensin II", "A-II" ], "offsets": [ [ 20, 24 ], [ 4, 18 ], [ 68, 72 ] ] }, { "pmid": "16220064", "text": "Effective inhibition of A-II is provided by the latest class of antihypertensive medications, the AT1 receptor blockers (ARBs).", "type": "CHEMICAL", "entities": [ "A-II" ], "offsets": [ [ 24, 28 ] ] }, { "pmid": "16220064", "text": "The most recent member of this drug class to be approved by the Food and Drug Administration, olmesartan medoxomil, contains unique features that may explain its clinical efficacy.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil" ], "offsets": [ [ 94, 114 ] ] }, { "pmid": "16220064", "text": "Key structural elements of olmesartan medoxomil include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil" ], "offsets": [ [ 27, 47 ] ] }, { "pmid": "16220064", "text": "After oral administration, olmesartan medoxomil is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil" ], "offsets": [ [ 27, 47 ] ] }, { "pmid": "16220064", "text": "The marked antihypertensive efficacy of olmesartan medoxomil may result from a unique pharmacological interaction of the drug with the AT1 receptor, resulting in a potent, long-lasting, dose-dependent blockade of A-II.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil", "A-II" ], "offsets": [ [ 40, 60 ], [ 213, 217 ] ] }, { "pmid": "16245075", "text": "Effects of granulocyte colony-stimulating factor (G-CSF) and neutrophil elastase inhibitor (ONO-5046) on acid-induced lung injury in rats.\n", "type": "CHEMICAL", "entities": [ "ONO-5046" ], "offsets": [ [ 92, 100 ] ] }, { "pmid": "16245075", "text": "We examined the effects of the high dose of granulocyte-colony stimulating factor (G-CSF), which is capable of increasing peripheral neutrophils, and a specific neutrophil elastase inhibitor (ONO-5046) on acid lung injury in rats.", "type": "CHEMICAL", "entities": [ "ONO-5046" ], "offsets": [ [ 192, 200 ] ] }, { "pmid": "16245075", "text": "Animals were anesthetized and normal saline (NS, 2 mL kg(-1)) or hydrochloric acid (HCl, 0.1 N 2 mL kg(-1)) was then instilled into trachea.", "type": "CHEMICAL", "entities": [ "hydrochloric acid", "HCl" ], "offsets": [ [ 65, 82 ], [ 84, 87 ] ] }, { "pmid": "16245075", "text": "Thirty minutes before HCl instillation, G-CSF (150 microg kg(-1)) was injected subcutaneously or ONO-5046 (10 mg kg(-1) h(-1)) was infused continuously into the right jugular vein.", "type": "CHEMICAL", "entities": [ "HCl", "ONO-5046" ], "offsets": [ [ 22, 25 ], [ 97, 105 ] ] }, { "pmid": "16245075", "text": "Five hours after HCl or NS instillation, bronchoalveolar lavage fluid (BALF) and lung tissue samples were obtained.", "type": "CHEMICAL", "entities": [ "HCl" ], "offsets": [ [ 17, 20 ] ] }, { "pmid": "16245075", "text": "HCl aspiration markedly increased these values in BALF and W/D ratio.", "type": "CHEMICAL", "entities": [ "HCl" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "16245075", "text": "Both ONO-5046 and G-CSF attenuated the parameters increased by acid-induced lung injury in rats.", "type": "CHEMICAL", "entities": [ "ONO-5046" ], "offsets": [ [ 5, 13 ] ] }, { "pmid": "16247743", "text": "Guidance on the use of miglustat for treating patients with type 1 Gaucher disease.\n", "type": "CHEMICAL", "entities": [ "miglustat" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "16247743", "text": "Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option.", "type": "CHEMICAL", "entities": [ "Miglustat", "imino sugar" ], "offsets": [ [ 0, 9 ], [ 14, 25 ] ] }, { "pmid": "16247743", "text": "Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately.", "type": "CHEMICAL", "entities": [ "miglustat", "miglustat", "miglustat" ], "offsets": [ [ 100, 109 ], [ 252, 261 ], [ 21, 30 ] ] }, { "pmid": "16247743", "text": "This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat.", "type": "CHEMICAL", "entities": [ "miglustat" ], "offsets": [ [ 258, 267 ] ] }, { "pmid": "16248990", "text": "Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors.\n", "type": "CHEMICAL", "entities": [ "galantamine", "ACh" ], "offsets": [ [ 52, 63 ], [ 74, 77 ] ] }, { "pmid": "16248990", "text": "The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain.", "type": "CHEMICAL", "entities": [ "[3H]-acetylcholine", "[3H]-ACh" ], "offsets": [ [ 220, 238 ], [ 240, 248 ] ] }, { "pmid": "16248990", "text": "Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01).", "type": "CHEMICAL", "entities": [ "ACh" ], "offsets": [ [ 128, 131 ] ] }, { "pmid": "16248990", "text": "This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor.", "type": "CHEMICAL", "entities": [ "atropine", "ATR" ], "offsets": [ [ 44, 52 ], [ 54, 57 ] ] }, { "pmid": "16248990", "text": "After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist.", "type": "CHEMICAL", "entities": [ "ATR", "haloperidol", "HAL", "dopamine" ], "offsets": [ [ 72, 75 ], [ 121, 132 ], [ 134, 137 ], [ 155, 163 ] ] }, { "pmid": "16248990", "text": "In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA.", "type": "CHEMICAL", "entities": [ "[3H]-ACh" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "16248990", "text": "To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors.", "type": "CHEMICAL", "entities": [ "[3H]-ACh", "mecamylamine", "MEC" ], "offsets": [ [ 65, 73 ], [ 83, 95 ], [ 97, 100 ] ] }, { "pmid": "16248990", "text": "MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC.", "type": "CHEMICAL", "entities": [ "MEC", "ATR", "MEC" ], "offsets": [ [ 0, 3 ], [ 127, 130 ], [ 135, 138 ] ] }, { "pmid": "16248990", "text": "Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01).", "type": "CHEMICAL", "entities": [ "[3H]-ACh" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "16253547", "text": "Rat hepatic stellate cells become retinoid unresponsive during activation.\n", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "16253547", "text": "Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen.", "type": "CHEMICAL", "entities": [ "Vitamin A" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "16253547", "text": "It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes.", "type": "CHEMICAL", "entities": [ "Vitamin A" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "16253547", "text": "We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic.", "type": "CHEMICAL", "entities": [ "retinoids" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "16253547", "text": "We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular retinoid levels; (3) maintain expression of HSC nuclear receptors for retinoic acid (RAR) in HSC that are becoming activated or are chronically activated.", "type": "CHEMICAL", "entities": [ "retinoids", "retinoid", "retinoic acid" ], "offsets": [ [ 21, 30 ], [ 99, 107 ], [ 169, 182 ] ] }, { "pmid": "16253547", "text": "Markers of activation in freshly isolated HSC were decreased by either retinol or retinoic acid without increases in HSC retinoid concentration.", "type": "CHEMICAL", "entities": [ "retinol", "retinoic acid", "retinoid" ], "offsets": [ [ 71, 78 ], [ 82, 95 ], [ 121, 129 ] ] }, { "pmid": "16253547", "text": "mRNA levels for RAR-alpha, RAR-beta and RAR-gamma, the nuclear receptors for retinoic acid, decreased during activation of freshly isolated HSC even with retinoid supplementation.", "type": "CHEMICAL", "entities": [ "retinoic acid", "retinoid" ], "offsets": [ [ 77, 90 ], [ 154, 162 ] ] }, { "pmid": "16253547", "text": "RAR-alpha, RAR-beta and RAR-gamma mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after retinoic acid supplementation.", "type": "CHEMICAL", "entities": [ "retinoic acid" ], "offsets": [ [ 132, 145 ] ] }, { "pmid": "16253547", "text": "Activation markers in chronically activated HSC were only slightly decreased after retinoid exposure.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 83, 91 ] ] }, { "pmid": "16253547", "text": "We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation.", "type": "CHEMICAL", "entities": [ "retinoids" ], "offsets": [ [ 50, 59 ] ] }, { "pmid": "16324695", "text": "Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor.", "type": "CHEMICAL", "entities": [ "fenoterol", "isoprenaline", "methacholine" ], "offsets": [ [ 110, 119 ], [ 130, 142 ], [ 182, 194 ] ] }, { "pmid": "16324695", "text": "Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization.", "type": "CHEMICAL", "entities": [ "PMA", "isoprenaline", "phorbol 12-myristate 13-acetate" ], "offsets": [ [ 101, 104 ], [ 149, 161 ], [ 68, 99 ] ] }, { "pmid": "16324695", "text": "To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol.", "type": "CHEMICAL", "entities": [ "fenoterol" ], "offsets": [ [ 178, 187 ] ] }, { "pmid": "16324695", "text": "This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization.", "type": "CHEMICAL", "entities": [ "isoprenaline", "PMA", "fenoterol" ], "offsets": [ [ 54, 66 ], [ 136, 139 ], [ 144, 153 ] ] }, { "pmid": "16324695", "text": "Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented.", "type": "CHEMICAL", "entities": [ "2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide", "GF 109203X", "isoprenaline", "PMA", "fenoterol" ], "offsets": [ [ 37, 108 ], [ 110, 120 ], [ 167, 179 ], [ 266, 269 ], [ 274, 283 ] ] }, { "pmid": "16336752", "text": "Tyrosine kinase inhibitors are quinazoline-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling.", "type": "CHEMICAL", "entities": [ "Tyrosine", "quinazoline", "tyrosine" ], "offsets": [ [ 0, 8 ], [ 31, 42 ], [ 126, 134 ] ] }, { "pmid": "16373326", "text": "Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles.\n", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "16373326", "text": "Reabsorption of amino acids is an important function of the renal proximal tubule.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 16, 27 ] ] }, { "pmid": "16373326", "text": "pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV).", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "16373326", "text": "The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system.", "type": "CHEMICAL", "entities": [ "amino acid", "H(+)" ], "offsets": [ [ 100, 110 ], [ 95, 99 ] ] }, { "pmid": "16373326", "text": "The rabbit PAT1 cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1).", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 160, 171 ] ] }, { "pmid": "16373326", "text": "When expressed heterologously in a mammalian cell line, rabbit PAT1 mediates pH-dependent, Na(+)-independent uptake of proline, glycine, l-alanine and alpha-(methylamino)isobutyric acid.", "type": "CHEMICAL", "entities": [ "Na(+)", "proline", "glycine", "l-alanine", "alpha-(methylamino)isobutyric acid" ], "offsets": [ [ 91, 96 ], [ 119, 126 ], [ 128, 135 ], [ 137, 146 ], [ 151, 185 ] ] }, { "pmid": "16373326", "text": "Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM).", "type": "CHEMICAL", "entities": [ "Proline" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "16373326", "text": "A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient.", "type": "CHEMICAL", "entities": [ "Na+", "H+" ], "offsets": [ [ 174, 177 ], [ 222, 224 ] ] }, { "pmid": "16373326", "text": "In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system.", "type": "CHEMICAL", "entities": [ "Na+", "proline" ], "offsets": [ [ 19, 22 ], [ 102, 109 ] ] }, { "pmid": "16373326", "text": "The functional characteristics of rabbit PAT1 in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria.", "type": "CHEMICAL", "entities": [ "proline", "glycine", "hydroxyproline" ], "offsets": [ [ 139, 146 ], [ 148, 155 ], [ 160, 174 ] ] }, { "pmid": "16388933", "text": "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade.\n", "type": "CHEMICAL", "entities": [ "monoamine" ], "offsets": [ [ 89, 98 ] ] }, { "pmid": "16388933", "text": "In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood.", "type": "CHEMICAL", "entities": [ "noradrenaline", "reboxetine", "desipramine", "serotonin", "fluoxetine", "clomipramine" ], "offsets": [ [ 56, 69 ], [ 83, 93 ], [ 98, 109 ], [ 119, 128 ], [ 142, 152 ], [ 157, 169 ] ] }, { "pmid": "16388933", "text": "In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production.", "type": "CHEMICAL", "entities": [ "tricyclic", "monoamine", "trimipramine" ], "offsets": [ [ 56, 65 ], [ 99, 108 ], [ 40, 52 ] ] }, { "pmid": "16388933", "text": "All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters.", "type": "CHEMICAL", "entities": [ "serotonin", "noradrenaline" ], "offsets": [ [ 137, 146 ], [ 150, 163 ] ] }, { "pmid": "16388933", "text": "The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake.", "type": "CHEMICAL", "entities": [ "trimipramine", "monoamine" ], "offsets": [ [ 14, 26 ], [ 197, 206 ] ] }, { "pmid": "16388933", "text": "Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine.", "type": "CHEMICAL", "entities": [ "noradrenaline", "reboxetine", "desipramine" ], "offsets": [ [ 176, 189 ], [ 210, 220 ], [ 225, 236 ] ] }, { "pmid": "16418149", "text": "Effect of cyproheptadine on serum leptin levels.\n", "type": "CHEMICAL", "entities": [ "cyproheptadine" ], "offsets": [ [ 10, 24 ] ] }, { "pmid": "16418149", "text": "Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 16, 26 ] ] }, { "pmid": "16418149", "text": "Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain.", "type": "CHEMICAL", "entities": [ "Cyproheptadine", "piperidine", "antihistamine" ], "offsets": [ [ 0, 14 ], [ 20, 30 ], [ 31, 44 ] ] }, { "pmid": "16418149", "text": "Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies.", "type": "CHEMICAL", "entities": [ "cyproheptadine" ], "offsets": [ [ 25, 39 ] ] }, { "pmid": "16418149", "text": "This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders.", "type": "CHEMICAL", "entities": [ "cyproheptadine" ], "offsets": [ [ 74, 88 ] ] }, { "pmid": "16418149", "text": "Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days.", "type": "CHEMICAL", "entities": [ "cyproheptadine" ], "offsets": [ [ 67, 81 ] ] }, { "pmid": "16418149", "text": "The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05).", "type": "CHEMICAL", "entities": [ "cyproheptadine" ], "offsets": [ [ 187, 201 ] ] }, { "pmid": "16418149", "text": "This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors.", "type": "CHEMICAL", "entities": [ "cyproheptadine", "cyproheptadine" ], "offsets": [ [ 47, 61 ], [ 113, 127 ] ] }, { "pmid": "16424790", "text": "Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice.\n", "type": "CHEMICAL", "entities": [ "captopril", "methionine", "enalapril", "sulfhydryl" ], "offsets": [ [ 14, 23 ], [ 157, 167 ], [ 28, 37 ], [ 63, 73 ] ] }, { "pmid": "16424790", "text": "To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats.", "type": "CHEMICAL", "entities": [ "methionine", "sulfhydryl", "SH", "angiotensin" ], "offsets": [ [ 169, 179 ], [ 23, 33 ], [ 36, 38 ], [ 93, 104 ] ] }, { "pmid": "16424790", "text": "We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats.", "type": "CHEMICAL", "entities": [ "Captopril", "SH", "enalapril", "SH", "N-acetylcysteine", "SH", "methionine" ], "offsets": [ [ 27, 36 ], [ 61, 63 ], [ 72, 81 ], [ 109, 111 ], [ 120, 136 ], [ 144, 146 ], [ 210, 220 ] ] }, { "pmid": "16424790", "text": "Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day.", "type": "CHEMICAL", "entities": [ "L-methionine", "Captopril", "Captopril", "Captopril", "enalapril", "N-acetylcysteine", "L-methionine" ], "offsets": [ [ 81, 93 ], [ 110, 119 ], [ 144, 153 ], [ 176, 185 ], [ 198, 207 ], [ 220, 236 ], [ 346, 358 ] ] }, { "pmid": "16424790", "text": "Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined.", "type": "CHEMICAL", "entities": [ "Acetylcholine", "ACh", "sodium nitroprusside", "SNP" ], "offsets": [ [ 0, 13 ], [ 15, 18 ], [ 68, 88 ], [ 90, 93 ] ] }, { "pmid": "16424790", "text": "Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed.", "type": "CHEMICAL", "entities": [ "malondialdehyde", "MDA", "nitric oxide", "NO", "superoxide" ], "offsets": [ [ 38, 53 ], [ 55, 58 ], [ 61, 73 ], [ 75, 77 ], [ 80, 90 ] ] }, { "pmid": "16424790", "text": "It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group.", "type": "CHEMICAL", "entities": [ "L-methionine", "malondialdehyde", "NO", "angiotensin" ], "offsets": [ [ 50, 62 ], [ 161, 176 ], [ 254, 256 ], [ 332, 343 ] ] }, { "pmid": "16424790", "text": "Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine.", "type": "CHEMICAL", "entities": [ "Captopril", "ACh", "malondialdehyde", "NO", "L-methionine" ], "offsets": [ [ 40, 49 ], [ 137, 140 ], [ 180, 195 ], [ 220, 222 ], [ 289, 301 ] ] }, { "pmid": "16424790", "text": "However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE.", "type": "CHEMICAL", "entities": [ "Captopril", "enalapril", "N-acetylcysteine" ], "offsets": [ [ 55, 64 ], [ 89, 98 ], [ 115, 131 ] ] }, { "pmid": "16424790", "text": "These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels.", "type": "CHEMICAL", "entities": [ "Captopril", "L-methionine", "Captopril", "NO" ], "offsets": [ [ 29, 38 ], [ 107, 119 ], [ 159, 168 ], [ 233, 235 ] ] }, { "pmid": "16424790", "text": "Furthermore, this protective effect may be concerned with the sulfhydryl group.", "type": "CHEMICAL", "entities": [ "sulfhydryl" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "16474853", "text": "Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment.\n", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 71, 80 ] ] }, { "pmid": "16474853", "text": "Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile.", "type": "CHEMICAL", "entities": [ "Sorafenib", "bis-aryl ureas" ], "offsets": [ [ 0, 9 ], [ 72, 86 ] ] }, { "pmid": "16474853", "text": "Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 37, 46 ] ] }, { "pmid": "16474853", "text": "In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT.", "type": "CHEMICAL", "entities": [ "sorafenib", "tyrosine" ], "offsets": [ [ 13, 22 ], [ 82, 90 ] ] }, { "pmid": "16474853", "text": "Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "16474853", "text": "A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "16474853", "text": "Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC).", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 80, 89 ] ] }, { "pmid": "16474853", "text": "The partial response rate was 2% for sorafenib and 0% for placebo.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 37, 46 ] ] }, { "pmid": "16474853", "text": "Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "16474853", "text": "Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated.", "type": "CHEMICAL", "entities": [ "Sorafenib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16474853", "text": "Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "16495926", "text": "A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours.\n", "type": "CHEMICAL", "entities": [ "retinoid", "bexarotene", "LGD1069", "targretin" ], "offsets": [ [ 12, 20 ], [ 40, 50 ], [ 52, 59 ], [ 61, 70 ] ] }, { "pmid": "16495926", "text": "The present study determined the influence of a retinoid X receptor agonist bexarotene on angiogenesis and metastasis in solid tumours.", "type": "CHEMICAL", "entities": [ "retinoid", "bexarotene" ], "offsets": [ [ 48, 56 ], [ 76, 86 ] ] }, { "pmid": "16495926", "text": "In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 69, 79 ] ] }, { "pmid": "16495926", "text": "In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "16495926", "text": "To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 163, 173 ] ] }, { "pmid": "16495926", "text": "Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 21, 31 ] ] }, { "pmid": "16495926", "text": "Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "16495926", "text": "Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 53, 63 ] ] }, { "pmid": "16495926", "text": "The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "16495926", "text": "Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours.", "type": "CHEMICAL", "entities": [ "bexarotene" ], "offsets": [ [ 44, 54 ] ] }, { "pmid": "16513877", "text": "All antipsychotics act on the dopamine D(2) receptor.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "16513877", "text": "Patients experiencing their first episode of schizophrenia (N=61) were genotyped for two DRD2 promoter region polymorphisms (A-241G and -141C Ins/Del) and were randomly assigned to receive 16 weeks of treatment with either risperidone or olanzapine.", "type": "CHEMICAL", "entities": [ "risperidone", "olanzapine" ], "offsets": [ [ 223, 234 ], [ 238, 248 ] ] }, { "pmid": "16532916", "text": "Intrauterine pressure, ischemia markers, and experienced pain during administration of a vasopressin V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea.\n", "type": "CHEMICAL", "entities": [ "vasopressin", "vasopressin" ], "offsets": [ [ 144, 155 ], [ 89, 100 ] ] }, { "pmid": "16532916", "text": "A model to study the effect of vasopressin V1a antagonist in dysmenorrhea.", "type": "CHEMICAL", "entities": [ "vasopressin" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "16532916", "text": "At each menstruation a bolus injection of 10 pmol/kg of vasopressin was administered before and during infusion of either 300 microg/min of atosiban or placebo.", "type": "CHEMICAL", "entities": [ "atosiban", "vasopressin" ], "offsets": [ [ 140, 148 ], [ 56, 67 ] ] }, { "pmid": "16532916", "text": "Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each vasopressin injection as well as before and after the start of either atosiban or placebo infusion.", "type": "CHEMICAL", "entities": [ "vasopressin", "atosiban" ], "offsets": [ [ 106, 117 ], [ 176, 184 ] ] }, { "pmid": "16532916", "text": "Vasopressin injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects.", "type": "CHEMICAL", "entities": [ "Vasopressin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16532916", "text": "The vasopressin-induced rise in area under the curve was lower during atosiban administration than during infusion of placebo in both groups.", "type": "CHEMICAL", "entities": [ "vasopressin", "atosiban" ], "offsets": [ [ 4, 15 ], [ 70, 78 ] ] }, { "pmid": "16532916", "text": "None of the ischemia markers differed between or within groups at vasopressin injections or atosiban/placebo infusions.", "type": "CHEMICAL", "entities": [ "vasopressin", "atosiban" ], "offsets": [ [ 66, 77 ], [ 92, 100 ] ] }, { "pmid": "16532916", "text": "In subjects with dysmenorrhea the increase in pain following the administration of vasopressin was significantly lower during atosiban than during placebo infusion.", "type": "CHEMICAL", "entities": [ "vasopressin", "atosiban" ], "offsets": [ [ 83, 94 ], [ 126, 134 ] ] }, { "pmid": "16532916", "text": "Healthy volunteers experienced only slight discomfort after the vasopressin injections.", "type": "CHEMICAL", "entities": [ "vasopressin" ], "offsets": [ [ 64, 75 ] ] }, { "pmid": "16532916", "text": "Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea.", "type": "CHEMICAL", "entities": [ "Atosiban", "vasopressin" ], "offsets": [ [ 0, 8 ], [ 17, 28 ] ] }, { "pmid": "16532916", "text": "The dysmenorrhea pain evoked by vasopressin correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one V1a-like receptor.", "type": "CHEMICAL", "entities": [ "vasopressin" ], "offsets": [ [ 32, 43 ] ] }, { "pmid": "16538493", "text": "Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker?\nBACKGROUND AND AIMS:", "type": "CHEMICAL", "entities": [ "Thymidylate" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16538493", "text": "Thymidylate synthase (TS) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (5-FU).", "type": "CHEMICAL", "entities": [ "5-fluorouracil", "5-FU", "Thymidylate" ], "offsets": [ [ 86, 100 ], [ 102, 106 ], [ 0, 11 ] ] }, { "pmid": "16580895", "text": "Enzymatic and biochemical properties of a novel human serine dehydratase isoform.\n", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 54, 60 ] ] }, { "pmid": "16580895", "text": "A cDNA clone similar to human serine dehydratase (SDH) is deposited in the GenBank/EMBL databases, but its structural and functional bases remain unknown.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 30, 36 ] ] }, { "pmid": "16580895", "text": "The purified protein showed l-serine and l-threonine dehydratase activity, demonstrating to be an isoform of SDH.", "type": "CHEMICAL", "entities": [ "l-serine", "l-threonine" ], "offsets": [ [ 28, 36 ], [ 41, 52 ] ] }, { "pmid": "16580895", "text": "Removal of Pro128 from the hepatic SDH consisting of 328 residues, which is missing in the corresponding position of the isoform consisting of 329 residues, significantly changed the Michaelis constants and Kd value for pyridoxal 5'-phosphate, whereas addition of a proline residue to the isoform was without effect.", "type": "CHEMICAL", "entities": [ "pyridoxal 5'-phosphate", "proline" ], "offsets": [ [ 220, 242 ], [ 266, 273 ] ] }, { "pmid": "16599255", "text": "Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents.\n", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 31, 40 ] ] }, { "pmid": "16599255", "text": "Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the acetylcholinesterase inhibitor tacrine.", "type": "CHEMICAL", "entities": [ "N", "histamine", "tacrine", "histamine" ], "offsets": [ [ 141, 142 ], [ 20, 29 ], [ 236, 243 ], [ 97, 106 ] ] }, { "pmid": "16599255", "text": "H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of acetylcholine are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "histamine", "acetylcholine" ], "offsets": [ [ 65, 74 ], [ 114, 127 ] ] }, { "pmid": "16599255", "text": "Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of acetylcholinesterase and of butyrylcholinesterase which is another catalytic enzyme hydrolysing acetylcholine.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 208, 221 ] ] }, { "pmid": "16599255", "text": "Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine.", "type": "CHEMICAL", "entities": [ "histamine", "tacrine" ], "offsets": [ [ 53, 62 ], [ 201, 208 ] ] }, { "pmid": "16609060", "text": "Dacarbazine remains the only \"standard\" agent.", "type": "CHEMICAL", "entities": [ "Dacarbazine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16609060", "text": "For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors.", "type": "CHEMICAL", "entities": [ "sorafenib", "PD-0325901", "rapamycin", "rapamycin" ], "offsets": [ [ 60, 69 ], [ 121, 131 ], [ 215, 224 ], [ 259, 268 ] ] }, { "pmid": "16618126", "text": "The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter.", "type": "CHEMICAL", "entities": [ "ATP", "phosphatidylserine", "PS" ], "offsets": [ [ 154, 157 ], [ 44, 62 ], [ 64, 66 ] ] }, { "pmid": "16618126", "text": "This aminophospholipid \"flippase\" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents.", "type": "CHEMICAL", "entities": [ "PS", "vanadate", "Ca(2+)", "sulfhydryl" ], "offsets": [ [ 57, 59 ], [ 120, 128 ], [ 130, 136 ], [ 158, 168 ] ] }, { "pmid": "16618126", "text": "A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry.", "type": "CHEMICAL", "entities": [ "PS" ], "offsets": [ [ 12, 14 ] ] }, { "pmid": "16618126", "text": "To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified.", "type": "CHEMICAL", "entities": [ "PS" ], "offsets": [ [ 73, 75 ] ] }, { "pmid": "16618126", "text": "The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS.", "type": "CHEMICAL", "entities": [ "phosphatidylcholine", "phosphatidic acid", "phosphatidylinositol", "phosphatidylglycerol", "phosphatidylethanolamine", "PE", "PS" ], "offsets": [ [ 80, 99 ], [ 101, 118 ], [ 123, 143 ], [ 171, 191 ], [ 195, 219 ], [ 221, 223 ], [ 256, 258 ] ] }, { "pmid": "16618126", "text": "The selectivity for PS is dependent upon multiple elements of the lipid structure.", "type": "CHEMICAL", "entities": [ "PS" ], "offsets": [ [ 20, 22 ] ] }, { "pmid": "16618126", "text": "Similar to the plasma membrane PS transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer.", "type": "CHEMICAL", "entities": [ "sn-1,2-glycerol", "sn-2,3-glycerol", "PS" ], "offsets": [ [ 99, 114 ], [ 140, 155 ], [ 31, 33 ] ] }, { "pmid": "16618126", "text": "Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase.", "type": "CHEMICAL", "entities": [ "PS", "PS" ], "offsets": [ [ 26, 28 ], [ 93, 95 ] ] }, { "pmid": "16618126", "text": "Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate Atp8a1.", "type": "CHEMICAL", "entities": [ "phosphatidylserine-O-methyl ester", "lysophosphatidylserine", "glycerophosphoserine", "phosphoserine" ], "offsets": [ [ 61, 94 ], [ 96, 118 ], [ 120, 140 ], [ 146, 159 ] ] }, { "pmid": "16618126", "text": "Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators.", "type": "CHEMICAL", "entities": [ "PE", "phosphatidylhydroxypropionate", "phosphatidylhomoserine" ], "offsets": [ [ 28, 30 ], [ 32, 61 ], [ 67, 89 ] ] }, { "pmid": "16618126", "text": "However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating Atp8a1 activity.", "type": "CHEMICAL", "entities": [ "N-methyl-phosphatidylserine", "PS" ], "offsets": [ [ 9, 36 ], [ 115, 117 ] ] }, { "pmid": "16618126", "text": "These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase.", "type": "CHEMICAL", "entities": [ "PS", "glycerol", "serine" ], "offsets": [ [ 155, 157 ], [ 187, 195 ], [ 204, 210 ] ] }, { "pmid": "16622728", "text": "Although there was neither symptoms of dyspnea nor typical observations on a chest X-ray examination, low levels of oxygen saturation and findings of high-resolution chest computed tomographic scanning suggested a possibility of interstitial pneumonia.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 116, 122 ] ] }, { "pmid": "16647263", "text": "High-mannose-type glycan modifications of dihydrofolate reductase using glycan-methotrexate conjugates.\n", "type": "CHEMICAL", "entities": [ "dihydrofolate", "mannose", "methotrexate" ], "offsets": [ [ 42, 55 ], [ 5, 12 ], [ 79, 91 ] ] }, { "pmid": "16647263", "text": "Various high-mannose-type glycan modifications of dihydrofolate reductase (DHFR) were achieved by ligand-based approach using glycan-methotrexate (MTX) conjugates as tight binding glycan bearing ligands for DHFR.", "type": "CHEMICAL", "entities": [ "mannose", "methotrexate", "MTX", "dihydrofolate" ], "offsets": [ [ 13, 20 ], [ 133, 145 ], [ 147, 150 ], [ 50, 63 ] ] }, { "pmid": "16647263", "text": "The resulting glycan-MTX conjugates and the corresponding artificial glycoproteins could be useful as oligosaccharide- and glycoprotein-probes to perform quantitative analysis of glycan recognizing protein such as lectins, glycosyltransferases or glycosidases.", "type": "CHEMICAL", "entities": [ "MTX" ], "offsets": [ [ 21, 24 ] ] }, { "pmid": "16647263", "text": "Moreover, artificial glycoproteins having two different high-mannose-type glycans were developed for the first time by a combination of two different types of glycan modification strategies.", "type": "CHEMICAL", "entities": [ "mannose" ], "offsets": [ [ 61, 68 ] ] }, { "pmid": "16719808", "text": "NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.\n", "type": "CHEMICAL", "entities": [ "NMDA", "cholesterol", "glutamate", "NMDA" ], "offsets": [ [ 0, 4 ], [ 118, 129 ], [ 189, 198 ], [ 52, 56 ] ] }, { "pmid": "16719808", "text": "Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels.", "type": "CHEMICAL", "entities": [ "NMDA", "Glutamate", "N-methyl-D-asparate" ], "offsets": [ [ 48, 52 ], [ 0, 9 ], [ 27, 46 ] ] }, { "pmid": "16719808", "text": "They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors.", "type": "CHEMICAL", "entities": [ "magnesium" ], "offsets": [ [ 161, 170 ] ] }, { "pmid": "16719808", "text": "On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 24, 28 ] ] }, { "pmid": "16719808", "text": "NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "16719808", "text": "This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases.", "type": "CHEMICAL", "entities": [ "NMDA", "Memantine" ], "offsets": [ [ 33, 37 ], [ 136, 145 ] ] }, { "pmid": "16719808", "text": "The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD).", "type": "CHEMICAL", "entities": [ "NMDA", "tyrosine", "cholesterol", "calcium" ], "offsets": [ [ 61, 65 ], [ 128, 136 ], [ 148, 159 ], [ 197, 204 ] ] }, { "pmid": "16729906", "text": "Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma.\n", "type": "CHEMICAL", "entities": [ "Sorafenib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "16729906", "text": "Sorafenib (BAY 43-9006) is a small-molecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis.", "type": "CHEMICAL", "entities": [ "Sorafenib", "BAY 43-9006", "tyrosine" ], "offsets": [ [ 0, 9 ], [ 11, 22 ], [ 115, 123 ] ] }, { "pmid": "16729906", "text": "Based on the significant improvement in progression-free survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "16729906", "text": "In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "16729906", "text": "As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "16781459", "text": "Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide.\n", "type": "CHEMICAL", "entities": [ "Hydrogen sulfide", "nitric oxide" ], "offsets": [ [ 0, 16 ], [ 26, 38 ] ] }, { "pmid": "16781459", "text": "Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored.", "type": "CHEMICAL", "entities": [ "L-cysteine", "L-Cys", "H(2)S", "Hydrogen sulfide", "nitric oxide", "NO", "cystathionine", "cystathionine" ], "offsets": [ [ 170, 180 ], [ 182, 187 ], [ 18, 23 ], [ 0, 16 ], [ 244, 256 ], [ 258, 260 ], [ 92, 105 ], [ 131, 144 ] ] }, { "pmid": "16781459", "text": "Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS).", "type": "CHEMICAL", "entities": [ "H(2)S", "NO", "NO" ], "offsets": [ [ 51, 56 ], [ 77, 79 ], [ 105, 107 ] ] }, { "pmid": "16781459", "text": "Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK).", "type": "CHEMICAL", "entities": [ "H(2)S", "H(2)S", "NaSH", "H(2)S" ], "offsets": [ [ 5, 10 ], [ 46, 51 ], [ 60, 64 ], [ 68, 73 ] ] }, { "pmid": "16781459", "text": "Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production.", "type": "CHEMICAL", "entities": [ "H(2)S", "NaHS", "NO" ], "offsets": [ [ 18, 23 ], [ 27, 31 ], [ 88, 90 ] ] }, { "pmid": "16781459", "text": "Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid.", "type": "CHEMICAL", "entities": [ "beta-cyano-L-alanine", "NO", "L-Cys", "H(2)S", "aminooxyacetic acid" ], "offsets": [ [ 202, 222 ], [ 10, 12 ], [ 128, 133 ], [ 151, 156 ], [ 252, 271 ] ] }, { "pmid": "16781459", "text": "While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1.", "type": "CHEMICAL", "entities": [ "carbon monoxide", "CO", "H(2)S", "NO", "H(2)S", "H(2)S", "H(2)S" ], "offsets": [ [ 628, 643 ], [ 645, 647 ], [ 192, 197 ], [ 221, 223 ], [ 296, 301 ], [ 423, 428 ], [ 470, 475 ] ] }, { "pmid": "16781459", "text": "CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO.", "type": "CHEMICAL", "entities": [ "CO", "NO", "H(2)S", "NO", "CO" ], "offsets": [ [ 0, 2 ], [ 40, 42 ], [ 148, 153 ], [ 166, 168 ], [ 288, 290 ] ] }, { "pmid": "16809898", "text": "Effect of chronic renal failure on arginase and argininosuccinate synthetase expression.\n", "type": "CHEMICAL", "entities": [ "argininosuccinate" ], "offsets": [ [ 48, 65 ] ] }, { "pmid": "16809898", "text": "BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis.", "type": "CHEMICAL", "entities": [ "L-arg", "urea", "nitric oxide", "L-arginine" ], "offsets": [ [ 24, 29 ], [ 87, 91 ], [ 96, 108 ], [ 12, 22 ] ] }, { "pmid": "16809898", "text": "Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase.", "type": "CHEMICAL", "entities": [ "argininosuccinate", "L-arg", "argininosuccinate" ], "offsets": [ [ 103, 120 ], [ 11, 16 ], [ 70, 87 ] ] }, { "pmid": "16809898", "text": "L-arg is converted to urea by arginase I in the liver and arginase II in the kidney.", "type": "CHEMICAL", "entities": [ "L-arg", "urea" ], "offsets": [ [ 0, 5 ], [ 22, 26 ] ] }, { "pmid": "16809898", "text": "Normally, the liver fully consumes L-arg for urea generation and does not contribute to its circulating pool.", "type": "CHEMICAL", "entities": [ "L-arg", "urea" ], "offsets": [ [ 35, 40 ], [ 45, 49 ] ] }, { "pmid": "16809898", "text": "Instead, much of the circulating L-arg is produced by the kidney.", "type": "CHEMICAL", "entities": [ "L-arg" ], "offsets": [ [ 33, 38 ] ] }, { "pmid": "16809898", "text": "If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF.", "type": "CHEMICAL", "entities": [ "L-arg", "L-arg" ], "offsets": [ [ 16, 21 ], [ 97, 102 ] ] }, { "pmid": "16809898", "text": "We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of arginase.", "type": "CHEMICAL", "entities": [ "L-arg" ], "offsets": [ [ 44, 49 ] ] }, { "pmid": "16809898", "text": "METHODS: Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation.", "type": "CHEMICAL", "entities": [ "Argininosuccinate" ], "offsets": [ [ 9, 26 ] ] }, { "pmid": "16809898", "text": "In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro.", "type": "CHEMICAL", "entities": [ "urea" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "16809898", "text": "However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates.", "type": "CHEMICAL", "entities": [ "urea" ], "offsets": [ [ 134, 138 ] ] }, { "pmid": "16809898", "text": "CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine.", "type": "CHEMICAL", "entities": [ "argininosuccinate" ], "offsets": [ [ 33, 50 ] ] }, { "pmid": "16809898", "text": "Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity.", "type": "CHEMICAL", "entities": [ "urea" ], "offsets": [ [ 101, 105 ] ] }, { "pmid": "16809898", "text": "The latter, in turn, attenuates L-arg catabolism and urea production and, thereby, mitigates the fall in plasma L-arg.", "type": "CHEMICAL", "entities": [ "L-arg", "L-arg" ], "offsets": [ [ 32, 37 ], [ 112, 117 ] ] }, { "pmid": "16843091", "text": "Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.\n", "type": "CHEMICAL", "entities": [ "Vasopressin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "16843091", "text": "It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses.", "type": "CHEMICAL", "entities": [ "AVP", "arginine vasopressin" ], "offsets": [ [ 79, 82 ], [ 57, 77 ] ] }, { "pmid": "16843091", "text": "In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor.", "type": "CHEMICAL", "entities": [ "vasopressin" ], "offsets": [ [ 115, 126 ] ] }, { "pmid": "16843091", "text": "Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks.", "type": "CHEMICAL", "entities": [ "AVP" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "16843091", "text": "However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463.", "type": "CHEMICAL", "entities": [ "VPA-985", "lixivaptan", "YM-087", "conivaptan", "OPC-41061", "tolvaptan", "SR-121463" ], "offsets": [ [ 110, 117 ], [ 119, 129 ], [ 132, 138 ], [ 140, 150 ], [ 153, 162 ], [ 164, 173 ], [ 180, 189 ] ] }, { "pmid": "16843091", "text": "Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.", "type": "CHEMICAL", "entities": [ "vasopressin" ], "offsets": [ [ 125, 136 ] ] }, { "pmid": "1686208", "text": "Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.\n", "type": "CHEMICAL", "entities": [ "dimethindene", "histamine", "chlorpheniramine" ], "offsets": [ [ 107, 119 ], [ 13, 22 ], [ 86, 102 ] ] }, { "pmid": "1686208", "text": "The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans.", "type": "CHEMICAL", "entities": [ "(+)- and (-)-chlorpheniramine", "(+)- and (-)-dimethindene" ], "offsets": [ [ 21, 50 ], [ 60, 85 ] ] }, { "pmid": "1686208", "text": "Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos.", "type": "CHEMICAL", "entities": [ "triprolidine hydrochloride" ], "offsets": [ [ 28, 54 ] ] }, { "pmid": "1686208", "text": "2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene.", "type": "CHEMICAL", "entities": [ "triprolidine", "(+)-chlorpheniramine", "(-)-dimethindene", "(+)-chlorpheniramine", "(-)-dimethindene" ], "offsets": [ [ 45, 57 ], [ 59, 79 ], [ 84, 100 ], [ 162, 182 ], [ 187, 203 ] ] }, { "pmid": "1686208", "text": "Performance on digit symbol substitution was impaired with (+)-chlorpheniramine.", "type": "CHEMICAL", "entities": [ "(+)-chlorpheniramine" ], "offsets": [ [ 59, 79 ] ] }, { "pmid": "1686208", "text": "3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo.", "type": "CHEMICAL", "entities": [ "(-)-chlorpheniramine", "(+)-dimethindene" ], "offsets": [ [ 28, 48 ], [ 53, 69 ] ] }, { "pmid": "1686208", "text": "In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 131, 140 ] ] }, { "pmid": "16866189", "text": "BG did not show a clastogenic effect, but was anti-clastogenic in both cell lines used, and at all concentrations tested (2.5, 5 and 10 microg/mL) in combination with damage inducing agents (methylmethane sulfonate in cell line CHO-k1, and methylmethane sulfonate or 2-aminoanthracene in cell line HTC).", "type": "CHEMICAL", "entities": [ "methylmethane sulfonate", "methylmethane sulfonate", "2-aminoanthracene" ], "offsets": [ [ 191, 214 ], [ 240, 263 ], [ 267, 284 ] ] }, { "pmid": "16866189", "text": "BG also showed a protective effect in the presence of a DNA polymerase beta inhibitor (cytosine arabinoside-3-phosphate, Ara-C), demonstrating that BG does not act through an anti-mutagenic mechanism of action involving DNA polymerase beta.", "type": "CHEMICAL", "entities": [ "cytosine arabinoside-3-phosphate", "Ara-C" ], "offsets": [ [ 87, 119 ], [ 121, 126 ] ] }, { "pmid": "16867246", "text": "Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients.\n", "type": "CHEMICAL", "entities": [ "chlorpromazine" ], "offsets": [ [ 38, 52 ] ] }, { "pmid": "16867246", "text": "In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients.", "type": "CHEMICAL", "entities": [ "chlorpromazine" ], "offsets": [ [ 50, 64 ] ] }, { "pmid": "16867246", "text": "We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks.", "type": "CHEMICAL", "entities": [ "nucleotide", "chlorpromazine" ], "offsets": [ [ 31, 41 ], [ 254, 268 ] ] }, { "pmid": "16867246", "text": "Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia.", "type": "CHEMICAL", "entities": [ "chlorpromazine" ], "offsets": [ [ 170, 184 ] ] }, { "pmid": "16879709", "text": "Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain.\n", "type": "CHEMICAL", "entities": [ "glutamic acid" ], "offsets": [ [ 37, 50 ] ] }, { "pmid": "16879709", "text": "Previously, we reported that l-glutamic acid decarboxylase isoform 65 (GAD65) could be cleaved in vitro to release a stable truncated form which lacks amino acid 1-69 from the N-terminus, GAD65(Delta1-69).", "type": "CHEMICAL", "entities": [ "amino acid", "N", "l-glutamic acid" ], "offsets": [ [ 151, 161 ], [ 176, 177 ], [ 29, 44 ] ] }, { "pmid": "16879709", "text": "Furthermore, we demonstrated that this conversion was calcium dependent.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 54, 61 ] ] }, { "pmid": "16879709", "text": "Calcium-chelating reagents such as EDTA and 1,2-bis-(o-aminphenoxy)-ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxy-methyl ester prevented the cleavage of GAD65.", "type": "CHEMICAL", "entities": [ "Calcium", "EDTA", "1,2-bis-(o-aminphenoxy)-ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxy-methyl ester" ], "offsets": [ [ 0, 7 ], [ 35, 39 ], [ 44, 129 ] ] }, { "pmid": "16879709", "text": "In addition, our data suggested that calpain, a calcium-dependent cysteine protease, is activated upon neuronal stimulation and could be responsible for the conversion of full-length GAD65 to truncated GAD65 in the brain.", "type": "CHEMICAL", "entities": [ "calcium", "cysteine" ], "offsets": [ [ 48, 55 ], [ 66, 74 ] ] }, { "pmid": "16901402", "text": "Agents that specifically target BRAF, such as sorafenib, as well as new molecules that function both upstream and downstream of BRAF, are being actively investigated.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "16901636", "text": "Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination.", "type": "CHEMICAL", "entities": [ "rosuvastatin", "candesartan", "HMG-CoA" ], "offsets": [ [ 108, 120 ], [ 63, 74 ], [ 80, 87 ] ] }, { "pmid": "16901636", "text": "Our purpose was to test the impact of single and/or combined treatment with the AT(1)-receptor blocker candesartan and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats.", "type": "CHEMICAL", "entities": [ "candesartan", "HMG-CoA", "rosuvastatin" ], "offsets": [ [ 103, 114 ], [ 123, 130 ], [ 151, 163 ] ] }, { "pmid": "16901636", "text": "L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS).", "type": "CHEMICAL", "entities": [ "L-NAME", "nitric oxide" ], "offsets": [ [ 0, 6 ], [ 90, 102 ] ] }, { "pmid": "16901636", "text": "Rats received candesartan 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with candesartan pre- and posttreatment.", "type": "CHEMICAL", "entities": [ "candesartan", "rosuvastatin", "candesartan" ], "offsets": [ [ 14, 25 ], [ 109, 121 ], [ 177, 188 ] ] }, { "pmid": "16901636", "text": "In addition, candesartan and rosuvastatin were combined with L-NAME.", "type": "CHEMICAL", "entities": [ "candesartan", "rosuvastatin", "L-NAME" ], "offsets": [ [ 13, 24 ], [ 29, 41 ], [ 61, 67 ] ] }, { "pmid": "16901636", "text": "As result, compared to controls (109+/-12 mm(3)) infarct size with candesartan (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or rosuvastatin (69+/-14 mm(3); P<0.05) was smaller.", "type": "CHEMICAL", "entities": [ "candesartan", "rosuvastatin" ], "offsets": [ [ 67, 78 ], [ 149, 161 ] ] }, { "pmid": "16901636", "text": "Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over candesartan pretreatment alone.", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 164, 175 ] ] }, { "pmid": "16901636", "text": "Compared to controls (2.08+/-0.28) only candesartan pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05).", "type": "CHEMICAL", "entities": [ "candesartan" ], "offsets": [ [ 40, 51 ] ] }, { "pmid": "16901636", "text": "L-NAME abolished the reduction in infarct size and improvement in neuroscore.", "type": "CHEMICAL", "entities": [ "L-NAME" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "16901636", "text": "In conclusion, both, candesartan or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with candesartan pretreatment.", "type": "CHEMICAL", "entities": [ "candesartan", "rosuvastatin", "candesartan" ], "offsets": [ [ 21, 32 ], [ 36, 48 ], [ 156, 167 ] ] }, { "pmid": "16901636", "text": "Combined treatment was superior to rosuvastatin alone, but not to candesartan.", "type": "CHEMICAL", "entities": [ "rosuvastatin", "candesartan" ], "offsets": [ [ 35, 47 ], [ 66, 77 ] ] }, { "pmid": "16902423", "text": "Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI.", "type": "CHEMICAL", "entities": [ "adenosine triphosphate" ], "offsets": [ [ 83, 105 ] ] }, { "pmid": "16902423", "text": "A combination of oligonucleotide arrays, multiplex PCR analysis and single-nucleotide polymorphism genotyping revealed a heterozygous intragenic deletion in exon 8.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 75, 85 ] ] }, { "pmid": "16905533", "text": "Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma.\n", "type": "CHEMICAL", "entities": [ "diacylglycerol" ], "offsets": [ [ 37, 51 ] ] }, { "pmid": "16905533", "text": "Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK).", "type": "CHEMICAL", "entities": [ "phosphatidic acid", "Diacylglycerol", "DAG" ], "offsets": [ [ 99, 116 ], [ 0, 14 ], [ 16, 19 ] ] }, { "pmid": "16905533", "text": "gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro.", "type": "CHEMICAL", "entities": [ "Ca2+", "phosphatidylserine", "diolein" ], "offsets": [ [ 91, 95 ], [ 107, 125 ], [ 126, 133 ] ] }, { "pmid": "16905533", "text": "Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma.", "type": "CHEMICAL", "entities": [ "phosphorylated Ser", "Ser" ], "offsets": [ [ 72, 90 ], [ 99, 102 ] ] }, { "pmid": "16905533", "text": "The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant.", "type": "CHEMICAL", "entities": [ "glutamic acid", "Ser", "Ser" ], "offsets": [ [ 144, 157 ], [ 102, 105 ], [ 114, 117 ] ] }, { "pmid": "1692236", "text": "Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum acetylcholinesterase has been extensively characterized with respect to its anticholinesterase properties.", "type": "CHEMICAL", "entities": [ "diisopropyl phosphorofluoridate" ], "offsets": [ [ 43, 74 ] ] }, { "pmid": "1692236", "text": "Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds.", "type": "CHEMICAL", "entities": [ "guanidine" ], "offsets": [ [ 286, 295 ] ] }, { "pmid": "1692236", "text": "Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CH3P(O)(O-)-AChE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase.", "type": "CHEMICAL", "entities": [ "oxygen", "P", "CH3P(O)(O-)", "organophosphoryl", "organophosphates" ], "offsets": [ [ 98, 104 ], [ 121, 122 ], [ 129, 140 ], [ 219, 235 ], [ 14, 30 ] ] }, { "pmid": "16950805", "text": "Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes.\n", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 11, 21 ] ] }, { "pmid": "16950805", "text": "Folic acid plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation.", "type": "CHEMICAL", "entities": [ "Folic acid", "uracil", "thymine" ], "offsets": [ [ 0, 10 ], [ 115, 121 ], [ 125, 132 ] ] }, { "pmid": "16950805", "text": "Besides dietary habits, folic acid metabolism is influenced by genetic polymorphism.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "16950805", "text": "The C677T polymorphism of the methylene-tetrahydrofolate reductase (MTHFR) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on folate status.", "type": "CHEMICAL", "entities": [ "methylene-tetrahydrofolate", "folate" ], "offsets": [ [ 30, 56 ], [ 197, 203 ] ] }, { "pmid": "16950805", "text": "In this work the effect of folic acid deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different MTHFR genotype (four for each genotype).", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 27, 37 ] ] }, { "pmid": "16950805", "text": "Cells were grown for 9 days with 12, 24 and 120 nM folic acid and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 51, 61 ] ] }, { "pmid": "16950805", "text": "In other experiments, cells were grown with various folic acid concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "16950805", "text": "The results obtained indicate that folic acid deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the MTHFR genotype.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "16950805", "text": "The effect of folic acid was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "16950805", "text": "Also nucleoplasmic bridges and buds were significantly increased under low folate supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the MTHFR genotype (P = 0.006) on this biomarker.", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 75, 81 ] ] }, { "pmid": "16950805", "text": "Folic acid concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low folic acid was mainly accounted for by carriers of the variant MTHFR allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance.", "type": "CHEMICAL", "entities": [ "Folic acid", "folic acid" ], "offsets": [ [ 0, 10 ], [ 157, 167 ] ] }, { "pmid": "16950805", "text": "The effect of folic acid level on this end-point was modulated by the MTHFR genotype (P for interaction = 0.02), with TT cells grown at low folic acid concentration apparently resistant to the induction of radiation-induced bridges.", "type": "CHEMICAL", "entities": [ "folic acid", "folic acid" ], "offsets": [ [ 14, 24 ], [ 140, 150 ] ] }, { "pmid": "16950805", "text": "Finally, the effect of in vitro folate deprivation on global DNA methylation was evaluated in lymphocytes of six homozygous subjects (three CC and three TT).", "type": "CHEMICAL", "entities": [ "folate" ], "offsets": [ [ 32, 38 ] ] }, { "pmid": "16950805", "text": "The results obtained suggest that, under the conditions of this work, folic acid deprivation is associated with global DNA hypermethylation.", "type": "CHEMICAL", "entities": [ "folic acid" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "16964330", "text": "Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole.", "type": "CHEMICAL", "entities": [ "amphotericin B", "fluconazole", "itraconazole" ], "offsets": [ [ 99, 113 ], [ 115, 126 ], [ 131, 143 ] ] }, { "pmid": "16964330", "text": "Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management.", "type": "CHEMICAL", "entities": [ "voriconazole", "posaconazole", "ravuconazole", "caspofungin", "micafungin" ], "offsets": [ [ 69, 81 ], [ 83, 95 ], [ 97, 109 ], [ 111, 122 ], [ 127, 137 ] ] }, { "pmid": "16964330", "text": "The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents.", "type": "CHEMICAL", "entities": [ "allylamines", "phenylmorpholines", "amphotericin B", "ergosterol", "sterols", "ergosterol", "azole" ], "offsets": [ [ 189, 200 ], [ 202, 219 ], [ 19, 33 ], [ 39, 49 ], [ 69, 76 ], [ 136, 146 ], [ 224, 229 ] ] }, { "pmid": "16964330", "text": "The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p.", "type": "CHEMICAL", "entities": [ "azole" ], "offsets": [ [ 29, 34 ] ] }, { "pmid": "16964330", "text": "The phenylmorpholines, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase).", "type": "CHEMICAL", "entities": [ "phenylmorpholines", "amorolfine" ], "offsets": [ [ 4, 21 ], [ 32, 42 ] ] }, { "pmid": "16964330", "text": "The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2.", "type": "CHEMICAL", "entities": [ "sordarins" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "16964330", "text": "Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402.", "type": "CHEMICAL", "entities": [ "SCH57504", "xylarin", "hypoxysordarin", "GR135402", "zofimarin", "BE31045" ], "offsets": [ [ 49, 57 ], [ 59, 66 ], [ 68, 82 ], [ 87, 95 ], [ 29, 38 ], [ 40, 47 ] ] }, { "pmid": "16964330", "text": "In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored.", "type": "CHEMICAL", "entities": [ "azole", "echinocandins" ], "offsets": [ [ 67, 72 ], [ 95, 108 ] ] }, { "pmid": "16964330", "text": "Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans.", "type": "CHEMICAL", "entities": [ "N", "myristate", "histidine", "aminobenzothiazoles", "quinolines", "benzofurans" ], "offsets": [ [ 81, 82 ], [ 138, 147 ], [ 152, 161 ], [ 205, 224 ], [ 226, 236 ], [ 241, 252 ] ] }, { "pmid": "16964330", "text": "Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target.", "type": "CHEMICAL", "entities": [ "uridine di-phospho sugars" ], "offsets": [ [ 47, 72 ] ] }, { "pmid": "16965760", "text": "D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation.\n", "type": "CHEMICAL", "entities": [ "D-myo-inositol 1-phosphate", "D-myo-inositol 1,4,5-tris phosphate" ], "offsets": [ [ 0, 26 ], [ 45, 80 ] ] }, { "pmid": "16965760", "text": "Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays.", "type": "CHEMICAL", "entities": [ "Ca2+", "D-myo-inositol 1,4,5-trisphosphate", "IP3", "inositol phosphate" ], "offsets": [ [ 125, 129 ], [ 143, 177 ], [ 179, 182 ], [ 250, 268 ] ] }, { "pmid": "16965760", "text": "A specific detection of IP3 production was also established using IP3 binding proteins.", "type": "CHEMICAL", "entities": [ "IP3", "IP3" ], "offsets": [ [ 66, 69 ], [ 24, 27 ] ] }, { "pmid": "16965760", "text": "The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses.", "type": "CHEMICAL", "entities": [ "IP3" ], "offsets": [ [ 22, 25 ] ] }, { "pmid": "16965760", "text": "Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade.", "type": "CHEMICAL", "entities": [ "IP3", "inositol phosphate" ], "offsets": [ [ 13, 16 ], [ 46, 64 ] ] }, { "pmid": "16965760", "text": "It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade.", "type": "CHEMICAL", "entities": [ "lithium chloride", "LiCl", "D-myo-inositol 1-phosphate", "IP3" ], "offsets": [ [ 35, 51 ], [ 53, 57 ], [ 68, 94 ], [ 191, 194 ] ] }, { "pmid": "16965760", "text": "We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation.", "type": "CHEMICAL", "entities": [ "IP1", "IP3" ], "offsets": [ [ 18, 21 ], [ 52, 55 ] ] }, { "pmid": "16965760", "text": "It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 42, 46 ] ] }, { "pmid": "16965760", "text": "Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates.", "type": "CHEMICAL", "entities": [ "D-myo-inositol 1 monophosphate", "IP1", "inositol phosphates" ], "offsets": [ [ 40, 70 ], [ 72, 75 ], [ 192, 211 ] ] }, { "pmid": "16970975", "text": "Non-enzymatic interactions of glyoxylate with lysine, arginine, and glucosamine: a study of advanced non-enzymatic glycation like compounds.\n", "type": "CHEMICAL", "entities": [ "glyoxylate", "lysine", "arginine", "glucosamine" ], "offsets": [ [ 30, 40 ], [ 46, 52 ], [ 54, 62 ], [ 68, 79 ] ] }, { "pmid": "16970975", "text": "Glyoxylate is a 2 carbon aldo acid that is formed in hepatic tissue from glycolate.", "type": "CHEMICAL", "entities": [ "Glyoxylate", "glycolate", "carbon aldo acid" ], "offsets": [ [ 0, 10 ], [ 73, 82 ], [ 18, 34 ] ] }, { "pmid": "16970975", "text": "Once formed, the molecule can be converted to glycine by alanine-glyoxylate aminotransferase (AGAT).", "type": "CHEMICAL", "entities": [ "glycine", "alanine", "glyoxylate" ], "offsets": [ [ 46, 53 ], [ 57, 64 ], [ 65, 75 ] ] }, { "pmid": "16970975", "text": "In defects of AGAT, glyoxylate is transformed to oxalate, resulting in high levels of oxalate in the body.", "type": "CHEMICAL", "entities": [ "oxalate", "oxalate", "glyoxylate" ], "offsets": [ [ 49, 56 ], [ 86, 93 ], [ 20, 30 ] ] }, { "pmid": "16970975", "text": "First, it was to determine, if akin to D-glucose, D-fructose or DL-glyceraldehyde, glyoxylate was susceptible to non-enzymatic attack by amino containing molecules such as lysine, arginine or glucosamine.", "type": "CHEMICAL", "entities": [ "D-glucose", "D-fructose", "DL-glyceraldehyde", "glyoxylate", "amino", "lysine", "arginine", "glucosamine" ], "offsets": [ [ 39, 48 ], [ 50, 60 ], [ 64, 81 ], [ 83, 93 ], [ 137, 142 ], [ 172, 178 ], [ 180, 188 ], [ 192, 203 ] ] }, { "pmid": "16970975", "text": "Second, if by virtue of its molecular structure and size, glyoxylate was as reactive a reagent in non-enzymatic reactions as DL-glyceraldehyde; i.e., a glycose that we previously demonstrated to be a more effective glycating agent than D-glucose or D-fructose.", "type": "CHEMICAL", "entities": [ "glyoxylate", "DL-glyceraldehyde", "glycose", "D-glucose", "D-fructose" ], "offsets": [ [ 58, 68 ], [ 125, 142 ], [ 152, 159 ], [ 236, 245 ], [ 249, 259 ] ] }, { "pmid": "16970975", "text": "Using capillary electrophoresis (CE), high performance liquid chromatography and UV and fluorescence spectroscopy, glyoxylate was found to be a highly reactive precursor of advanced glycation like end products (AGLEs) and a more effective promoter of non-enzymatic end products than D-glucose, D-fructose or DL-glyceraldehyde.", "type": "CHEMICAL", "entities": [ "glyoxylate", "D-glucose", "D-fructose", "DL-glyceraldehyde" ], "offsets": [ [ 115, 125 ], [ 283, 292 ], [ 294, 304 ], [ 308, 325 ] ] }, { "pmid": "16980198", "text": "Cortisol metabolism in hypertension.\n", "type": "CHEMICAL", "entities": [ "Cortisol" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "16980198", "text": "Corticosteroids are critically involved in blood pressure regulation.", "type": "CHEMICAL", "entities": [ "Corticosteroids" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "16980198", "text": "Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure.", "type": "CHEMICAL", "entities": [ "steroids" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "16980198", "text": "At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs).", "type": "CHEMICAL", "entities": [ "11beta-hydroxysteroid" ], "offsets": [ [ 63, 84 ] ] }, { "pmid": "16980198", "text": "11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action.", "type": "CHEMICAL", "entities": [ "cortisone", "cortisol" ], "offsets": [ [ 22, 31 ], [ 35, 43 ] ] }, { "pmid": "16980198", "text": "By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol.", "type": "CHEMICAL", "entities": [ "aldosterone", "cortisol", "cortisone", "cortisol" ], "offsets": [ [ 49, 60 ], [ 139, 147 ], [ 151, 160 ], [ 226, 234 ] ] }, { "pmid": "16980198", "text": "Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 145, 153 ] ] }, { "pmid": "16980198", "text": "Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype.", "type": "CHEMICAL", "entities": [ "carbenoxolone" ], "offsets": [ [ 73, 86 ] ] }, { "pmid": "16982809", "text": "PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells.\n", "type": "CHEMICAL", "entities": [ "retinoic acid" ], "offsets": [ [ 49, 62 ] ] }, { "pmid": "16982809", "text": "Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2).", "type": "CHEMICAL", "entities": [ "retinoic acid", "retinol", "retinal", "retinol", "retinaldehyde" ], "offsets": [ [ 45, 58 ], [ 99, 106 ], [ 111, 118 ], [ 148, 155 ], [ 177, 190 ] ] }, { "pmid": "16982809", "text": "PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol.", "type": "CHEMICAL", "entities": [ "retinol", "all-trans retinoic acid", "ATRA" ], "offsets": [ [ 140, 147 ], [ 104, 127 ], [ 129, 133 ] ] }, { "pmid": "16982809", "text": "ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression.", "type": "CHEMICAL", "entities": [ "ATRA", "retinoic acid" ], "offsets": [ [ 0, 4 ], [ 57, 70 ] ] }, { "pmid": "16982809", "text": "The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation.", "type": "CHEMICAL", "entities": [ "retinoic acid" ], "offsets": [ [ 4, 17 ] ] }, { "pmid": "16982809", "text": "Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 94, 102 ] ] }, { "pmid": "16982809", "text": "These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "17015817", "text": "Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects.\n", "type": "CHEMICAL", "entities": [ "Ramelteon" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17015817", "text": "Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for insomnia treatment.", "type": "CHEMICAL", "entities": [ "Ramelteon" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17015817", "text": "To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug.", "type": "CHEMICAL", "entities": [ "ramelteon", "triazolam", "benzodiazepine" ], "offsets": [ [ 102, 111 ], [ 126, 135 ], [ 147, 161 ] ] }, { "pmid": "17015817", "text": "In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days.", "type": "CHEMICAL", "entities": [ "triazolam", "ramelteon" ], "offsets": [ [ 109, 118 ], [ 78, 87 ] ] }, { "pmid": "17015817", "text": "Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse.", "type": "CHEMICAL", "entities": [ "ramelteon" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "17015817", "text": "In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo.", "type": "CHEMICAL", "entities": [ "ramelteon" ], "offsets": [ [ 94, 103 ] ] }, { "pmid": "17015817", "text": "Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure.", "type": "CHEMICAL", "entities": [ "ramelteon" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "17015817", "text": "In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability.", "type": "CHEMICAL", "entities": [ "triazolam" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "17015817", "text": "Ramelteon demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications.", "type": "CHEMICAL", "entities": [ "Ramelteon" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17016511", "text": "Inhibition of cardiac voltage-gated sodium channels by grape polyphenols.\n", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "17016511", "text": "The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including quercetin, catechin and resveratrol.", "type": "CHEMICAL", "entities": [ "quercetin", "catechin", "resveratrol" ], "offsets": [ [ 144, 153 ], [ 155, 163 ], [ 168, 179 ] ] }, { "pmid": "17016511", "text": "Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "17016511", "text": "Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively.", "type": "CHEMICAL", "entities": [ "calcium", "calcium", "Calcium" ], "offsets": [ [ 7, 14 ], [ 67, 74 ], [ 89, 96 ] ] }, { "pmid": "17016511", "text": "The red grape polyphenols quercetin, catechin and resveratrol blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively.", "type": "CHEMICAL", "entities": [ "quercetin", "catechin", "resveratrol" ], "offsets": [ [ 26, 35 ], [ 37, 45 ], [ 50, 61 ] ] }, { "pmid": "17016511", "text": "In contrast to lidocaine, resveratrol did not exhibit any frequency-dependence of peak INa block.", "type": "CHEMICAL", "entities": [ "lidocaine", "resveratrol" ], "offsets": [ [ 15, 24 ], [ 26, 37 ] ] }, { "pmid": "17016511", "text": "Late INa induced by the VGSC long QT mutant R1623Q was reduced by resveratrol and quercetin.", "type": "CHEMICAL", "entities": [ "resveratrol", "quercetin" ], "offsets": [ [ 66, 77 ], [ 82, 91 ] ] }, { "pmid": "17016511", "text": "Resveratrol and quercetin also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively.", "type": "CHEMICAL", "entities": [ "Resveratrol", "quercetin" ], "offsets": [ [ 0, 11 ], [ 16, 25 ] ] }, { "pmid": "17016511", "text": "In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by resveratrol.", "type": "CHEMICAL", "entities": [ "resveratrol", "calcium" ], "offsets": [ [ 106, 117 ], [ 67, 74 ] ] }, { "pmid": "17016511", "text": "ATXII-induced contractile dysfunction was delayed and reduced by resveratrol.", "type": "CHEMICAL", "entities": [ "resveratrol" ], "offsets": [ [ 65, 76 ] ] }, { "pmid": "17016621", "text": "Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction.\n", "type": "CHEMICAL", "entities": [ "amrubicin", "amrubicinol" ], "offsets": [ [ 63, 72 ], [ 77, 88 ] ] }, { "pmid": "17016621", "text": "The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro.", "type": "CHEMICAL", "entities": [ "AMR", "amrubicinol", "AMROH", "amrubicin" ], "offsets": [ [ 26, 29 ], [ 58, 69 ], [ 71, 76 ], [ 15, 24 ] ] }, { "pmid": "17016621", "text": "The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone.", "type": "CHEMICAL", "entities": [ "AMR", "AMROH" ], "offsets": [ [ 125, 128 ], [ 149, 154 ] ] }, { "pmid": "17016621", "text": "The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH.", "type": "CHEMICAL", "entities": [ "AMR", "AMROH" ], "offsets": [ [ 192, 195 ], [ 199, 204 ] ] }, { "pmid": "17016621", "text": "Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width.", "type": "CHEMICAL", "entities": [ "AMR", "AMROH" ], "offsets": [ [ 27, 30 ], [ 34, 39 ] ] }, { "pmid": "17016621", "text": "Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH.", "type": "CHEMICAL", "entities": [ "AMR", "AMROH" ], "offsets": [ [ 214, 217 ], [ 222, 227 ] ] }, { "pmid": "17016621", "text": "Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA topoisomerase II inhibitors.", "type": "CHEMICAL", "entities": [ "AMR", "AMROH", "adriamycin", "etoposide", "VP-16" ], "offsets": [ [ 11, 14 ], [ 19, 24 ], [ 26, 36 ], [ 41, 50 ], [ 52, 57 ] ] }, { "pmid": "17016621", "text": "The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments.", "type": "CHEMICAL", "entities": [ "AMROH" ], "offsets": [ [ 83, 88 ] ] }, { "pmid": "17033106", "text": "Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy.", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 40, 49 ] ] }, { "pmid": "17033106", "text": "In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between aspirin and H. pylori on ulcerogenesis.", "type": "CHEMICAL", "entities": [ "aspirin", "aspirin" ], "offsets": [ [ 98, 105 ], [ 261, 268 ] ] }, { "pmid": "17033106", "text": "Accumulated evidence in humans and animals shows that both aspirin and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 59, 66 ] ] }, { "pmid": "17033106", "text": "It was, therefore, proposed that H. pylori may in fact, antagonize, aspirin-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from COX-2 expression and activity and to the overexpression of growth factors such as TGF alpha and VEGF.", "type": "CHEMICAL", "entities": [ "aspirin", "PGE(2)" ], "offsets": [ [ 68, 75 ], [ 166, 172 ] ] }, { "pmid": "17041099", "text": "The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity.\n", "type": "CHEMICAL", "entities": [ "methylthioadenosine", "pemetrexed" ], "offsets": [ [ 52, 71 ], [ 89, 99 ] ] }, { "pmid": "17041099", "text": "Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis.", "type": "CHEMICAL", "entities": [ "thymidylate", "glycinamide ribonucleotide", "purine" ], "offsets": [ [ 55, 66 ], [ 107, 133 ], [ 178, 184 ] ] }, { "pmid": "17041099", "text": "Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma.", "type": "CHEMICAL", "entities": [ "purines", "adenine", "methylthioadenosine", "Methylthioadenosine" ], "offsets": [ [ 50, 57 ], [ 71, 78 ], [ 84, 103 ], [ 0, 19 ] ] }, { "pmid": "17041099", "text": "The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i)", "type": "CHEMICAL", "entities": [ "pemetrexed" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "17041099", "text": "Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations.", "type": "CHEMICAL", "entities": [ "pemetrexed", "pemetrexed" ], "offsets": [ [ 73, 83 ], [ 164, 174 ] ] }, { "pmid": "17041099", "text": "ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells.", "type": "CHEMICAL", "entities": [ "pemetrexed", "thymidine", "pemetrexed" ], "offsets": [ [ 22, 32 ], [ 52, 61 ], [ 77, 87 ] ] }, { "pmid": "17041099", "text": "Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA.", "type": "CHEMICAL", "entities": [ "pemetrexed", "thymidine" ], "offsets": [ [ 68, 78 ], [ 131, 140 ] ] }, { "pmid": "17041099", "text": "An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine.", "type": "CHEMICAL", "entities": [ "pemetrexed", "thymidine" ], "offsets": [ [ 69, 79 ], [ 128, 137 ] ] }, { "pmid": "17041099", "text": "These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS.", "type": "CHEMICAL", "entities": [ "pemetrexed" ], "offsets": [ [ 75, 85 ] ] }, { "pmid": "17041099", "text": "There is a modest salutary effect when the pemetrexed target is GARFT alone.", "type": "CHEMICAL", "entities": [ "pemetrexed" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "17082235", "text": "Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach.\n", "type": "CHEMICAL", "entities": [ "Sulfonylureas", "glinides" ], "offsets": [ [ 0, 13 ], [ 18, 26 ] ] }, { "pmid": "17082235", "text": "Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones).", "type": "CHEMICAL", "entities": [ "sulfonylurea", "sulfonylureas", "glinides", "thiazolidinediones" ], "offsets": [ [ 84, 96 ], [ 135, 148 ], [ 150, 158 ], [ 260, 278 ] ] }, { "pmid": "17082235", "text": "Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity.", "type": "CHEMICAL", "entities": [ "sulfonylureas", "glinides" ], "offsets": [ [ 20, 33 ], [ 38, 46 ] ] }, { "pmid": "17082235", "text": "Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment.", "type": "CHEMICAL", "entities": [ "gliquidone", "glipizide", "sulfonylureas", "nateglinide", "glinide" ], "offsets": [ [ 30, 40 ], [ 45, 54 ], [ 60, 73 ], [ 87, 98 ], [ 102, 109 ] ] }, { "pmid": "17082235", "text": "The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression.", "type": "CHEMICAL", "entities": [ "gliquidone", "pioglitazone" ], "offsets": [ [ 36, 46 ], [ 76, 88 ] ] }, { "pmid": "17082235", "text": "This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma.", "type": "CHEMICAL", "entities": [ "sulfonylureas", "glinides", "sulfonylurea" ], "offsets": [ [ 28, 41 ], [ 46, 54 ], [ 212, 224 ] ] }, { "pmid": "17082235", "text": "Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists.", "type": "CHEMICAL", "entities": [ "Glinides", "sulfonylureas", "acidified sulfonamides" ], "offsets": [ [ 0, 8 ], [ 10, 23 ], [ 35, 57 ] ] }, { "pmid": "17088426", "text": "PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases.\n", "type": "CHEMICAL", "entities": [ "PGE(1)", "cAMP" ], "offsets": [ [ 0, 6 ], [ 89, 93 ] ] }, { "pmid": "17088426", "text": "There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages.", "type": "CHEMICAL", "entities": [ "cyclic adenosine monophosphate", "cAMP" ], "offsets": [ [ 41, 71 ], [ 73, 77 ] ] }, { "pmid": "17088426", "text": "Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of cAMP, but the mechanisms responsible for limiting the diffusion of cAMP largely remain to be clarified.", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP" ], "offsets": [ [ 127, 131 ], [ 194, 198 ] ] }, { "pmid": "17088426", "text": "In this study, by performing real-time imaging of cAMP, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different cAMP concentration in human embryonic kidney 293 cells.", "type": "CHEMICAL", "entities": [ "cAMP", "prostaglandin 1", "cAMP" ], "offsets": [ [ 50, 54 ], [ 69, 84 ], [ 165, 169 ] ] }, { "pmid": "17088426", "text": "By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 198, 202 ] ] }, { "pmid": "17088426", "text": "We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to cAMP diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different cAMP concentrations irrespective of their distance from the site of cAMP synthesis.", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP", "cAMP" ], "offsets": [ [ 100, 104 ], [ 247, 251 ], [ 315, 319 ] ] }, { "pmid": "17089011", "text": "DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes.\n", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "17089011", "text": "Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas.", "type": "CHEMICAL", "entities": [ "Fatty acid" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17089011", "text": "SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions.", "type": "CHEMICAL", "entities": [ "doxorubicin", "etopoxide", "VP-16" ], "offsets": [ [ 82, 93 ], [ 98, 107 ], [ 109, 114 ] ] }, { "pmid": "17089011", "text": "We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine.", "type": "CHEMICAL", "entities": [ "5-fluorouracil", "cisplatin", "paclitaxel", "vincristine" ], "offsets": [ [ 106, 120 ], [ 142, 151 ], [ 191, 201 ], [ 206, 217 ] ] }, { "pmid": "17094978", "text": "Mifepristone alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate.\n", "type": "CHEMICAL", "entities": [ "Mifepristone", "medroxyprogesterone acetate", "steroid" ], "offsets": [ [ 0, 12 ], [ 100, 127 ], [ 46, 53 ] ] }, { "pmid": "17094978", "text": "OBJECTIVE: To evaluate the effect of mifepristone on the expression of endometrial steroid receptors and their co-factors in depot medroxyprogesterone acetate (DMPA) users.", "type": "CHEMICAL", "entities": [ "medroxyprogesterone acetate", "steroid" ], "offsets": [ [ 131, 158 ], [ 83, 90 ] ] }, { "pmid": "17094978", "text": "Two pills (25 mg each) of placebo or mifepristone were administered every 14 days during the DMPA therapy.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 37, 49 ] ] }, { "pmid": "17094978", "text": "MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively.", "type": "CHEMICAL", "entities": [ "estrogen", "progesterone", "androgen" ], "offsets": [ [ 43, 51 ], [ 107, 119 ], [ 158, 166 ] ] }, { "pmid": "17094978", "text": "Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry.", "type": "CHEMICAL", "entities": [ "Steroid", "retinoid", "thyroid-hormone" ], "offsets": [ [ 0, 7 ], [ 63, 71 ], [ 76, 91 ] ] }, { "pmid": "17094978", "text": "RESULT(S): The expression of endometrial ERalpha, PRAB, PRB, and SRC-1 was increased significantly after 1 week of mifepristone, but the increase was no longer seen after 10 weeks.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 115, 127 ] ] }, { "pmid": "17094978", "text": "CONCLUSION(S): Short-term exposure of mifepristone in new starters of DMPA increases the expression of endometrial ERalpha, PRAB, PRB, and SRC-1 and promotes cell proliferation.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 38, 50 ] ] }, { "pmid": "17094978", "text": "Prolonged exposure to mifepristone does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy.", "type": "CHEMICAL", "entities": [ "mifepristone" ], "offsets": [ [ 22, 34 ] ] }, { "pmid": "17097861", "text": "To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis.", "type": "CHEMICAL", "entities": [ "d-galactosamine", "GalN" ], "offsets": [ [ 116, 131 ], [ 133, 137 ] ] }, { "pmid": "17097861", "text": "In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls.", "type": "CHEMICAL", "entities": [ "glucose", "GalN" ], "offsets": [ [ 22, 29 ], [ 90, 94 ] ] }, { "pmid": "17097861", "text": "Levels of mRNA encoding insulin 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats.", "type": "CHEMICAL", "entities": [ "GalN" ], "offsets": [ [ 96, 100 ] ] }, { "pmid": "17097861", "text": "This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in insulin 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats.", "type": "CHEMICAL", "entities": [ "actinomycin D", "GalN" ], "offsets": [ [ 65, 78 ], [ 257, 261 ] ] }, { "pmid": "17097861", "text": "The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats.", "type": "CHEMICAL", "entities": [ "GalN" ], "offsets": [ [ 69, 73 ] ] }, { "pmid": "17112405", "text": "Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice.\n", "type": "CHEMICAL", "entities": [ "Cysteinyl leukotriene", "N-methyl-D-aspartate" ], "offsets": [ [ 0, 21 ], [ 48, 68 ] ] }, { "pmid": "17112405", "text": "AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain.", "type": "CHEMICAL", "entities": [ "N-methyl-D-aspartate", "NMDA", "cysteinyl leukotriene" ], "offsets": [ [ 92, 112 ], [ 114, 118 ], [ 26, 47 ] ] }, { "pmid": "17112405", "text": "Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 28, 32 ] ] }, { "pmid": "17112405", "text": "The changes in CysLT1 receptor expression 24 h after NMDA injection and the effects of a CysLT1 receptor antagonist, pranlukast (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed.", "type": "CHEMICAL", "entities": [ "NMDA", "pranlukast", "NMDA", "ketamine", "edaravone" ], "offsets": [ [ 53, 57 ], [ 117, 127 ], [ 153, 157 ], [ 179, 187 ], [ 220, 229 ] ] }, { "pmid": "17112405", "text": "In the NMDA-injured brain, the CysLT1 receptor mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 7, 11 ] ] }, { "pmid": "17112405", "text": "Pranlukast, ketamine and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and ketamine inhibited the upregulated expression of the CysLT1 receptor.", "type": "CHEMICAL", "entities": [ "Pranlukast", "ketamine", "edaravone", "NMDA", "pranlukast", "ketamine" ], "offsets": [ [ 0, 10 ], [ 12, 20 ], [ 25, 34 ], [ 45, 49 ], [ 66, 76 ], [ 93, 101 ] ] }, { "pmid": "17112405", "text": "CysLT1 receptor expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by CysLT1 receptor antagonists, indicating that the increased CysLT1 receptor is involved in NMDA excitotoxicity.", "type": "CHEMICAL", "entities": [ "NMDA", "NMDA", "NMDA" ], "offsets": [ [ 59, 63 ], [ 79, 83 ], [ 209, 213 ] ] }, { "pmid": "17119350", "text": "We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by paclitaxel.", "type": "CHEMICAL", "entities": [ "serine", "NH2", "paclitaxel" ], "offsets": [ [ 117, 123 ], [ 138, 141 ], [ 378, 388 ] ] }, { "pmid": "17119350", "text": "In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens.", "type": "CHEMICAL", "entities": [ "estrogen", "progesterone" ], "offsets": [ [ 90, 98 ], [ 100, 112 ] ] }, { "pmid": "1712335", "text": "Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol.\n", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 96, 106 ] ] }, { "pmid": "1712335", "text": "The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats.", "type": "CHEMICAL", "entities": [ "racemic carvedilol" ], "offsets": [ [ 98, 116 ] ] }, { "pmid": "1712335", "text": "In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 46, 56 ] ] }, { "pmid": "1712335", "text": "Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 83, 93 ] ] }, { "pmid": "1712335", "text": "Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 37, 47 ] ] }, { "pmid": "1712335", "text": "Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol.", "type": "CHEMICAL", "entities": [ "Carvedilol", "isoproterenol" ], "offsets": [ [ 0, 10 ], [ 131, 144 ] ] }, { "pmid": "1712335", "text": "This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II.", "type": "CHEMICAL", "entities": [ "carvedilol", "salbutamol" ], "offsets": [ [ 18, 28 ], [ 128, 138 ] ] }, { "pmid": "1712335", "text": "Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype.", "type": "CHEMICAL", "entities": [ "carvedilol" ], "offsets": [ [ 6, 16 ] ] }, { "pmid": "1712335", "text": "Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses.", "type": "CHEMICAL", "entities": [ "Carvedilol", "cirazoline", "B-HT 933", "carvedilol" ], "offsets": [ [ 0, 10 ], [ 100, 110 ], [ 205, 213 ], [ 231, 241 ] ] }, { "pmid": "1712335", "text": "Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity.", "type": "CHEMICAL", "entities": [ "Carvedilol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "1712335", "text": "The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies.", "type": "CHEMICAL", "entities": [ "calcium", "carvedilol", "carvedilol", "calcium", "calcium", "BAY-K-8644", "calcium" ], "offsets": [ [ 197, 204 ], [ 237, 247 ], [ 279, 289 ], [ 300, 307 ], [ 32, 39 ], [ 59, 69 ], [ 130, 137 ] ] }, { "pmid": "1712335", "text": "In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors.", "type": "CHEMICAL", "entities": [ "carvedilol", "prazosin", "propranolol", "carvedilol" ], "offsets": [ [ 82, 92 ], [ 207, 215 ], [ 282, 293 ], [ 383, 393 ] ] }, { "pmid": "1712335", "text": "We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)", "type": "CHEMICAL", "entities": [ "carvedilol", "calcium" ], "offsets": [ [ 27, 37 ], [ 141, 148 ] ] }, { "pmid": "17126311", "text": "A 51-year-old male patient, with a clinical history of two prior episodes of renal colic with urinary stone excretion (reported as uric acid stones in the first episode and as calcium oxalate stones in the second), was admitted to the hospital with severe non-oliguric renal failure (1.06 mmol/L serum creatinine), severe hyponatremia (114 mmol/L Na(+)), metabolic acidosis (14 mmol/L HCO(3)(-))", "type": "CHEMICAL", "entities": [ "uric acid", "calcium oxalate", "creatinine", "Na(+)", "HCO(3)(-)" ], "offsets": [ [ 131, 140 ], [ 176, 191 ], [ 302, 312 ], [ 347, 352 ], [ 385, 394 ] ] }, { "pmid": "17126311", "text": "Results of renal biopsy prompted us to undertake a biochemical and molecular biological evaluation of the patient for suspected adenine phosphoribosyltransferase (APRT) deficiency.", "type": "CHEMICAL", "entities": [ "adenine" ], "offsets": [ [ 128, 135 ] ] }, { "pmid": "17126311", "text": "HPLC analysis of serum and urine, for determining purine derivative profile, showed the pathological presence of adenine in both biological fluids (3.57 micromol/L and 7.11 micromol/mmol creatinine in serum and urine, respectively; not detectable in both fluids in healthy controls).", "type": "CHEMICAL", "entities": [ "adenine", "creatinine", "purine" ], "offsets": [ [ 113, 120 ], [ 187, 197 ], [ 50, 56 ] ] }, { "pmid": "17126311", "text": "Analysis of the patient family showed that heterozygotes for this APRT gene mutation, in spite of a 69% lower APRT enzymatic activity than that of healthy subjects, had no detectable adenine concentrations in both serum and urine.", "type": "CHEMICAL", "entities": [ "adenine" ], "offsets": [ [ 183, 190 ] ] }, { "pmid": "17128263", "text": "Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B.\nGrowth hormone binds to its membrane receptor (GHR), whereby it regulates many cellular functions, including proliferation, differentiation and chemotaxis.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 120, 128 ] ] }, { "pmid": "17128263", "text": "Here, we demonstrate that phospholipase Cgamma1 (PLCgamma1) modulates the action of growth hormone-mediated signalling by interacting with tyrosine kinase Jak2 (janus kinase 2) in a growth hormone-dependent manner.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 139, 147 ] ] }, { "pmid": "17128263", "text": "Interestingly, PLCgamma1 physically linked Jak2 and protein tyrosine phosphatase-1B (PTP-1B) by binding to both using different domains, and this process was implicated in the modulation of cytokine signalling through Jak2.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "17138606", "text": "Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery.\n", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 64, 68 ] ] }, { "pmid": "17138606", "text": "5-Hydroxytryptamine (5-HT) activates colonic splanchnic afferents, a mechanism by which it has been implicated in generating symptoms in postinfectious and postinflammatory states in humans.", "type": "CHEMICAL", "entities": [ "5-Hydroxytryptamine", "5-HT" ], "offsets": [ [ 0, 19 ], [ 21, 25 ] ] }, { "pmid": "17138606", "text": "Here we compared mechanisms of colonic afferent activation by 5-HT and mechanical stimuli in normal and inflamed rat colon, and after recovery from inflammation.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 62, 66 ] ] }, { "pmid": "17138606", "text": "Colonic inflammation was induced in rats by dextran sulphate sodium.", "type": "CHEMICAL", "entities": [ "dextran sulphate sodium" ], "offsets": [ [ 44, 67 ] ] }, { "pmid": "17138606", "text": "Single-fibre recordings of colonic lumbar splanchnic afferents revealed that 58% of endings responded to 5-HT (10(-4) m) in controls, 88% in acute inflammation (P<0.05) and 75% after 21 days recovery (P < 0.05 versus control).", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 105, 109 ] ] }, { "pmid": "17138606", "text": "Maximal responses to 5-HT were also larger, and the estimated EC50 was reduced from 3.2 x 10(-6) to 8 x 10(-7) m in acute inflammation and recovered to 2 x 10(-6) m after recovery.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 21, 25 ] ] }, { "pmid": "17138606", "text": "5-HT3 receptor antagonism with alosetron reduced responses to 5-HT in controls but not during inflammation.", "type": "CHEMICAL", "entities": [ "alosetron", "5-HT" ], "offsets": [ [ 31, 40 ], [ 62, 66 ] ] }, { "pmid": "17138606", "text": "Responses to the mast cell degranulator 48/80 mimicked those to 5-HT in inflamed tissue but not in controls, and more 5-HT-containing mast cells were seen close to calcitonin gene-related peptide-containing fibres in inflamed serosa.", "type": "CHEMICAL", "entities": [ "5-HT", "5-HT" ], "offsets": [ [ 64, 68 ], [ 118, 122 ] ] }, { "pmid": "17138606", "text": "We conclude that colonic serosal and mesenteric endings exhibit increased sensitivity to 5-HT in inflammation, with both an increase in proportion of responders and an increase in sensitivity, which is maintained after healing of inflammation.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 89, 93 ] ] }, { "pmid": "17138644", "text": "The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle.\n", "type": "CHEMICAL", "entities": [ "progesterone", "progesterone" ], "offsets": [ [ 46, 58 ], [ 81, 93 ] ] }, { "pmid": "17138644", "text": "Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor.", "type": "CHEMICAL", "entities": [ "progesterone" ], "offsets": [ [ 6, 18 ] ] }, { "pmid": "17138644", "text": "Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear.", "type": "CHEMICAL", "entities": [ "Progestin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17138644", "text": "Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation.", "type": "CHEMICAL", "entities": [ "progestin" ], "offsets": [ [ 224, 233 ] ] }, { "pmid": "17138644", "text": "Progestin induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src.", "type": "CHEMICAL", "entities": [ "progesterone", "Progestin", "progesterone" ], "offsets": [ [ 249, 261 ], [ 0, 9 ], [ 57, 69 ] ] }, { "pmid": "17138644", "text": "Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression.", "type": "CHEMICAL", "entities": [ "Progestin", "progestin", "progesterone" ], "offsets": [ [ 0, 9 ], [ 116, 125 ], [ 297, 309 ] ] }, { "pmid": "17146052", "text": "Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 237, 245 ] ] }, { "pmid": "17146052", "text": "Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 134, 142 ] ] }, { "pmid": "17146052", "text": "i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice.", "type": "CHEMICAL", "entities": [ "picrotoxin", "gamma-aminobutyric acid" ], "offsets": [ [ 41, 51 ], [ 69, 92 ] ] }, { "pmid": "17150756", "text": "Molecular recognition of histidine tRNA by histidyl-tRNA synthetase from hyperthermophilic archaeon, Aeropyrum pernix K1.\n", "type": "CHEMICAL", "entities": [ "histidine" ], "offsets": [ [ 25, 34 ] ] }, { "pmid": "17150756", "text": "To investigate the recognition sites of histidine tRNA for histidyl-tRNA synthetase from an extreme hyperthermophilic archaeon, Aeropyrum pernix K1, we examined histidylation activities by using overexpressed histidyl-tRNA synthetase and various histidine tRNA transcripts that were prepared by in vitro transcription system.", "type": "CHEMICAL", "entities": [ "histidyl", "histidine", "histidine" ], "offsets": [ [ 209, 217 ], [ 246, 255 ], [ 40, 49 ] ] }, { "pmid": "17150756", "text": "Results indicated that anticodon was not recognized by the histidyl-tRNA synthetase similar to that of Escherichia coli histidine tRNA recognition system.", "type": "CHEMICAL", "entities": [ "histidyl", "histidine" ], "offsets": [ [ 59, 67 ], [ 120, 129 ] ] }, { "pmid": "17154506", "text": "Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography.\n", "type": "CHEMICAL", "entities": [ "serotonin", "carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes" ], "offsets": [ [ 192, 201 ], [ 56, 140 ] ] }, { "pmid": "17154506", "text": "2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells.", "type": "CHEMICAL", "entities": [ "2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane", "2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane", "mZBrENT", "serotonin", "dopamine", "norepinephrine", "mZIENT" ], "offsets": [ [ 82, 148 ], [ 0, 65 ], [ 150, 157 ], [ 218, 227 ], [ 229, 237 ], [ 243, 257 ], [ 67, 73 ] ] }, { "pmid": "17154506", "text": "Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms.", "type": "CHEMICAL", "entities": [ "halogen" ], "offsets": [ [ 143, 150 ] ] }, { "pmid": "17154506", "text": "MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection.", "type": "CHEMICAL", "entities": [ "11C", "11C" ], "offsets": [ [ 44, 47 ], [ 55, 58 ] ] }, { "pmid": "17154506", "text": "Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT.", "type": "CHEMICAL", "entities": [ "citalopram", "methylphenidate" ], "offsets": [ [ 19, 29 ], [ 34, 49 ] ] }, { "pmid": "17163232", "text": "Pharmacokinetics of olmesartan medoxomil plus hydrochlorothiazide combination in healthy subjects.\n", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil", "hydrochlorothiazide" ], "offsets": [ [ 20, 40 ], [ 46, 65 ] ] }, { "pmid": "17163232", "text": "Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists.", "type": "CHEMICAL", "entities": [ "angiotensin II" ], "offsets": [ [ 124, 138 ] ] }, { "pmid": "17163232", "text": "This trial investigated the possibility of pharmacokinetic interactions between the AT1 receptor antagonist olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide in healthy subjects.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil", "thiazide", "hydrochlorothiazide" ], "offsets": [ [ 108, 128 ], [ 137, 145 ], [ 155, 174 ] ] }, { "pmid": "17163232", "text": "METHODS: Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: olmesartan medoxomil 20 mg once daily (regimen A), hydrochlorothiazide 25 mg once daily (regimen B), or olmesartan medoxomil 20 mg once daily plus hydrochlorothiazide 25 mg once daily (regimen C).", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil", "hydrochlorothiazide", "olmesartan medoxomil", "hydrochlorothiazide" ], "offsets": [ [ 187, 207 ], [ 238, 257 ], [ 291, 311 ], [ 334, 353 ] ] }, { "pmid": "17163232", "text": "Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide.", "type": "CHEMICAL", "entities": [ "olmesartan", "olmesartan medoxomil", "hydrochlorothiazide" ], "offsets": [ [ 104, 114 ], [ 141, 161 ], [ 167, 186 ] ] }, { "pmid": "17163232", "text": "For olmesartan, comparison of monotherapy with combination therapy showed that for AUCss,tau and Css,max point estimates were close to unity, demonstrating bioequivalence.", "type": "CHEMICAL", "entities": [ "olmesartan" ], "offsets": [ [ 4, 14 ] ] }, { "pmid": "17163232", "text": "For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,tau and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven.", "type": "CHEMICAL", "entities": [ "hydrochlorothiazide" ], "offsets": [ [ 4, 23 ] ] }, { "pmid": "17163232", "text": "Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence.", "type": "CHEMICAL", "entities": [ "olmesartan", "hydrochlorothiazide" ], "offsets": [ [ 23, 33 ], [ 38, 57 ] ] }, { "pmid": "17163232", "text": "Both olmesartan medoxomil and hydrochlorothiazide were well tolerated.", "type": "CHEMICAL", "entities": [ "hydrochlorothiazide", "olmesartan medoxomil" ], "offsets": [ [ 30, 49 ], [ 5, 25 ] ] }, { "pmid": "17163232", "text": "These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg, and therefore dosage adjustment should not be necessary when they are co-administered.", "type": "CHEMICAL", "entities": [ "olmesartan medoxomil", "hydrochlorothiazide" ], "offsets": [ [ 118, 138 ], [ 149, 168 ] ] }, { "pmid": "17179482", "text": "The effects of cromolyn on tumor growth in vivo were investigated in three orthotopic models (n = 20 mice per model) by administration of cromolyn (5 mg/kg body weight, daily) with and without gemcitabine (125 mg/kg body weight, biweekly), the drug currently used to treat pancreatic cancer.", "type": "CHEMICAL", "entities": [ "gemcitabine" ], "offsets": [ [ 193, 204 ] ] }, { "pmid": "17179482", "text": "In vivo, cromolyn inhibited tumor growth in mice bearing tumor with endogenous S100P (BxPC-3: control, mean = 1.6 x 10(9) photons/s, versus cromolyn, mean = 4.4 x 10(8) photons/s, difference = 1.2 x 10(9) photons/s; 95% CI = 6.2 x 10(8) to 1.6 x 10(9) photons/s; P<.001, n = 5; MPanc-96: control, mean = 1.1 x 10(10) photons/s, versus cromolyn, mean = 4.8 x 10(9) photons/s, difference = 6.2 x 10(9) photons/s; 95% CI = 1.9 x 10(9) to 1.0 x 10(10) photons/s; P = .009, n = 5) and increased the effectiveness of gemcitabine (BxPC-3: gemcitabine, mean = 9.2 x 10(8) photons/s, versus combination, mean = 1.8 x 10(8) photons/s, difference = 7.4 x 10(8) photons/s; 95% CI = 4.5 x 10(8) to 1.0 x 10(9) photons/s; P<.001; MPanc-96: gemcitabine, mean = 4.1 x 10(9) photons/s, versus combination, mean = 2.0 x 10(9) photons/s, difference = 2.1 x 10(9) photons/s; 95% CI = 4.4 x 10(8) to 3.8 x 10(9) photons/s; P<.001).", "type": "CHEMICAL", "entities": [ "gemcitabine", "gemcitabine", "gemcitabine" ], "offsets": [ [ 511, 522 ], [ 532, 543 ], [ 726, 737 ] ] }, { "pmid": "17179482", "text": "Cromolyn binds S100P, prevents activation of RAGE, inhibits tumor growth, and increases the effectiveness of gemcitabine in experimental models.", "type": "CHEMICAL", "entities": [ "gemcitabine" ], "offsets": [ [ 109, 120 ] ] }, { "pmid": "17194211", "text": "Biosynthesis of selenocysteine on its tRNA in eukaryotes.\n", "type": "CHEMICAL", "entities": [ "selenocysteine" ], "offsets": [ [ 16, 30 ] ] }, { "pmid": "17194211", "text": "Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code.", "type": "CHEMICAL", "entities": [ "Selenocysteine", "amino acid", "Sec" ], "offsets": [ [ 0, 14 ], [ 106, 116 ], [ 16, 19 ] ] }, { "pmid": "17194211", "text": "However, the means by which Sec is synthesized in eukaryotes is not known.", "type": "CHEMICAL", "entities": [ "Sec" ], "offsets": [ [ 28, 31 ] ] }, { "pmid": "17194211", "text": "Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen.", "type": "CHEMICAL", "entities": [ "Sec", "pyridoxal phosphate" ], "offsets": [ [ 83, 86 ], [ 132, 151 ] ] }, { "pmid": "17194211", "text": "SecS required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec).", "type": "CHEMICAL", "entities": [ "O-phosphoseryl", "selenocysteyl", "selenophosphate" ], "offsets": [ [ 34, 48 ], [ 90, 103 ], [ 14, 29 ] ] }, { "pmid": "17194211", "text": "Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and SecS.", "type": "CHEMICAL", "entities": [ "Sec", "selenide", "ATP", "serine", "seryl", "O-phosphoseryl", "selenophosphate" ], "offsets": [ [ 28, 31 ], [ 74, 82 ], [ 84, 87 ], [ 93, 99 ], [ 122, 127 ], [ 145, 159 ], [ 183, 198 ] ] }, { "pmid": "17194211", "text": "By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase.", "type": "CHEMICAL", "entities": [ "Sec", "O-phosphoseryl" ], "offsets": [ [ 30, 33 ], [ 149, 163 ] ] }, { "pmid": "17194211", "text": "In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not.", "type": "CHEMICAL", "entities": [ "selenophosphate", "monoselenophosphate", "selenophosphate" ], "offsets": [ [ 27, 42 ], [ 73, 92 ], [ 106, 121 ] ] }, { "pmid": "17194886", "text": "Effects of triflusal and aspirin in a rat model of cerebral ischemia.\n", "type": "CHEMICAL", "entities": [ "triflusal", "aspirin" ], "offsets": [ [ 11, 20 ], [ 25, 32 ] ] }, { "pmid": "17194886", "text": "Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia.", "type": "CHEMICAL", "entities": [ "Triflusal", "3-hydroxy-4-trifluoromethylbenzoic acid" ], "offsets": [ [ 0, 9 ], [ 67, 106 ] ] }, { "pmid": "17194886", "text": "An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS:", "type": "CHEMICAL", "entities": [ "aspirin", "triflusal" ], "offsets": [ [ 91, 98 ], [ 77, 86 ] ] }, { "pmid": "17194886", "text": "Rats received oral administration of either triflusal or aspirin.", "type": "CHEMICAL", "entities": [ "triflusal", "aspirin" ], "offsets": [ [ 44, 53 ], [ 57, 64 ] ] }, { "pmid": "17194886", "text": "Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment.", "type": "CHEMICAL", "entities": [ "triflusal", "aspirin" ], "offsets": [ [ 5, 14 ], [ 19, 26 ] ] }, { "pmid": "17194886", "text": "Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining.", "type": "CHEMICAL", "entities": [ "Triflusal", "aspirin" ], "offsets": [ [ 0, 9 ], [ 24, 31 ] ] }, { "pmid": "17194886", "text": "Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion.", "type": "CHEMICAL", "entities": [ "Triflusal" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17194886", "text": "The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia.", "type": "CHEMICAL", "entities": [ "triflusal", "aspirin" ], "offsets": [ [ 25, 34 ], [ 39, 46 ] ] }, { "pmid": "17194886", "text": "Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.", "type": "CHEMICAL", "entities": [ "triflusal" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "17203585", "text": "The expression of glycans was examined by lectin-histochemistry using Vicia villosa lectin (VVL) for terminal alpha/beta N-acetylgalactosamine (alpha/beta GalNAc); Galanthus nivalus lectin (GNL) for terminal mannose alpha-1,3 (Man alpha-1,3); Peanut agglutinin (PNA) for galactose beta-1,3N-acetylgalactosamine (Gal beta-1,3 GalNAc); Erythrina cristagalli lectin (ECL) for galactose beta-1,4 N-acetylglucosamine (Gal beta-1,4 GlcNAc); Sambucus nigra lectin (SNA) for sialic acid alpha-2.6 galactose (SA alpha-2,6 Gal); Maackia amurensis lectin II (MAL II) for sialic acid alpha-2,3 (SA alpha-2,3); Wheat germ agglutinin (WGA) for terminal N-acetylglucosamine with/ without sialic acid (GlcNAc wo SA); succynilated WGA (sWGA) for terminal N-acetylglucosamine without sialic acid (terminal GlcNAc without SA); Griffonia simplicifolia lectin II (GSL II) for terminal alpha/beta N-acetylglucosamine (alpha/beta GlcNAc terminal); and Lotus tetragonolobus lectin (LTL) alpha-fucose.", "type": "CHEMICAL", "entities": [ "alpha/beta GlcNAc", "alpha-fucose", "alpha/beta N-acetylgalactosamine", "alpha/beta GalNAc", "mannose alpha-1,3", "N-acetylglucosamine", "Man alpha-1,3", "galactose beta-1,3N-acetylgalactosamine", "Gal beta-1,3 GalNAc", "galactose beta-1,4 N-acetylglucosamine", "Gal beta-1,4 GlcNAc", "sialic acid alpha-2.6 galactose", "SA alpha-2,6 Gal", "sialic acid alpha-2,3", "SA alpha-2,3", "sialic acid", "GlcNAc", "SA", "N-acetylglucosamine", "sialic acid", "GlcNAc", "SA", "alpha/beta N-acetylglucosamine" ], "offsets": [ [ 896, 913 ], [ 963, 975 ], [ 110, 142 ], [ 144, 161 ], [ 208, 225 ], [ 639, 658 ], [ 227, 240 ], [ 271, 310 ], [ 312, 331 ], [ 373, 411 ], [ 413, 432 ], [ 467, 498 ], [ 500, 516 ], [ 560, 581 ], [ 583, 595 ], [ 673, 684 ], [ 686, 692 ], [ 696, 698 ], [ 738, 757 ], [ 766, 777 ], [ 788, 794 ], [ 803, 805 ], [ 864, 894 ] ] }, { "pmid": "17203585", "text": "Expression of alpha/beta GalNAc, alpha-fucose and GlcNAc in other hippocampal subflields was positive, with no differences between groups.", "type": "CHEMICAL", "entities": [ "GalNAc", "alpha-fucose", "GlcNAc" ], "offsets": [ [ 25, 31 ], [ 33, 45 ], [ 50, 56 ] ] }, { "pmid": "17203585", "text": "However, expression of Man alpha-1,3 was significantly higher in the CA1, CA2, CA3, and CA4 subfields in the Trained group.", "type": "CHEMICAL", "entities": [ "Man alpha-1,3" ], "offsets": [ [ 23, 36 ] ] }, { "pmid": "17203585", "text": "On the other hand, expression of Gal beta-1,3 GalNAc was significantly low in CA4 and DG in the Trained group.", "type": "CHEMICAL", "entities": [ "Gal beta-1,3 GalNAc" ], "offsets": [ [ 33, 52 ] ] }, { "pmid": "17207582", "text": "Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2.\n", "type": "CHEMICAL", "entities": [ "Glutamate", "glutamate" ], "offsets": [ [ 0, 9 ], [ 21, 30 ] ] }, { "pmid": "17207582", "text": "The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins.", "type": "CHEMICAL", "entities": [ "AMPA", "glutamate" ], "offsets": [ [ 119, 123 ], [ 4, 13 ] ] }, { "pmid": "17207582", "text": "Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures.", "type": "CHEMICAL", "entities": [ "glutamate", "glutamate" ], "offsets": [ [ 20, 29 ], [ 111, 120 ] ] }, { "pmid": "17207582", "text": "Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin.", "type": "CHEMICAL", "entities": [ "MG132", "glutamate", "carbobenzoxyl-leucinyl-leucinyl-leucinal" ], "offsets": [ [ 95, 100 ], [ 28, 37 ], [ 53, 93 ] ] }, { "pmid": "17207582", "text": "The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist.", "type": "CHEMICAL", "entities": [ "MK-801", "N-methyl-d-aspartate", "NMDA", "6-cyano-7-nitroquinoxaline-2,3-dione", "CNQX", "AMPA" ], "offsets": [ [ 37, 43 ], [ 48, 68 ], [ 70, 74 ], [ 108, 144 ], [ 146, 150 ], [ 156, 160 ] ] }, { "pmid": "17207582", "text": "EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation.", "type": "CHEMICAL", "entities": [ "EGTA", "1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis", "BAPTA", "Ca2+", "nifedipine", "Ca2+" ], "offsets": [ [ 0, 4 ], [ 9, 75 ], [ 77, 82 ], [ 89, 93 ], [ 113, 123 ], [ 135, 139 ] ] }, { "pmid": "17207582", "text": "Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons.", "type": "CHEMICAL", "entities": [ "MG132", "glutamate" ], "offsets": [ [ 13, 18 ], [ 29, 38 ] ] }, { "pmid": "17207582", "text": "Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression.", "type": "CHEMICAL", "entities": [ "glutamate", "NMDA", "Ca2+" ], "offsets": [ [ 25, 34 ], [ 86, 90 ], [ 100, 104 ] ] }, { "pmid": "17207992", "text": "Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline in calcium absorption.\n1,25(OH)(2)D(3) regulates calcium homeostasis through its actions in the intestine, bone, and kidney.", "type": "CHEMICAL", "entities": [ "Vitamin D", "1,25(OH)(2)D(3)", "calcium", "calcium" ], "offsets": [ [ 35, 44 ], [ 154, 169 ], [ 180, 187 ], [ 134, 141 ] ] }, { "pmid": "17207992", "text": "To determine if VDR's actions in the proximal small intestine can sufficiently restore calcium homeostasis, we generated transgenic mice expressing hVDR exclusively in the duodenum of mVDR-null mice by using the adenosine deaminase enhancer (hVDR+/mVDR-null).", "type": "CHEMICAL", "entities": [ "calcium", "adenosine" ], "offsets": [ [ 87, 94 ], [ 212, 221 ] ] }, { "pmid": "17207992", "text": "However, when 90-day-old rachitic mice were fed a rescue diet, serum calcium improved in hVDR+/mVDR-null mice, but not in mVDR-null mice.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 69, 76 ] ] }, { "pmid": "17207992", "text": "In conclusion, transgenic hVDR in the proximal small intestine of hVDR+/mVDR-null mice was transcriptionally active and regulated calcium absorption, but VDR actions elsewhere in the intestine are probably necessary to support adequate calcium homeostasis.", "type": "CHEMICAL", "entities": [ "calcium", "calcium" ], "offsets": [ [ 130, 137 ], [ 236, 243 ] ] }, { "pmid": "17207992", "text": "In addition, hVDR+/mVDR-null mice responded better to the late rescue diet suggesting that expression of VDR in the proximal small intestine protected the calcium absorbing machinery from age-dependent decline.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 155, 162 ] ] }, { "pmid": "17223000", "text": "The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and mucin secretion in human airway epithelial cells.\n", "type": "CHEMICAL", "entities": [ "leukotriene", "leukotriene D4" ], "offsets": [ [ 29, 40 ], [ 64, 78 ] ] }, { "pmid": "17223000", "text": "Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin.", "type": "CHEMICAL", "entities": [ "prostaglandin", "leukotriene" ], "offsets": [ [ 72, 85 ], [ 90, 101 ] ] }, { "pmid": "17223000", "text": "However, the relationship of leukotrienes with mucin genes expression is not clear.", "type": "CHEMICAL", "entities": [ "leukotrienes" ], "offsets": [ [ 29, 41 ] ] }, { "pmid": "17223000", "text": "The aim of this study is to evaluate MUC2/5AC gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells.", "type": "CHEMICAL", "entities": [ "leukotriene" ], "offsets": [ [ 89, 100 ] ] }, { "pmid": "17223000", "text": "The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells.", "type": "CHEMICAL", "entities": [ "leukotriene", "pranlukast hydrate", "ONO-1078", "leukotriene D(4)" ], "offsets": [ [ 39, 50 ], [ 72, 90 ], [ 92, 100 ], [ 14, 30 ] ] }, { "pmid": "17223000", "text": "Leukotriene D(4) upregulated MUC2/5AC gene expression and mucin secretion in a dose dependent pattern.", "type": "CHEMICAL", "entities": [ "Leukotriene D(4)" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17223000", "text": "Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and mucin secretion.", "type": "CHEMICAL", "entities": [ "Pranlukast hydrate", "ONO-1078", "leukotriene D(4)" ], "offsets": [ [ 0, 18 ], [ 20, 28 ], [ 60, 76 ] ] }, { "pmid": "17223000", "text": "These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and mucin secretion in the human airway epithelium.", "type": "CHEMICAL", "entities": [ "leukotriene" ], "offsets": [ [ 31, 42 ] ] }, { "pmid": "17224860", "text": "Effect of isolated isoflavone supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women.\n", "type": "CHEMICAL", "entities": [ "isoflavone", "cholesterol" ], "offsets": [ [ 19, 29 ], [ 65, 76 ] ] }, { "pmid": "17224860", "text": "Isoflavones may display beneficial health effects in postmenopausal women.", "type": "CHEMICAL", "entities": [ "Isoflavones" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "17224860", "text": "We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages.", "type": "CHEMICAL", "entities": [ "cholesterol", "adenosine triphosphate", "cholesterol", "isoflavone" ], "offsets": [ [ 114, 125 ], [ 152, 174 ], [ 215, 226 ], [ 48, 58 ] ] }, { "pmid": "17224860", "text": "DESIGN: Postmenopausal women (n=56) were treated with either isoflavone or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period.", "type": "CHEMICAL", "entities": [ "isoflavone" ], "offsets": [ [ 61, 71 ] ] }, { "pmid": "17224860", "text": "[H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed.", "type": "CHEMICAL", "entities": [ "[H]-Cholesterol", "cholesterol" ], "offsets": [ [ 0, 15 ], [ 138, 149 ] ] }, { "pmid": "17224860", "text": "Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after isoflavone and placebo treatment, respectively.", "type": "CHEMICAL", "entities": [ "cholesterol", "isoflavone" ], "offsets": [ [ 43, 54 ], [ 85, 95 ] ] }, { "pmid": "17224860", "text": "Thus, isoflavone supplementation did not affect ABCA1-dependent cholesterol efflux to serum.", "type": "CHEMICAL", "entities": [ "isoflavone", "cholesterol" ], "offsets": [ [ 6, 16 ], [ 64, 75 ] ] }, { "pmid": "17224860", "text": "However, as a novel finding, isoflavone treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations.", "type": "CHEMICAL", "entities": [ "isoflavone" ], "offsets": [ [ 29, 39 ] ] }, { "pmid": "17224860", "text": "ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women.", "type": "CHEMICAL", "entities": [ "equol", "cholesterol", "equol" ], "offsets": [ [ 105, 110 ], [ 18, 29 ], [ 81, 86 ] ] }, { "pmid": "17224860", "text": "In postmenopausal women, isolated isoflavone treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects.", "type": "CHEMICAL", "entities": [ "isoflavone", "cholesterol" ], "offsets": [ [ 34, 44 ], [ 87, 98 ] ] }, { "pmid": "17229632", "text": "The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors.\n", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "17229632", "text": "Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 10, 18 ] ] }, { "pmid": "17229632", "text": "Sorafenib (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families.", "type": "CHEMICAL", "entities": [ "tyrosine", "Sorafenib", "BAY43-9006", "Nexavar" ], "offsets": [ [ 177, 185 ], [ 0, 9 ], [ 11, 21 ], [ 23, 30 ] ] }, { "pmid": "17229632", "text": "We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies.", "type": "CHEMICAL", "entities": [ "sorafenib", "tyrosine" ], "offsets": [ [ 32, 41 ], [ 80, 88 ] ] }, { "pmid": "17229632", "text": "We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "17229632", "text": "The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies.", "type": "CHEMICAL", "entities": [ "sorafenib", "phospho" ], "offsets": [ [ 21, 30 ], [ 112, 119 ] ] }, { "pmid": "17229632", "text": "We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "17229632", "text": "Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines.", "type": "CHEMICAL", "entities": [ "Sorafenib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "17229632", "text": "The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib.", "type": "CHEMICAL", "entities": [ "imatinib", "sorafenib" ], "offsets": [ [ 4, 12 ], [ 110, 119 ] ] }, { "pmid": "17229632", "text": "These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3.", "type": "CHEMICAL", "entities": [ "sorafenib" ], "offsets": [ [ 50, 59 ] ] }, { "pmid": "17251323", "text": "Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients.", "type": "CHEMICAL", "entities": [ "Na(+)" ], "offsets": [ [ 43, 48 ] ] }, { "pmid": "17251323", "text": "Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations.", "type": "CHEMICAL", "entities": [ "amiloride" ], "offsets": [ [ 97, 106 ] ] }, { "pmid": "17251323", "text": "We hypothesized that corticosteroid exposure modulates epithelial Na(+) channel (ENaC) expression and/or activity in bovine mammary epithelial cells.", "type": "CHEMICAL", "entities": [ "Na(+)" ], "offsets": [ [ 66, 71 ] ] }, { "pmid": "17251323", "text": "BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk.", "type": "CHEMICAL", "entities": [ "lactose" ], "offsets": [ [ 148, 155 ] ] }, { "pmid": "17251323", "text": "Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels.", "type": "CHEMICAL", "entities": [ "dexamethasone", "cortisol", "prednisolone", "aldosterone", "amiloride", "benzamil" ], "offsets": [ [ 29, 42 ], [ 44, 52 ], [ 57, 69 ], [ 80, 91 ], [ 203, 212 ], [ 216, 224 ] ] }, { "pmid": "17251323", "text": "Exposure to mifepristone (a glucocorticoid receptor antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA.", "type": "CHEMICAL", "entities": [ "mifepristone", "spironolactone", "amiloride" ], "offsets": [ [ 12, 24 ], [ 73, 87 ], [ 186, 195 ] ] }, { "pmid": "17251323", "text": "We conclude that Na(+) movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the beta- and gamma-subunits of ENaC. ENaC expression and activity could account for the low Na(+) concentration that is typical of milk.", "type": "CHEMICAL", "entities": [ "Na(+)", "Na(+)" ], "offsets": [ [ 17, 22 ], [ 264, 269 ] ] }, { "pmid": "17259377", "text": "Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy.\n", "type": "CHEMICAL", "entities": [ "Salicylate" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17259377", "text": "It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "17259377", "text": "To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats.", "type": "CHEMICAL", "entities": [ "sodium salicylate", "sulfasalazine", "salicylate", "aspirin" ], "offsets": [ [ 117, 134 ], [ 140, 153 ], [ 84, 94 ], [ 108, 115 ] ] }, { "pmid": "17259377", "text": "Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia.", "type": "CHEMICAL", "entities": [ "salicylate" ], "offsets": [ [ 229, 239 ] ] }, { "pmid": "17259377", "text": "In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 47, 58 ] ] }, { "pmid": "17259377", "text": "Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina.", "type": "CHEMICAL", "entities": [ "aspirin", "salicylate" ], "offsets": [ [ 5, 12 ], [ 41, 51 ] ] }, { "pmid": "17259377", "text": "All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections.", "type": "CHEMICAL", "entities": [ "salicylates" ], "offsets": [ [ 10, 21 ] ] }, { "pmid": "17259377", "text": "Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate.", "type": "CHEMICAL", "entities": [ "Sulfasalazine", "salicylates", "nitric oxide" ], "offsets": [ [ 0, 13 ], [ 47, 58 ], [ 265, 277 ] ] }, { "pmid": "17259377", "text": "Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.", "type": "CHEMICAL", "entities": [ "Salicylates" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "1727721", "text": "Localization of an 11 beta hydroxysteroid dehydrogenase activity to the distal nephron.", "type": "CHEMICAL", "entities": [ "11 beta hydroxysteroid" ], "offsets": [ [ 19, 41 ] ] }, { "pmid": "1727721", "text": "An 11 beta hydroxysteroid dehydrogenase (11 beta HSD) activity has been localized in the rat kidney by a histochemical technique which links steroid metabolism with the production of a color reaction.", "type": "CHEMICAL", "entities": [ "11 beta hydroxysteroid", "steroid" ], "offsets": [ [ 3, 25 ], [ 141, 148 ] ] }, { "pmid": "1727721", "text": "Oxidation of 11 beta-hydroxyandrostenedione was observed in cortical distal convoluted tubules and in medullary collecting ducts.", "type": "CHEMICAL", "entities": [ "11 beta-hydroxyandrostenedione" ], "offsets": [ [ 13, 43 ] ] }, { "pmid": "1727721", "text": "Carbenoxolone abolished staining, no reaction was obtained with androstenedione hydroxylated at the 17 or 19 position, and oxidation of 11 beta-hydroxyandrostenedione was nicotinamide-adenine dinucleotide (NAD) dependent.", "type": "CHEMICAL", "entities": [ "Carbenoxolone", "androstenedione", "11 beta-hydroxyandrostenedione", "nicotinamide-adenine dinucleotide", "NAD" ], "offsets": [ [ 0, 13 ], [ 64, 79 ], [ 136, 166 ], [ 171, 204 ], [ 206, 209 ] ] }, { "pmid": "1727721", "text": "These results demonstrate the presence of a dehydrogenase activity separate from the nicotinamide-adenine dinucleotide phosphate (NADP)-dependent 11 beta hydroxysteroid dehydrogenase recently purified and cloned from rat liver.", "type": "CHEMICAL", "entities": [ "nicotinamide-adenine dinucleotide phosphate", "NADP", "11 beta hydroxysteroid" ], "offsets": [ [ 85, 128 ], [ 130, 134 ], [ 146, 168 ] ] }, { "pmid": "1727721", "text": "We have named this activity 11 beta HSD2 to distinguish it from the NADP-dependent 11 beta HSD.", "type": "CHEMICAL", "entities": [ "NADP" ], "offsets": [ [ 68, 72 ] ] }, { "pmid": "1727721", "text": "No reaction product was obtained using cortisol or corticosterone as substrate with either NAD or NADP as cofactor.", "type": "CHEMICAL", "entities": [ "cortisol", "corticosterone", "NAD", "NADP" ], "offsets": [ [ 39, 47 ], [ 51, 65 ], [ 91, 94 ], [ 98, 102 ] ] }, { "pmid": "1727721", "text": "Furthermore incubation of tissue sections with 11 beta androstenedione in the presence of deoxycorticosterone completely inhibited cytochemical staining.", "type": "CHEMICAL", "entities": [ "11 beta androstenedione", "deoxycorticosterone" ], "offsets": [ [ 47, 70 ], [ 90, 109 ] ] }, { "pmid": "1727721", "text": "These results support the crucial role played by an 11 beta hydroxysteroid dehydrogenase in the local protection of type I receptors in mineralocorticoid selective tissues.", "type": "CHEMICAL", "entities": [ "11 beta hydroxysteroid" ], "offsets": [ [ 52, 74 ] ] }, { "pmid": "17289086", "text": "Effect of long-term fluoxetine treatment on the human serotonin transporter in Caco-2 cells.\n", "type": "CHEMICAL", "entities": [ "fluoxetine", "serotonin" ], "offsets": [ [ 20, 30 ], [ 54, 63 ] ] }, { "pmid": "17289086", "text": "Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) broadly used in the treatment of human mood disorders and gastrointestinal diseases involving the serotoninergic system.", "type": "CHEMICAL", "entities": [ "Fluoxetine", "serotonin" ], "offsets": [ [ 0, 10 ], [ 26, 35 ] ] }, { "pmid": "17289086", "text": "The chronic effect of SSRIs on the activity of the serotonin transporter (SERT) has been less studied and the results have been contradictory.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 51, 60 ] ] }, { "pmid": "17289086", "text": "The aim of this study was to determine the specific effect of long-term fluoxetine treatment on human serotonin transporter (hSERT) in vitro, by using the human enterocyte-like cell line Caco-2.", "type": "CHEMICAL", "entities": [ "fluoxetine", "serotonin" ], "offsets": [ [ 72, 82 ], [ 102, 111 ] ] }, { "pmid": "17289086", "text": "Results show that fluoxetine diminished the 5-HT uptake in a concentration-dependent way and that this effect was reversible.", "type": "CHEMICAL", "entities": [ "fluoxetine", "5-HT" ], "offsets": [ [ 18, 28 ], [ 44, 48 ] ] }, { "pmid": "17289086", "text": "Fluoxetine affected mainly the hSERT transport rate by reducing the availability of the transporter in the membrane with no significant alteration of either the total hSERT protein content or the hSERT mRNA level.", "type": "CHEMICAL", "entities": [ "Fluoxetine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17289086", "text": "These results suggest that the effect of fluoxetine on the expression of hSERT is post-translational and has shown itself to be independent of PKC and PKA activity.", "type": "CHEMICAL", "entities": [ "fluoxetine" ], "offsets": [ [ 41, 51 ] ] }, { "pmid": "17289086", "text": "This study may be useful to clarify the effect of the long-term fluoxetine therapy in both gastrointestinal and central nervous system disorders.", "type": "CHEMICAL", "entities": [ "fluoxetine" ], "offsets": [ [ 64, 74 ] ] }, { "pmid": "17289088", "text": "Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).", "type": "CHEMICAL", "entities": [ "ACh", "choline", "ACh", "acetylcholine" ], "offsets": [ [ 95, 98 ], [ 101, 108 ], [ 194, 197 ], [ 80, 93 ] ] }, { "pmid": "17289088", "text": "Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs.", "type": "CHEMICAL", "entities": [ "ACh" ], "offsets": [ [ 151, 154 ] ] }, { "pmid": "17289088", "text": "In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 75, 79 ] ] }, { "pmid": "17289088", "text": "Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells.", "type": "CHEMICAL", "entities": [ "ACh" ], "offsets": [ [ 148, 151 ] ] }, { "pmid": "17289088", "text": "The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 4, 15 ] ] }, { "pmid": "17289088", "text": "We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity.", "type": "CHEMICAL", "entities": [ "simvastatin", "cholesterol" ], "offsets": [ [ 14, 25 ], [ 136, 147 ] ] }, { "pmid": "17289088", "text": "Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.", "type": "CHEMICAL", "entities": [ "simvastatin" ], "offsets": [ [ 164, 175 ] ] }, { "pmid": "17341305", "text": "Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment.\n", "type": "CHEMICAL", "entities": [ "estrogen", "progesterone" ], "offsets": [ [ 15, 23 ], [ 43, 55 ] ] }, { "pmid": "17341305", "text": "Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice.", "type": "CHEMICAL", "entities": [ "MPA", "estrogen", "progesterone", "Medroxyprogesterone acetate" ], "offsets": [ [ 29, 32 ], [ 42, 50 ], [ 78, 90 ], [ 0, 27 ] ] }, { "pmid": "17341305", "text": "We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering.", "type": "CHEMICAL", "entities": [ "MPA" ], "offsets": [ [ 28, 31 ] ] }, { "pmid": "17341305", "text": "Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands.", "type": "CHEMICAL", "entities": [ "MPA", "progesterone", "MPA", "progesterone", "MPA" ], "offsets": [ [ 140, 143 ], [ 148, 160 ], [ 204, 207 ], [ 220, 232 ], [ 73, 76 ] ] }, { "pmid": "17341305", "text": "The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice.", "type": "CHEMICAL", "entities": [ "MPA" ], "offsets": [ [ 27, 30 ] ] }, { "pmid": "17341305", "text": "In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR.", "type": "CHEMICAL", "entities": [ "progesterone", "MPA" ], "offsets": [ [ 58, 70 ], [ 74, 77 ] ] }, { "pmid": "17341305", "text": "MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice.", "type": "CHEMICAL", "entities": [ "MPA" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "17341305", "text": "The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05).", "type": "CHEMICAL", "entities": [ "progestin" ], "offsets": [ [ 171, 180 ] ] }, { "pmid": "17341305", "text": "PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains.", "type": "CHEMICAL", "entities": [ "progestin" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "17341305", "text": "C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action.", "type": "CHEMICAL", "entities": [ "MPA" ], "offsets": [ [ 40, 43 ] ] }, { "pmid": "17341305", "text": "MPA and progesterone have different effects on mammary glands.", "type": "CHEMICAL", "entities": [ "MPA", "progesterone" ], "offsets": [ [ 0, 3 ], [ 8, 20 ] ] }, { "pmid": "17350061", "text": "Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism.\n", "type": "CHEMICAL", "entities": [ "estrogen", "steroid", "inorganic arsenic" ], "offsets": [ [ 143, 151 ], [ 176, 183 ], [ 27, 44 ] ] }, { "pmid": "17350061", "text": "Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood.", "type": "CHEMICAL", "entities": [ "inorganic arsenic" ], "offsets": [ [ 12, 29 ] ] }, { "pmid": "17350061", "text": "To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation.", "type": "CHEMICAL", "entities": [ "arsenic", "arsenic" ], "offsets": [ [ 71, 78 ], [ 178, 185 ] ] }, { "pmid": "17350061", "text": "At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "17350061", "text": "Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism.", "type": "CHEMICAL", "entities": [ "Arsenic", "estrogen", "steroid" ], "offsets": [ [ 0, 7 ], [ 168, 176 ], [ 190, 197 ] ] }, { "pmid": "17350061", "text": "Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed.", "type": "CHEMICAL", "entities": [ "estrogen", "proline" ], "offsets": [ [ 28, 36 ], [ 150, 157 ] ] }, { "pmid": "17350061", "text": "Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed.", "type": "CHEMICAL", "entities": [ "Estrogen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "17350061", "text": "Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production).", "type": "CHEMICAL", "entities": [ "steroid", "17beta-hydroxysteroid", "estradiol", "testosterone" ], "offsets": [ [ 28, 35 ], [ 124, 145 ], [ 187, 196 ], [ 261, 273 ] ] }, { "pmid": "17350061", "text": "The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed.", "type": "CHEMICAL", "entities": [ "thioether", "S", "methionine", "methionine", "betaine", "homocysteine" ], "offsets": [ [ 150, 159 ], [ 160, 161 ], [ 41, 51 ], [ 72, 82 ], [ 107, 114 ], [ 115, 127 ] ] }, { "pmid": "17350061", "text": "Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism.", "type": "CHEMICAL", "entities": [ "inorganic arsenic", "estrogen", "steroid", "methionine" ], "offsets": [ [ 33, 50 ], [ 153, 161 ], [ 176, 183 ], [ 187, 197 ] ] }, { "pmid": "17352828", "text": "Monosodium urate crystals stimulate monocytes and macrophages to release IL-1beta through the NALP3 component of the inflammasome.", "type": "CHEMICAL", "entities": [ "Monosodium urate" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "17352828", "text": "The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation.", "type": "CHEMICAL", "entities": [ "monosodium urate" ], "offsets": [ [ 77, 93 ] ] }, { "pmid": "17355872", "text": "Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin.\n", "type": "CHEMICAL", "entities": [ "NAD+", "suramin" ], "offsets": [ [ 44, 48 ], [ 80, 87 ] ] }, { "pmid": "17355872", "text": "Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer.", "type": "CHEMICAL", "entities": [ "NAD(+)" ], "offsets": [ [ 13, 19 ] ] }, { "pmid": "17355872", "text": "We identified suramin as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM.", "type": "CHEMICAL", "entities": [ "suramin", "NAD(+)" ], "offsets": [ [ 14, 21 ], [ 96, 102 ] ] }, { "pmid": "17355872", "text": "To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to suramin.", "type": "CHEMICAL", "entities": [ "ADP", "suramin" ], "offsets": [ [ 139, 142 ], [ 170, 177 ] ] }, { "pmid": "17355872", "text": "Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that suramin binds into the NAD(+), the product, and the substrate-binding site.", "type": "CHEMICAL", "entities": [ "suramin", "NAD(+)" ], "offsets": [ [ 113, 120 ], [ 136, 142 ] ] }, { "pmid": "17369066", "text": "Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase.\n", "type": "CHEMICAL", "entities": [ "methionine", "folate", "methionine" ], "offsets": [ [ 25, 35 ], [ 40, 46 ], [ 79, 89 ] ] }, { "pmid": "17369066", "text": "Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine.", "type": "CHEMICAL", "entities": [ "thymidylate", "homocysteine", "methionine", "folate", "carbon", "purines" ], "offsets": [ [ 165, 176 ], [ 202, 214 ], [ 223, 233 ], [ 88, 94 ], [ 120, 126 ], [ 153, 160 ] ] }, { "pmid": "17369066", "text": "In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis.", "type": "CHEMICAL", "entities": [ "methionine", "methyltetrahydrofolate", "folate", "purine", "thymidylate" ], "offsets": [ [ 11, 21 ], [ 73, 95 ], [ 114, 120 ], [ 146, 152 ], [ 157, 168 ] ] }, { "pmid": "17369066", "text": "Complete ablation of methionine synthase activity in mice results in embryonic lethality.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 21, 31 ] ] }, { "pmid": "17369066", "text": "Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation.", "type": "CHEMICAL", "entities": [ "methyltetrahydrofolate", "AdoMet", "AdoHcy" ], "offsets": [ [ 79, 101 ], [ 171, 177 ], [ 178, 184 ] ] }, { "pmid": "17369066", "text": "We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase.", "type": "CHEMICAL", "entities": [ "methionine", "methionine" ], "offsets": [ [ 89, 99 ], [ 160, 170 ] ] }, { "pmid": "17369066", "text": "This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity.", "type": "CHEMICAL", "entities": [ "methionine", "methionine" ], "offsets": [ [ 139, 149 ], [ 40, 50 ] ] }, { "pmid": "17369066", "text": "Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate.", "type": "CHEMICAL", "entities": [ "homocyst(e)ine", "methionine", "methyltetrahydrofolate" ], "offsets": [ [ 39, 53 ], [ 72, 82 ], [ 105, 127 ] ] }, { "pmid": "17369066", "text": "Unexpectedly, Mtrr(gt/gt) mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues.", "type": "CHEMICAL", "entities": [ "AdoMet", "AdoHcy" ], "offsets": [ [ 60, 66 ], [ 67, 73 ] ] }, { "pmid": "17369066", "text": "The different metabolite profiles in the various genetic mouse models for hyperhomocyst(e)inemia may be useful in understanding biological effects of elevated homocyst(e)ine.", "type": "CHEMICAL", "entities": [ "homocyst(e)ine" ], "offsets": [ [ 159, 173 ] ] }, { "pmid": "17369473", "text": "Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration.\n", "type": "CHEMICAL", "entities": [ "Metformin", "AMP", "phenformin", "AMP" ], "offsets": [ [ 0, 9 ], [ 100, 103 ], [ 14, 24 ], [ 34, 37 ] ] }, { "pmid": "17369473", "text": "AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP).", "type": "CHEMICAL", "entities": [ "AMP", "ATP", "AMP", "AMP", "ATP", "AMP", "AMP" ], "offsets": [ [ 133, 136 ], [ 140, 143 ], [ 151, 154 ], [ 0, 3 ], [ 155, 158 ], [ 100, 103 ], [ 120, 123 ] ] }, { "pmid": "17369473", "text": "Metformin and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP.", "type": "CHEMICAL", "entities": [ "Metformin", "phenformin", "biguanides", "AMP", "ATP" ], "offsets": [ [ 0, 9 ], [ 14, 24 ], [ 36, 46 ], [ 112, 115 ], [ 116, 119 ] ] }, { "pmid": "17369473", "text": "This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic", "type": "CHEMICAL", "entities": [ "biguanides" ], "offsets": [ [ 43, 53 ] ] }, { "pmid": "17369473", "text": "[AMP].", "type": "CHEMICAL", "entities": [ "AMP", "AMP", "AMP" ], "offsets": [ [ 1, 4 ], [ 1, 4 ], [ 1, 4 ] ] }, { "pmid": "17369473", "text": "Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic", "type": "CHEMICAL", "entities": [ "phenformin", "metformin", "(31)P", "phosphocreatine", "ATP" ], "offsets": [ [ 110, 120 ], [ 130, 139 ], [ 145, 150 ], [ 164, 179 ], [ 181, 184 ] ] }, { "pmid": "17369473", "text": "At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an AMPK target.", "type": "CHEMICAL", "entities": [ "acetyl-CoA" ], "offsets": [ [ 153, 163 ] ] }, { "pmid": "17369473", "text": "In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min.", "type": "CHEMICAL", "entities": [ "phenformin", "AMP" ], "offsets": [ [ 23, 33 ], [ 104, 107 ] ] }, { "pmid": "17369473", "text": "In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min.", "type": "CHEMICAL", "entities": [ "metformin", "AMP", "acetyl-CoA" ], "offsets": [ [ 23, 32 ], [ 35, 38 ], [ 123, 133 ] ] }, { "pmid": "17369473", "text": "In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase.", "type": "CHEMICAL", "entities": [ "ATP", "metformin", "AMP", "AMP" ], "offsets": [ [ 75, 78 ], [ 3, 12 ], [ 49, 52 ], [ 71, 74 ] ] }, { "pmid": "17369473", "text": "In summary, phenformin and metformin increase AMPK activity and phosphorylation in the isolated heart.", "type": "CHEMICAL", "entities": [ "phenformin", "metformin" ], "offsets": [ [ 12, 22 ], [ 27, 36 ] ] }, { "pmid": "17369473", "text": "Total AMP content and total AMP/ATP did not change.", "type": "CHEMICAL", "entities": [ "AMP", "AMP", "ATP" ], "offsets": [ [ 6, 9 ], [ 28, 31 ], [ 32, 35 ] ] }, { "pmid": "17369473", "text": "Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not.", "type": "CHEMICAL", "entities": [ "AMP", "AMP", "AMP" ], "offsets": [ [ 11, 14 ], [ 46, 49 ], [ 114, 117 ] ] }, { "pmid": "17381051", "text": "The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population.\n", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 12, 23 ] ] }, { "pmid": "17381051", "text": "AIM: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 51, 62 ] ] }, { "pmid": "1738111", "text": "Characterization of 5-hydroxytryptamine1B receptors in rat spinal cord via [125I]iodocyanopindolol binding and inhibition of [3H]-5-hydroxytryptamine release.\n", "type": "CHEMICAL", "entities": [ "[3H]-5-hydroxytryptamine", "[125I]iodocyanopindolol" ], "offsets": [ [ 125, 149 ], [ 75, 98 ] ] }, { "pmid": "1738111", "text": "The aim of the present study in rat spinal cord synaptosomes was to compare the pharmacological characteristics of the serotonin (5-HT)1B receptor defined by [125I]iodocyanopindolol [( 125I] ICYP) binding and the 5-HT autoreceptor defined by inhibition of [3H]-5-HT release.", "type": "CHEMICAL", "entities": [ "[125I]iodocyanopindolol", "[( 125I] ICYP)", "5-HT", "serotonin", "[3H]-5-HT" ], "offsets": [ [ 158, 181 ], [ 182, 196 ], [ 213, 217 ], [ 119, 128 ], [ 256, 265 ] ] }, { "pmid": "1738111", "text": "In Percoll gradient Fractions 3 and 4 of spinal cord synaptosomes, a single saturable binding site for [125I]ICYP with a maximum binding of 70 and 134 fmol/mg, respectively, was demonstrated in the presence of 30 microM isoproterenol.", "type": "CHEMICAL", "entities": [ "[125I]ICYP", "isoproterenol" ], "offsets": [ [ 103, 113 ], [ 220, 233 ] ] }, { "pmid": "1738111", "text": "Competition for [125I]ICYP binding by various 5-HT agonists and antagonists also indicated a single site model based on a Hill coefficient of approximately 1.0.", "type": "CHEMICAL", "entities": [ "[125I]ICYP", "5-HT" ], "offsets": [ [ 16, 26 ], [ 46, 50 ] ] }, { "pmid": "1738111", "text": "The most potent compounds at displacing [125I]ICYP binding were RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), 5-carboxyamidotryptamine HCl, 5-methoxytryptamine, 5-HT and CGS 12066B (7-trifluoromethyl-4(4 methyl-1-pyrolo[1,2-a]-quinoxaline malate).", "type": "CHEMICAL", "entities": [ "[125I]ICYP", "RU 24969", "5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole", "5-carboxyamidotryptamine HCl", "5-methoxytryptamine", "5-HT", "CGS 12066B", "7-trifluoromethyl-4(4 methyl-1-pyrolo[1,2-a]-quinoxaline malate" ], "offsets": [ [ 40, 50 ], [ 64, 72 ], [ 74, 128 ], [ 131, 159 ], [ 161, 180 ], [ 182, 186 ], [ 191, 201 ], [ 203, 266 ] ] }, { "pmid": "1738111", "text": "[125I]ICYP binding was not altered by compounds with activity at 5-HT1A, 5-HT1C, 5-HT2, 5-HT3 or alpha-2 receptor sites.", "type": "CHEMICAL", "entities": [ "[125I]ICYP" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "1738111", "text": "Similar to the pharmacological characteristics of the 5HT1B site defined by [125I]ICYP, compounds most active at inhibiting 15 mM K(+)-stimulated release of [3H]-5-HT were RU24969 = 5-carboxyamidotryptamine HCl = CGS 12066B greater than 5-methoxytryptamine greater than 5-HT.", "type": "CHEMICAL", "entities": [ "5-HT", "[125I]ICYP", "K(+)", "[3H]-5-HT", "RU24969", "5-carboxyamidotryptamine", "HCl", "CGS 12066B", "5-methoxytryptamine" ], "offsets": [ [ 270, 274 ], [ 76, 86 ], [ 130, 134 ], [ 157, 166 ], [ 172, 179 ], [ 182, 206 ], [ 207, 210 ], [ 213, 223 ], [ 237, 256 ] ] }, { "pmid": "1738111", "text": "A correlation analysis of selective 5-HT1B compounds comparing the pKD for displacement of [125I]ICYP vs. the IC50 for inhibition of [3H]-5-HT release demonstrated the pharmacological similarity of the presynaptic inhibitory 5-HT autoreceptor and the 5-HT receptor site defined by [125I]ICYP binding in spinal cord synaptosomes (r = 0.791, P = .0193).", "type": "CHEMICAL", "entities": [ "[125I]ICYP", "[3H]-5-HT", "5-HT", "5-HT", "[125I]ICYP" ], "offsets": [ [ 91, 101 ], [ 133, 142 ], [ 225, 229 ], [ 251, 255 ], [ 281, 291 ] ] }, { "pmid": "1738111", "text": "Although [125I]ICYP binding was unaltered, alpha-2 agonists such as clonidine, norepinephrine and UK 14304", "type": "CHEMICAL", "entities": [ "[125I]ICYP", "clonidine", "norepinephrine", "UK 14304" ], "offsets": [ [ 9, 19 ], [ 68, 77 ], [ 79, 93 ], [ 98, 106 ] ] }, { "pmid": "1738111", "text": "[5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) as well as the alpha-2 antagonists rauwolscine and yohimbine also decreased the K(+)-stimulated release of [3H]-5-HT and phentolamine, an alpha-2 antagonist increased release.", "type": "CHEMICAL", "entities": [ "[5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline", "rauwolscine", "yohimbine", "K(+)", "[3H]-5-HT", "phentolamine" ], "offsets": [ [ 0, 47 ], [ 84, 95 ], [ 100, 109 ], [ 129, 133 ], [ 156, 165 ], [ 170, 182 ] ] }, { "pmid": "1738111", "text": "The action of these alpha-2 compounds to alter [3H]-5-HT release suggests the presence of heteroreceptors localized on 5-HT terminals in the spinal cord.", "type": "CHEMICAL", "entities": [ "[3H]-5-HT", "5-HT" ], "offsets": [ [ 47, 56 ], [ 119, 123 ] ] }, { "pmid": "1738111", "text": "These results point out that [125I]ICYP identifies the 5-HT1B receptor, and affinity of compounds for this site predicts action at the 5-HT1B autoreceptor.(ABSTRACT TRUNCATED AT 400 WORDS)", "type": "CHEMICAL", "entities": [ "[125I]ICYP" ], "offsets": [ [ 29, 39 ] ] }, { "pmid": "17382376", "text": "Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine.\n", "type": "CHEMICAL", "entities": [ "Histamine", "clozapine" ], "offsets": [ [ 0, 9 ], [ 121, 130 ] ] }, { "pmid": "17382376", "text": "Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine.", "type": "CHEMICAL", "entities": [ "Histamine", "clozapine" ], "offsets": [ [ 0, 9 ], [ 104, 113 ] ] }, { "pmid": "17382376", "text": "It is currently not known how much this H(1) antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine.", "type": "CHEMICAL", "entities": [ "clozapine", "clozapine" ], "offsets": [ [ 59, 68 ], [ 127, 136 ] ] }, { "pmid": "17382376", "text": "The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy.", "type": "CHEMICAL", "entities": [ "clozapine" ], "offsets": [ [ 189, 198 ] ] }, { "pmid": "17382376", "text": "The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine.", "type": "CHEMICAL", "entities": [ "glutamate", "dizocilpine", "MK-801", "clozapine" ], "offsets": [ [ 33, 42 ], [ 54, 65 ], [ 67, 73 ], [ 107, 116 ] ] }, { "pmid": "17382376", "text": "In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse.", "type": "CHEMICAL", "entities": [ "pyrilamine", "dizocilpine" ], "offsets": [ [ 68, 78 ], [ 97, 108 ] ] }, { "pmid": "17382376", "text": "In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response.", "type": "CHEMICAL", "entities": [ "pyrilamine", "clozapine" ], "offsets": [ [ 30, 40 ], [ 47, 56 ] ] }, { "pmid": "17382376", "text": "Pyrilamine, however, decreased the number of reference memory errors.", "type": "CHEMICAL", "entities": [ "Pyrilamine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17382376", "text": "We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM.", "type": "CHEMICAL", "entities": [ "nicotine", "clozapine", "nicotine", "pyrilamine" ], "offsets": [ [ 30, 38 ], [ 66, 75 ], [ 137, 145 ], [ 189, 199 ] ] }, { "pmid": "17382376", "text": "In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition.", "type": "CHEMICAL", "entities": [ "clozapine", "pyrilamine", "pyrilamine" ], "offsets": [ [ 38, 47 ], [ 112, 122 ], [ 130, 140 ] ] }, { "pmid": "17382376", "text": "Pyrilamine impaired working memory but improved reference memory in rats.", "type": "CHEMICAL", "entities": [ "Pyrilamine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "17382376", "text": "Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine.", "type": "CHEMICAL", "entities": [ "clozapine" ], "offsets": [ [ 104, 113 ] ] }, { "pmid": "17387686", "text": "Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to ethanol.\n", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 94, 101 ] ] }, { "pmid": "17387686", "text": "The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or ethanol exposure has been shown to influence the PtdSer level.", "type": "CHEMICAL", "entities": [ "docosahexaenoic acid", "DHA", "DHA", "ethanol" ], "offsets": [ [ 44, 64 ], [ 66, 69 ], [ 89, 92 ], [ 103, 110 ] ] }, { "pmid": "17387686", "text": "This study shows that ethanol exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "17387686", "text": "Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS).", "type": "CHEMICAL", "entities": [ "deuterium" ], "offsets": [ [ 37, 46 ] ] }, { "pmid": "17387686", "text": "These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn).", "type": "CHEMICAL", "entities": [ "1-stearoyl-2-docosahexaenoyl", "phosphatidylcholine", "PtdCho", "phosphatidylethanolamine", "PtdEtn" ], "offsets": [ [ 37, 65 ], [ 140, 159 ], [ 161, 167 ], [ 173, 197 ], [ 199, 205 ] ] }, { "pmid": "17387686", "text": "The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 139, 146 ] ] }, { "pmid": "17387686", "text": "PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 89, 96 ] ] }, { "pmid": "17387686", "text": "The mRNA expression of PtdSer synthase 1 (PSS1) and PtdSer synthase 2 (PSS2) was not reduced by ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 96, 103 ] ] }, { "pmid": "17387686", "text": "Similarly, the PSS1 enzyme level did not change after ethanol exposure but PSS2 could not be probed with the antibody available currently.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 54, 61 ] ] }, { "pmid": "17387686", "text": "Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to ethanol.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 168, 175 ] ] }, { "pmid": "17403374", "text": "In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "17403374", "text": "We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "17403374", "text": "KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 76, 86 ] ] }, { "pmid": "17403374", "text": "Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes.", "type": "CHEMICAL", "entities": [ "alanine", "amino acid", "alanine", "pyruvate" ], "offsets": [ [ 39, 46 ], [ 113, 123 ], [ 124, 131 ], [ 137, 145 ] ] }, { "pmid": "17403374", "text": "Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice.", "type": "CHEMICAL", "entities": [ "pyruvate", "alanine" ], "offsets": [ [ 63, 71 ], [ 81, 88 ] ] }, { "pmid": "17427197", "text": "D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium.\n", "type": "CHEMICAL", "entities": [ "D-glucose", "L-arginine", "nitric oxide" ], "offsets": [ [ 0, 9 ], [ 25, 35 ], [ 50, 62 ] ] }, { "pmid": "17427197", "text": "Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC).", "type": "CHEMICAL", "entities": [ "D-glucose" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "17427197", "text": "We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC.", "type": "CHEMICAL", "entities": [ "D-glucose", "L-arginine", "nitric oxide" ], "offsets": [ [ 19, 28 ], [ 44, 54 ], [ 69, 81 ] ] }, { "pmid": "17427197", "text": "TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose.", "type": "CHEMICAL", "entities": [ "D-glucose" ], "offsets": [ [ 99, 108 ] ] }, { "pmid": "17427197", "text": "TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport.", "type": "CHEMICAL", "entities": [ "L-arginine", "D-glucose", "D-glucose", "L-arginine" ], "offsets": [ [ 20, 30 ], [ 97, 106 ], [ 131, 140 ], [ 151, 161 ] ] }, { "pmid": "17427197", "text": "TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation.", "type": "CHEMICAL", "entities": [ "D-glucose", "L-[(3)H]citrulline", "L-[(3)H]arginine", "NO", "NO" ], "offsets": [ [ 19, 28 ], [ 127, 145 ], [ 161, 177 ], [ 188, 190 ], [ 218, 220 ] ] }, { "pmid": "17427197", "text": "TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor).", "type": "CHEMICAL", "entities": [ "D-glucose", "PD-98059" ], "offsets": [ [ 19, 28 ], [ 100, 108 ] ] }, { "pmid": "17427197", "text": "However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII.", "type": "CHEMICAL", "entities": [ "D-glucose" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "17427197", "text": "High D-glucose increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC.", "type": "CHEMICAL", "entities": [ "D-glucose", "L-arginine" ], "offsets": [ [ 5, 14 ], [ 25, 35 ] ] }, { "pmid": "17459764", "text": "n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells.\n", "type": "CHEMICAL", "entities": [ "n-3 and n-6 polyunsaturated fatty acids" ], "offsets": [ [ 0, 39 ] ] }, { "pmid": "17459764", "text": "Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes.", "type": "CHEMICAL", "entities": [ "Polyunsaturated fatty acids (PUFA) n-3" ], "offsets": [ [ 0, 38 ] ] }, { "pmid": "17459764", "text": "We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation.", "type": "CHEMICAL", "entities": [ "GLA", "n-6 PUFA", "arachidic acid", "saturated fatty acid", "eicosapentaenoic acid", "EPA", "n-3 PUFA", "gamma-linoleic acid" ], "offsets": [ [ 113, 116 ], [ 120, 128 ], [ 134, 148 ], [ 151, 171 ], [ 52, 73 ], [ 75, 78 ], [ 82, 90 ], [ 92, 111 ] ] }, { "pmid": "17459764", "text": "We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA).", "type": "CHEMICAL", "entities": [ "GLA", "EPA", "roziglitazone" ], "offsets": [ [ 49, 52 ], [ 57, 60 ], [ 84, 97 ] ] }, { "pmid": "17459764", "text": "Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone.", "type": "CHEMICAL", "entities": [ "PUFAs", "rosiglitazone" ], "offsets": [ [ 71, 76 ], [ 80, 93 ] ] }, { "pmid": "17459764", "text": "The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction.", "type": "CHEMICAL", "entities": [ "GW9662", "T0070907", "EPA", "GLA" ], "offsets": [ [ 26, 32 ], [ 37, 45 ], [ 140, 143 ], [ 148, 151 ] ] }, { "pmid": "17459764", "text": "Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation.", "type": "CHEMICAL", "entities": [ "arachidonyl fluorophosphonate", "PUFA", "arachidonic acid", "AA" ], "offsets": [ [ 31, 60 ], [ 73, 77 ], [ 128, 144 ], [ 184, 186 ] ] }, { "pmid": "17459764", "text": "These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells.", "type": "CHEMICAL", "entities": [ "n-3 and n-6 PUFA" ], "offsets": [ [ 32, 48 ] ] }, { "pmid": "17459764", "text": "Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6.", "type": "CHEMICAL", "entities": [ "EPA", "PUFAs n-3" ], "offsets": [ [ 42, 45 ], [ 179, 188 ] ] }, { "pmid": "17465221", "text": "Methylation-mediated silencing of genes is not altered by selenium treatment of prostate cancer cells.\n", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 58, 66 ] ] }, { "pmid": "17465221", "text": "The role of selenium in reducing the risk of multiple cancers has been described in the literature.", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 12, 20 ] ] }, { "pmid": "17465221", "text": "Although reports have described the antiproliferative and pro-apoptotic function of selenium by up-regulation of genes in these pathways, information is lacking on the target mechanisms of selenium on specific genes.", "type": "CHEMICAL", "entities": [ "selenium", "selenium" ], "offsets": [ [ 84, 92 ], [ 189, 197 ] ] }, { "pmid": "17465221", "text": "This study examines whether selenium treatment alters the methylation status of epigenetically silenced genes in prostate cancer cells.", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "17465221", "text": "MATERIALS AND METHODS: Methylation of glutathione sulfotransferase pi (GSTP1) and Ras associated family 1A (RASSF1A) genes was studied using methylation sensitive PCR (MS-PCR).", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "17465221", "text": "Treatment of prostate cancer cells with selenium did not alter the expression of genes that were silenced by DNA methylation.", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "17465221", "text": "Furthermore, the methylation status of these genes remained unaltered after treatment with seleno-DL-methionine.", "type": "CHEMICAL", "entities": [ "seleno-DL-methionine" ], "offsets": [ [ 91, 111 ] ] }, { "pmid": "17472819", "text": "Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial.\n", "type": "CHEMICAL", "entities": [ "arformoterol" ], "offsets": [ [ 10, 22 ] ] }, { "pmid": "17472819", "text": "The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD).", "type": "CHEMICAL", "entities": [ "[R,R] isomer of formoterol", "salmeterol xinafoate", "arformoterol tartrate" ], "offsets": [ [ 166, 192 ], [ 198, 218 ], [ 79, 100 ] ] }, { "pmid": "17472819", "text": "Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo.", "type": "CHEMICAL", "entities": [ "arformoterol", "salmeterol" ], "offsets": [ [ 82, 94 ], [ 158, 168 ] ] }, { "pmid": "17472819", "text": "Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001).", "type": "CHEMICAL", "entities": [ "arformoterol", "salmeterol" ], "offsets": [ [ 85, 97 ], [ 181, 191 ] ] }, { "pmid": "17472819", "text": "There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P or =70 years)", "type": "CHEMICAL", "entities": [ "Rasagiline" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18035186", "text": "Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the \"cheese reaction\").", "type": "CHEMICAL", "entities": [ "tyramine" ], "offsets": [ [ 99, 107 ] ] }, { "pmid": "18035186", "text": "However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine.", "type": "CHEMICAL", "entities": [ "tyramine", "tyramine" ], "offsets": [ [ 39, 47 ], [ 133, 141 ] ] }, { "pmid": "18035186", "text": "In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "18035186", "text": "CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "18056711", "text": "Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin.\n", "type": "CHEMICAL", "entities": [ "camptothecin" ], "offsets": [ [ 90, 102 ] ] }, { "pmid": "18056711", "text": "Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate.", "type": "CHEMICAL", "entities": [ "camptothecin", "CPT" ], "offsets": [ [ 53, 65 ], [ 67, 70 ] ] }, { "pmid": "18056711", "text": "Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket.", "type": "CHEMICAL", "entities": [ "C", "Tyr", "C" ], "offsets": [ [ 53, 54 ], [ 160, 163 ], [ 171, 172 ] ] }, { "pmid": "18056711", "text": "The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT.", "type": "CHEMICAL", "entities": [ "CPT" ], "offsets": [ [ 118, 121 ] ] }, { "pmid": "18056711", "text": "Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA.", "type": "CHEMICAL", "entities": [ "Gly", "C", "Tyr" ], "offsets": [ [ 46, 49 ], [ 106, 107 ], [ 197, 200 ] ] }, { "pmid": "18056711", "text": "In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu.", "type": "CHEMICAL", "entities": [ "Gly", "Leu" ], "offsets": [ [ 85, 88 ], [ 107, 110 ] ] }, { "pmid": "18056711", "text": "We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT.", "type": "CHEMICAL", "entities": [ "Gly", "CPT" ], "offsets": [ [ 42, 45 ], [ 90, 93 ] ] }, { "pmid": "18056711", "text": "Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro.", "type": "CHEMICAL", "entities": [ "CPT", "Gly", "Asp", "Glu", "Asn", "Gln", "Leu", "Ala" ], "offsets": [ [ 64, 67 ], [ 9, 12 ], [ 16, 19 ], [ 21, 24 ], [ 26, 29 ], [ 31, 34 ], [ 36, 39 ], [ 44, 47 ] ] }, { "pmid": "18056711", "text": "By contrast, Val or Phe substituents rendered the enzyme CPT-resistant.", "type": "CHEMICAL", "entities": [ "Val", "Phe", "CPT" ], "offsets": [ [ 13, 16 ], [ 20, 23 ], [ 57, 60 ] ] }, { "pmid": "18056711", "text": "Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage.", "type": "CHEMICAL", "entities": [ "Tyr", "CPT" ], "offsets": [ [ 78, 81 ], [ 150, 153 ] ] }, { "pmid": "18056711", "text": "We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate.", "type": "CHEMICAL", "entities": [ "Gly" ], "offsets": [ [ 33, 36 ] ] }, { "pmid": "18081314", "text": "Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin.\n", "type": "CHEMICAL", "entities": [ "prostacyclin", "prostacyclin" ], "offsets": [ [ 208, 220 ], [ 60, 72 ] ] }, { "pmid": "18081314", "text": "High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution.", "type": "CHEMICAL", "entities": [ "U46619", "prostaglandin H2", "prostacyclin", "PGI2" ], "offsets": [ [ 108, 114 ], [ 83, 99 ], [ 134, 146 ], [ 148, 152 ] ] }, { "pmid": "18081314", "text": "The binding of U46619 to the PGIS protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered PGIS in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "U46619", "C-11", "H2C", "H20", "U46619", "U46619" ], "offsets": [ [ 15, 21 ], [ 150, 154 ], [ 156, 159 ], [ 165, 168 ], [ 172, 178 ], [ 198, 204 ] ] }, { "pmid": "18081314", "text": "The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique.", "type": "CHEMICAL", "entities": [ "U46619", "1H" ], "offsets": [ [ 70, 76 ], [ 109, 111 ] ] }, { "pmid": "18081314", "text": "The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the PGIS in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape.", "type": "CHEMICAL", "entities": [ "H20", "H2", "H18", "H2", "H18", "H4", "U46619" ], "offsets": [ [ 34, 37 ], [ 42, 44 ], [ 46, 49 ], [ 54, 56 ], [ 62, 65 ], [ 70, 72 ], [ 257, 263 ] ] }, { "pmid": "18081314", "text": "The bound conformation of U46619 fits the crystal structure of the PGIS substrate binding pocket considerably better than that of the unbound U46619.", "type": "CHEMICAL", "entities": [ "U46619", "U46619" ], "offsets": [ [ 26, 32 ], [ 142, 148 ] ] }, { "pmid": "18081314", "text": "For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the PGIS crystal structure.", "type": "CHEMICAL", "entities": [ "U46619" ], "offsets": [ [ 249, 255 ] ] }, { "pmid": "18081314", "text": "The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of PGIS in the isomerization of PGH2 to prostacyclin.", "type": "CHEMICAL", "entities": [ "prostacyclin", "C-6", "C-9", "U46619", "PGH2" ], "offsets": [ [ 241, 253 ], [ 43, 46 ], [ 73, 76 ], [ 89, 95 ], [ 233, 237 ] ] }, { "pmid": "18220763", "text": "Sulfonylureas, biguanides, alpha-glucosidase, meglitinides, DPP-4 inhibitors and thiazolidinediones are among the classes of oral hypoglycemic drugs available to treat Type II diabetes, but concerns exist regarding safety and efficacy of these drugs.", "type": "CHEMICAL", "entities": [ "Sulfonylureas", "biguanides", "meglitinides", "DPP-4", "thiazolidinediones" ], "offsets": [ [ 0, 13 ], [ 15, 25 ], [ 46, 58 ], [ 60, 65 ], [ 81, 99 ] ] }, { "pmid": "18308814", "text": "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.\n", "type": "CHEMICAL", "entities": [ "Asenapine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "18308814", "text": "Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder.", "type": "CHEMICAL", "entities": [ "Asenapine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "18308814", "text": "We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs.", "type": "CHEMICAL", "entities": [ "asenapine" ], "offsets": [ [ 99, 108 ] ] }, { "pmid": "18308814", "text": "In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 129, 138 ] ] }, { "pmid": "18308814", "text": "[8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 8, 16 ] ] }, { "pmid": "18308814", "text": "[9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]).", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 11, 20 ] ] }, { "pmid": "18393142", "text": "Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development.", "type": "CHEMICAL", "entities": [ "vitamin K" ], "offsets": [ [ 146, 155 ] ] }, { "pmid": "18393142", "text": "This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran).", "type": "CHEMICAL", "entities": [ "pentasaccharide", "idraparinux", "rivaroxaban", "apixaban", "dabigatran" ], "offsets": [ [ 61, 76 ], [ 92, 103 ], [ 166, 177 ], [ 182, 190 ], [ 201, 211 ] ] }, { "pmid": "18423812", "text": "Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial.\n", "type": "CHEMICAL", "entities": [ "aldosterone" ], "offsets": [ [ 57, 68 ] ] }, { "pmid": "18423812", "text": "Agents inhibiting the renin-angiotensin-aldosterone (RAAS) system have an important role in slowing the progression of chronic kidney disease.", "type": "CHEMICAL", "entities": [ "aldosterone" ], "offsets": [ [ 40, 51 ] ] }, { "pmid": "18423812", "text": "We evaluated the hypothesis that the addition of an aldosterone receptor antagonist to an angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT-1) receptor blocker (ARB) (triple RAAS blockade) may provide an additional benefit compared with an ACE inhibitor and ARB (double RAAS blockade).", "type": "CHEMICAL", "entities": [ "aldosterone", "angiotensin II" ], "offsets": [ [ 52, 63 ], [ 140, 154 ] ] }, { "pmid": "18423812", "text": "In the 8-week run-in period, all participants received the ACE inhibitor cilazapril (5 mg), the ARB telmisartan (80 mg), and the diuretic hydrochlorothiazide (12.5 mg) as double RAAS blockade to achieve the target blood pressure of less than 130/80 mm", "type": "CHEMICAL", "entities": [ "cilazapril", "telmisarta", "hydrochlorothiazide" ], "offsets": [ [ 73, 83 ], [ 100, 110 ], [ 138, 157 ] ] }, { "pmid": "18423812", "text": "Participants were then randomly assigned to 2 treatment sequences, either the addition of spironolactone (25 mg) (triple RAAS blockade) through 8 weeks followed by double RAAS blockade through 8 weeks (sequence 1) or double RAAS blockade followed by triple RAAS blockade (sequence 2).", "type": "CHEMICAL", "entities": [ "spironolactone" ], "offsets": [ [ 90, 104 ] ] }, { "pmid": "18423812", "text": "Potassium levels increased significantly after triple therapy (P = 0.02).", "type": "CHEMICAL", "entities": [ "Potassium" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "18423812", "text": "CONCLUSIONS: Administration of an aldosterone receptor antagonist in addition to double RAAS blockade with an ACE inhibitor and ARB may slow the progression of chronic kidney disease.", "type": "CHEMICAL", "entities": [ "aldosterone" ], "offsets": [ [ 34, 45 ] ] }, { "pmid": "18439678", "text": "Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod.\nToll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP).", "type": "CHEMICAL", "entities": [ "imiquimod" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "18439678", "text": "Both porcine TLR7 and TLR8 proteins were expressed in cell lines and were N-glycosylated.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 74, 75 ] ] }, { "pmid": "18439678", "text": "Two imidazoquinoline molecules, imiquimod and gardiquimod, markedly activated both porcine TLR7 and TLR8 whereas only human TLR7, but not TLR8, was activated by the ligands.", "type": "CHEMICAL", "entities": [ "imidazoquinoline", "imiquimod", "gardiquimod" ], "offsets": [ [ 4, 20 ], [ 32, 41 ], [ 46, 57 ] ] }, { "pmid": "18439678", "text": "Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors.", "type": "CHEMICAL", "entities": [ "bafilomycin A(1)" ], "offsets": [ [ 92, 108 ] ] }, { "pmid": "18574460", "text": "High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues.\n", "type": "CHEMICAL", "entities": [ "sodium", "halogenated propofol" ], "offsets": [ [ 72, 78 ], [ 91, 111 ] ] }, { "pmid": "18574460", "text": "BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 41, 47 ] ] }, { "pmid": "18574460", "text": "We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293.", "type": "CHEMICAL", "entities": [ "propofol", "sodium", "4-chloropropofol", "sodium" ], "offsets": [ [ 78, 86 ], [ 129, 135 ], [ 188, 204 ], [ 218, 224 ] ] }, { "pmid": "18574460", "text": "KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency.", "type": "CHEMICAL", "entities": [ "4-Iodo", "4-bromo", "4-chloropropofol", "sodium" ], "offsets": [ [ 13, 19 ], [ 22, 29 ], [ 35, 51 ], [ 108, 114 ] ] }, { "pmid": "18574460", "text": "The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2.", "type": "CHEMICAL", "entities": [ "4-chloropropofol" ], "offsets": [ [ 128, 144 ] ] }, { "pmid": "18574460", "text": "Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2.", "type": "CHEMICAL", "entities": [ "4-iodopropofol", "4-bromopropofol", "4-chloropropofol", "4-chloropropofol" ], "offsets": [ [ 94, 108 ], [ 110, 125 ], [ 130, 146 ], [ 175, 191 ] ] }, { "pmid": "18574460", "text": "Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine.", "type": "CHEMICAL", "entities": [ "Halogenated propofol", "sodium", "lidocaine" ], "offsets": [ [ 0, 20 ], [ 59, 65 ], [ 192, 201 ] ] }, { "pmid": "18574460", "text": "Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions.", "type": "CHEMICAL", "entities": [ "halogenated propofol" ], "offsets": [ [ 70, 90 ] ] }, { "pmid": "18627212", "text": "Irbesartan: a review of its use in hypertension and diabetic nephropathy.\n", "type": "CHEMICAL", "entities": [ "Irbesartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18627212", "text": "Irbesartan (Aprovel, Avapro, Irbetan, Karvea), an angiotensin II receptor type 1 antagonist, is approved in many countries worldwide for the treatment of hypertension.", "type": "CHEMICAL", "entities": [ "Irbesartan", "Aprovel", "Avapro", "Irbetan", "Karvea", "angiotensin II" ], "offsets": [ [ 0, 10 ], [ 12, 19 ], [ 21, 27 ], [ 29, 36 ], [ 38, 44 ], [ 50, 64 ] ] }, { "pmid": "18627212", "text": "In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration.", "type": "CHEMICAL", "entities": [ "irbesartan" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "18627212", "text": "Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect.", "type": "CHEMICAL", "entities": [ "Irbesartan" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "18627212", "text": "In addition, irbesartan was generally well tolerated in clinical trials.", "type": "CHEMICAL", "entities": [ "irbesartan" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "18627212", "text": "Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy.", "type": "CHEMICAL", "entities": [ "irbesartan" ], "offsets": [ [ 6, 16 ] ] }, { "pmid": "18773878", "text": "DNA damage and homologous recombination signaling induced by thymidylate deprivation.\n", "type": "CHEMICAL", "entities": [ "thymidylate" ], "offsets": [ [ 61, 72 ] ] }, { "pmid": "18773878", "text": "DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood.", "type": "CHEMICAL", "entities": [ "thymidylate", "thymidylate" ], "offsets": [ [ 43, 54 ], [ 109, 120 ] ] }, { "pmid": "18773878", "text": "Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER).", "type": "CHEMICAL", "entities": [ "Thymidylate", "uracil" ], "offsets": [ [ 0, 11 ], [ 43, 49 ] ] }, { "pmid": "18773878", "text": "Thymidylate deprivation also induces cell cycle arrest during replication.", "type": "CHEMICAL", "entities": [ "Thymidylate" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "18773878", "text": "In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation.", "type": "CHEMICAL", "entities": [ "thymidylate" ], "offsets": [ [ 123, 134 ] ] }, { "pmid": "18773878", "text": "When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS.", "type": "CHEMICAL", "entities": [ "raltitrexed", "RTX" ], "offsets": [ [ 95, 106 ], [ 108, 111 ] ] }, { "pmid": "18773878", "text": "To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation.", "type": "CHEMICAL", "entities": [ "thymidylate" ], "offsets": [ [ 115, 126 ] ] }, { "pmid": "18773878", "text": "Activation of DNA damage signaling responses was examined following treatment with RTX.", "type": "CHEMICAL", "entities": [ "RTX" ], "offsets": [ [ 83, 86 ] ] }, { "pmid": "18773878", "text": "Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of RTX.", "type": "CHEMICAL", "entities": [ "RTX" ], "offsets": [ [ 143, 146 ] ] }, { "pmid": "18773878", "text": "Induction was much more striking following RTX treatment than with hydroxyurea, which is commonly used to inhibit replication.", "type": "CHEMICAL", "entities": [ "RTX", "hydroxyurea" ], "offsets": [ [ 43, 46 ], [ 67, 78 ] ] }, { "pmid": "18773878", "text": "RTX treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied.", "type": "CHEMICAL", "entities": [ "RTX" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "18773878", "text": "Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation.", "type": "CHEMICAL", "entities": [ "thymidylate", "thymidylate" ], "offsets": [ [ 100, 111 ], [ 161, 172 ] ] }, { "pmid": "18954704", "text": "Corticosteroids and human recombinant activated protein C for septic shock.\n", "type": "CHEMICAL", "entities": [ "Corticosteroids" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "18954704", "text": "This article summarizes the current knowledge on the benefit/risk profile from the use of low-dose corticosteroids and activated protein C in treating septic shock.", "type": "CHEMICAL", "entities": [ "corticosteroids" ], "offsets": [ [ 99, 114 ] ] }, { "pmid": "18954704", "text": "Physicians should consider using low-dose corticosteroids and drotrecogin alpha activated in the treatment of patients who have vasopressor-dependent septic shock with persistent signs of hypoperfusion, organ dysfunction, or hypotension.", "type": "CHEMICAL", "entities": [ "corticosteroids" ], "offsets": [ [ 42, 57 ] ] }, { "pmid": "18996527", "text": "Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine.\n", "type": "CHEMICAL", "entities": [ "nicotinamide", "N", "homocysteine" ], "offsets": [ [ 30, 42 ], [ 43, 44 ], [ 67, 79 ] ] }, { "pmid": "18996527", "text": "Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions.", "type": "CHEMICAL", "entities": [ "1-methylnicotinamide", "Nicotinamide", "N", "nicotinamide" ], "offsets": [ [ 84, 104 ], [ 0, 12 ], [ 13, 14 ], [ 68, 80 ] ] }, { "pmid": "18996527", "text": "Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures.", "type": "CHEMICAL", "entities": [ "Homocysteine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "18996527", "text": "Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the NNMT inhibitor 1-methylnicotinamide.", "type": "CHEMICAL", "entities": [ "Homocysteine", "1-methylnicotinamide" ], "offsets": [ [ 0, 12 ], [ 133, 153 ] ] }, { "pmid": "18996527", "text": "Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced NNMT enzyme activity in white adipose tissue of mice.", "type": "CHEMICAL", "entities": [ "NA", "Nicotinic acid" ], "offsets": [ [ 16, 18 ], [ 0, 14 ] ] }, { "pmid": "18996527", "text": "In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion.", "type": "CHEMICAL", "entities": [ "nicotinamide", "homocysteine" ], "offsets": [ [ 18, 30 ], [ 78, 90 ] ] }, { "pmid": "18996527", "text": "These data support the concept that adipose tissue NNMT contributes to the increased plasma homocysteine levels in patients treated with NA.", "type": "CHEMICAL", "entities": [ "homocysteine", "NA" ], "offsets": [ [ 92, 104 ], [ 137, 139 ] ] }, { "pmid": "19029287", "text": "Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms.\n", "type": "CHEMICAL", "entities": [ "calcium", "1,4-dihydropyridine" ], "offsets": [ [ 70, 77 ], [ 15, 34 ] ] }, { "pmid": "19029287", "text": "The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain.", "type": "CHEMICAL", "entities": [ "DHP", "calcium", "1,4-dihydropyridine" ], "offsets": [ [ 102, 105 ], [ 11, 18 ], [ 81, 100 ] ] }, { "pmid": "19029287", "text": "and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain.", "type": "CHEMICAL", "entities": [ "DHP" ], "offsets": [ [ 43, 46 ] ] }, { "pmid": "19029287", "text": "(+)-[(3)H]isradipine", "type": "CHEMICAL", "entities": [ "(+)-[(3)H]isradipine" ], "offsets": [ [ 0, 20 ] ] }, { "pmid": "19029287", "text": "Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels.", "type": "CHEMICAL", "entities": [ "(+)-[(3)H]isradipine", "nitrendipine", "nifedipine" ], "offsets": [ [ 14, 34 ], [ 200, 212 ], [ 217, 227 ] ] }, { "pmid": "19039322", "text": "Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.\n", "type": "CHEMICAL", "entities": [ "bosutinib" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "19039322", "text": "Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel.", "type": "CHEMICAL", "entities": [ "bosutinib" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "19039322", "text": "The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases.", "type": "CHEMICAL", "entities": [ "bosutinib", "tyrosine", "serine", "threonine" ], "offsets": [ [ 53, 62 ], [ 98, 106 ], [ 111, 117 ], [ 118, 127 ] ] }, { "pmid": "19039322", "text": "We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line.", "type": "CHEMICAL", "entities": [ "bosutinib" ], "offsets": [ [ 58, 67 ] ] }, { "pmid": "19039322", "text": "A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles.", "type": "CHEMICAL", "entities": [ "dasatinib", "bosutinib" ], "offsets": [ [ 31, 40 ], [ 16, 25 ] ] }, { "pmid": "19039322", "text": "Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases.", "type": "CHEMICAL", "entities": [ "Bosutinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "19039322", "text": "Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range.", "type": "CHEMICAL", "entities": [ "bosutinib" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "19039322", "text": "Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.", "type": "CHEMICAL", "entities": [ "bosutinib" ], "offsets": [ [ 9, 18 ] ] }, { "pmid": "1908244", "text": "The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent.\n", "type": "CHEMICAL", "entities": [ "estramustine" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "1908244", "text": "Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro.", "type": "CHEMICAL", "entities": [ "estramustine", "estrogen", "Estramustine" ], "offsets": [ [ 33, 45 ], [ 95, 103 ], [ 0, 12 ] ] }, { "pmid": "1908244", "text": "The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor", "type": "CHEMICAL", "entities": [ "estramustine phosphate" ], "offsets": [ [ 23, 45 ] ] }, { "pmid": "1908244", "text": "In the present study the binding of estramustine phosphate to MAP2 and tau was investigated.", "type": "CHEMICAL", "entities": [ "estramustine phosphate" ], "offsets": [ [ 36, 58 ] ] }, { "pmid": "1908244", "text": "Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains.", "type": "CHEMICAL", "entities": [ "estramustine phosphate", "amino acid" ], "offsets": [ [ 66, 88 ], [ 143, 153 ] ] }, { "pmid": "1908244", "text": "The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM.", "type": "CHEMICAL", "entities": [ "estramustine phosphate" ], "offsets": [ [ 26, 48 ] ] }, { "pmid": "1908244", "text": "The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation.", "type": "CHEMICAL", "entities": [ "estramustine phosphate" ], "offsets": [ [ 100, 122 ] ] }, { "pmid": "1908244", "text": "Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors.", "type": "CHEMICAL", "entities": [ "estramustine", "estramustine sulphate", "estramustine glucuronide" ], "offsets": [ [ 27, 39 ], [ 53, 74 ], [ 79, 103 ] ] }, { "pmid": "1908244", "text": "The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide.", "type": "CHEMICAL", "entities": [ "sulphate", "estramustine phosphate", "estramustine glucuronide" ], "offsets": [ [ 72, 80 ], [ 126, 148 ], [ 184, 208 ] ] }, { "pmid": "1908244", "text": "A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs.", "type": "CHEMICAL", "entities": [ "estramustine sarcosinate" ], "offsets": [ [ 33, 57 ] ] }, { "pmid": "1908244", "text": "The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology.", "type": "CHEMICAL", "entities": [ "estramustine" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "1908244", "text": "Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect.", "type": "CHEMICAL", "entities": [ "estramustine" ], "offsets": [ [ 49, 61 ] ] }, { "pmid": "1911436", "text": "Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog.\n", "type": "CHEMICAL", "entities": [ "5'-[p-(fluorosulfonyl)benzoyl]adenosine", "3 beta-hydroxy-5-ene-steroid" ], "offsets": [ [ 130, 169 ], [ 48, 76 ] ] }, { "pmid": "1911436", "text": "3 beta-Hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes.", "type": "CHEMICAL", "entities": [ "3 beta-Hydroxy-5-ene-steroid" ], "offsets": [ [ 0, 28 ] ] }, { "pmid": "1911436", "text": "Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein.", "type": "CHEMICAL", "entities": [ "alpha-bromoacetoxyprogesterone", "steroids" ], "offsets": [ [ 27, 57 ], [ 114, 122 ] ] }, { "pmid": "1911436", "text": "However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem.", "type": "CHEMICAL", "entities": [ "progestin", "NADH" ], "offsets": [ [ 98, 107 ], [ 23, 27 ] ] }, { "pmid": "1911436", "text": "Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+).", "type": "CHEMICAL", "entities": [ "3-keto-5-ene-steroid", "diphosphopyridine nucleotides", "NADH", "NAD+" ], "offsets": [ [ 17, 37 ], [ 95, 124 ], [ 126, 130 ], [ 132, 136 ] ] }, { "pmid": "1911436", "text": "The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM).", "type": "CHEMICAL", "entities": [ "nucleotide", "5'-[p-(fluorosulfonyl)benzoyl]adenosine", "FSA" ], "offsets": [ [ 22, 32 ], [ 41, 80 ], [ 82, 85 ] ] }, { "pmid": "1911436", "text": "FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM).", "type": "CHEMICAL", "entities": [ "NAD+" ], "offsets": [ [ 103, 107 ] ] }, { "pmid": "1911436", "text": "Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both).", "type": "CHEMICAL", "entities": [ "FSA" ], "offsets": [ [ 67, 70 ] ] }, { "pmid": "1911436", "text": "The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA.", "type": "CHEMICAL", "entities": [ "3 beta-hydroxysteroid", "pregnenolone", "FSA" ], "offsets": [ [ 4, 25 ], [ 37, 49 ], [ 116, 119 ] ] }, { "pmid": "19149483", "text": "Tyrosine kinase blockers: new hope for successful cancer therapy.\n", "type": "CHEMICAL", "entities": [ "Tyrosine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "19149483", "text": "Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth.", "type": "CHEMICAL", "entities": [ "Tyrosine" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "19149483", "text": "During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 73, 81 ] ] }, { "pmid": "19149483", "text": "The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia.", "type": "CHEMICAL", "entities": [ "Imatinib", "Imatinib mesylate", "Gleevec", "STI571" ], "offsets": [ [ 50, 58 ], [ 60, 77 ], [ 79, 86 ], [ 88, 94 ] ] }, { "pmid": "19149483", "text": "The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed.", "type": "CHEMICAL", "entities": [ "STI571" ], "offsets": [ [ 20, 26 ] ] }, { "pmid": "19149483", "text": "Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase.", "type": "CHEMICAL", "entities": [ "SU 11248", "Sutent", "AMN107", "Nilotinib", "INNO-406", "NS-187", "Dasatinib", "BMS-354825", "Gefitinib", "Iressa", "Erlotinib", "OSI-774", "Tarceva", "Sunitinib" ], "offsets": [ [ 202, 210 ], [ 212, 218 ], [ 255, 261 ], [ 263, 272 ], [ 278, 286 ], [ 288, 294 ], [ 65, 74 ], [ 76, 86 ], [ 138, 147 ], [ 149, 155 ], [ 158, 167 ], [ 169, 176 ], [ 178, 185 ], [ 191, 200 ] ] }, { "pmid": "19149483", "text": "The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).", "type": "CHEMICAL", "entities": [ "Lapatinib", "Lapatinib ditosylate", "Tykerb", "GW-572016", "Canertinib", "CI-1033", "Zactima", "ZD6474", "Vatalanib", "PTK787", "ZK 222584", "Sorafenib", "Bay 43-9006", "Nexavar", "Leflunomide", "SU101", "Arava" ], "offsets": [ [ 93, 102 ], [ 104, 124 ], [ 126, 132 ], [ 134, 143 ], [ 146, 156 ], [ 158, 165 ], [ 168, 175 ], [ 177, 183 ], [ 186, 195 ], [ 197, 203 ], [ 204, 213 ], [ 216, 225 ], [ 227, 238 ], [ 240, 247 ], [ 254, 265 ], [ 267, 272 ], [ 274, 279 ] ] }, { "pmid": "19149483", "text": "Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "19300583", "text": "Transdermal selegiline for the treatment of major depressive disorder.\n", "type": "CHEMICAL", "entities": [ "selegiline" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "19300583", "text": "Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects.", "type": "CHEMICAL", "entities": [ "monoamine" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "19300583", "text": "In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD).", "type": "CHEMICAL", "entities": [ "selegiline" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "19300583", "text": "Currently, the use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the \"cheese reaction\") when combined with dietary tyramine.", "type": "CHEMICAL", "entities": [ "phenelzine", "tranylcypromine", "tyramine", "tyramine" ], "offsets": [ [ 77, 87 ], [ 89, 104 ], [ 132, 140 ], [ 259, 267 ] ] }, { "pmid": "19300583", "text": "The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours.", "type": "CHEMICAL", "entities": [ "selegiline" ], "offsets": [ [ 4, 14 ] ] }, { "pmid": "19300583", "text": "bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect.", "type": "CHEMICAL", "entities": [ "tyramine", "selegiline" ], "offsets": [ [ 148, 156 ], [ 217, 227 ] ] }, { "pmid": "19300583", "text": "However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended.", "type": "CHEMICAL", "entities": [ "tyramine" ], "offsets": [ [ 86, 94 ] ] }, { "pmid": "19445548", "text": "Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents.\n", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD).", "type": "CHEMICAL", "entities": [ "Atomoxetine", "norepinephrine", "noradrenaline", "Strattera" ], "offsets": [ [ 0, 11 ], [ 42, 56 ], [ 58, 71 ], [ 13, 22 ] ] }, { "pmid": "19445548", "text": "Atomoxetine is effective and generally well tolerated.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts.", "type": "CHEMICAL", "entities": [ "methylphenidate", "methylphenidate", "methylphenidate", "methylphenidate", "amfetamine" ], "offsets": [ [ 155, 170 ], [ 242, 257 ], [ 278, 293 ], [ 341, 356 ], [ 385, 395 ] ] }, { "pmid": "19445548", "text": "Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 6, 17 ] ] }, { "pmid": "19445548", "text": "The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex.", "type": "CHEMICAL", "entities": [ "atomoxetine", "norepinephrine" ], "offsets": [ [ 27, 38 ], [ 123, 137 ] ] }, { "pmid": "19445548", "text": "Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors.", "type": "CHEMICAL", "entities": [ "Atomoxetine", "norepinephrine" ], "offsets": [ [ 0, 11 ], [ 52, 66 ] ] }, { "pmid": "19445548", "text": "Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem.", "type": "CHEMICAL", "entities": [ "Atomoxetine", "norepinephrine" ], "offsets": [ [ 0, 11 ], [ 62, 76 ] ] }, { "pmid": "19445548", "text": "Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 68, 79 ] ] }, { "pmid": "19445548", "text": "Data suggest that atomoxetine is unlikely to have any abuse potential.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "19445548", "text": "Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD.", "type": "CHEMICAL", "entities": [ "Atomoxetine", "methylphenidate" ], "offsets": [ [ 0, 11 ], [ 38, 53 ] ] }, { "pmid": "19445548", "text": "Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 215, 226 ] ] }, { "pmid": "19445548", "text": "Patients with hepatic insufficiency show an increase in atomoxetine exposure.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 56, 67 ] ] }, { "pmid": "19445548", "text": "CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers.", "type": "CHEMICAL", "entities": [ "paroxetine", "atomoxetine" ], "offsets": [ [ 27, 37 ], [ 70, 81 ] ] }, { "pmid": "19445548", "text": "Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 21, 32 ] ] }, { "pmid": "19445548", "text": "Atomoxetine also demonstrated efficacy in the longer term treatment of these patients.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 89, 100 ] ] }, { "pmid": "19445548", "text": "Atomoxetine efficacy did not appear to differ between children and adolescents.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Stimulant-naive patients also responded well to atomoxetine treatment.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 48, 59 ] ] }, { "pmid": "19445548", "text": "Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment).", "type": "CHEMICAL", "entities": [ "Atomoxetine", "methylphenidate", "atomoxetine" ], "offsets": [ [ 0, 11 ], [ 86, 101 ], [ 273, 284 ] ] }, { "pmid": "19445548", "text": "However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts.", "type": "CHEMICAL", "entities": [ "atomoxetine", "methylphenidate", "amfetamine" ], "offsets": [ [ 9, 20 ], [ 80, 95 ], [ 123, 133 ] ] }, { "pmid": "19445548", "text": "The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration.", "type": "CHEMICAL", "entities": [ "atomoxetine", "atomoxetine" ], "offsets": [ [ 16, 27 ], [ 176, 187 ] ] }, { "pmid": "19445548", "text": "Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy.", "type": "CHEMICAL", "entities": [ "atomoxetine", "atomoxetine" ], "offsets": [ [ 78, 89 ], [ 128, 139 ] ] }, { "pmid": "19445548", "text": "Atomoxetine was generally well tolerated in children and adolescents with ADHD.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Few patients discontinued atomoxetine treatment because of adverse events.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "19445548", "text": "Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers.", "type": "CHEMICAL", "entities": [ "Atomoxetine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19445548", "text": "Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 65, 76 ] ] }, { "pmid": "19445548", "text": "Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "19445548", "text": "A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo.", "type": "CHEMICAL", "entities": [ "atomoxetine" ], "offsets": [ [ 148, 159 ] ] }, { "pmid": "19445548", "text": "Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment.", "type": "CHEMICAL", "entities": [ "atomoxetine", "atomoxetine" ], "offsets": [ [ 8, 19 ], [ 179, 190 ] ] }, { "pmid": "19445548", "text": "Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD.", "type": "CHEMICAL", "entities": [ "atomoxetine", "methylphenidate", "dexamfetamine", "tricyclic" ], "offsets": [ [ 50, 61 ], [ 120, 135 ], [ 170, 183 ], [ 185, 194 ] ] }, { "pmid": "19531491", "text": "Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics.\n", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "19531491", "text": "Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme.", "type": "CHEMICAL", "entities": [ "glutamate", "l-glutamate", "2-oxoglutarate", "NAD(P)(+)" ], "offsets": [ [ 10, 19 ], [ 121, 132 ], [ 136, 150 ], [ 157, 166 ] ] }, { "pmid": "19531491", "text": "The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 120, 123 ] ] }, { "pmid": "19531491", "text": "Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate.", "type": "CHEMICAL", "entities": [ "epigallocatechin gallate", "epicatechin gallate" ], "offsets": [ [ 140, 164 ], [ 169, 188 ] ] }, { "pmid": "19531491", "text": "This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol.", "type": "CHEMICAL", "entities": [ "hexachlorophene", "GW5074", "bithionol" ], "offsets": [ [ 95, 110 ], [ 112, 118 ], [ 124, 133 ] ] }, { "pmid": "19531491", "text": "Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves.", "type": "CHEMICAL", "entities": [ "Hexachlorophene" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "19531491", "text": "In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits.", "type": "CHEMICAL", "entities": [ "GW5074", "bithionol" ], "offsets": [ [ 13, 19 ], [ 24, 33 ] ] }, { "pmid": "19690271", "text": "The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats.\n", "type": "CHEMICAL", "entities": [ "prostaglandin E2" ], "offsets": [ [ 57, 73 ] ] }, { "pmid": "19690271", "text": "Peripheral inflammatory pain is associated with an upregulation of spinal cord COX-2 (cyclooxygenase-2), with a subsequent increase in central prostaglandin E2 (PGE2) levels associated with the development of hyperalgesia.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2" ], "offsets": [ [ 143, 159 ], [ 161, 165 ] ] }, { "pmid": "19690271", "text": "In this study, we evaluated the effect of bupivacaine administered via a nerve block or via a systemic route on the spinal expression of PGE2 and COX in a model of peripheral inflammation in rats.", "type": "CHEMICAL", "entities": [ "bupivacaine", "PGE2" ], "offsets": [ [ 42, 53 ], [ 137, 141 ] ] }, { "pmid": "19690271", "text": "All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either bupivacaine 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either bupivacaine 0.5% or saline).", "type": "CHEMICAL", "entities": [ "bupivacaine", "bupivacaine" ], "offsets": [ [ 181, 192 ], [ 290, 301 ] ] }, { "pmid": "19690271", "text": "Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid PGE2 concentration and COX-1 and COX-2 expression in the spinal cord in dorsal root ganglions were measured.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 81, 85 ] ] }, { "pmid": "19690271", "text": "We confirmed that a bupivacaine block attenuates hyperalgesia and local inflammation in a model of inflammatory pain.", "type": "CHEMICAL", "entities": [ "bupivacaine" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "19690271", "text": "The subsequent production of PGE2 in cerebrospinal fluid was also impaired.", "type": "CHEMICAL", "entities": [ "PGE2" ], "offsets": [ [ 29, 33 ] ] }, { "pmid": "19690271", "text": "Systemic bupivacaine did not modify either the hyperalgesia and local inflammation or COX expression.", "type": "CHEMICAL", "entities": [ "bupivacaine" ], "offsets": [ [ 9, 20 ] ] }, { "pmid": "1978244", "text": "Two pharmacologically distinct alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role.\n", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 135, 139 ] ] }, { "pmid": "1978244", "text": "Using the alpha 1-adrenoceptor subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the alpha 1-adrenoceptor populations in rabbit aorta.", "type": "CHEMICAL", "entities": [ "5-methyl-urapidil", "chlorethylclonidine", "CEC", "WB4101" ], "offsets": [ [ 100, 117 ], [ 61, 80 ], [ 82, 85 ], [ 88, 94 ] ] }, { "pmid": "1978244", "text": "The alpha 1-adrenoceptor alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component.", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 96, 110 ] ] }, { "pmid": "1978244", "text": "The alpha 1-adrenoceptor occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 72, 88 ] ] }, { "pmid": "1978244", "text": "Radioligand binding studies with the nonselective alpha 1-adrenoceptor antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1).", "type": "CHEMICAL", "entities": [ "125I-BE2254", "CEC", "WB4101", "5-methylurapidil" ], "offsets": [ [ 94, 105 ], [ 166, 169 ], [ 235, 241 ], [ 262, 278 ] ] }, { "pmid": "1978244", "text": "Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol", "PI", "CEC", "CEC", "PI", "CEC" ], "offsets": [ [ 40, 60 ], [ 62, 64 ], [ 81, 84 ], [ 150, 153 ], [ 203, 205 ], [ 309, 312 ] ] }, { "pmid": "1978244", "text": "The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil.", "type": "CHEMICAL", "entities": [ "methoxamine", "WB4101", "5-methyl-urapidil", "WB4101", "5-methyl-urapidil" ], "offsets": [ [ 126, 137 ], [ 265, 271 ], [ 302, 319 ], [ 49, 55 ], [ 60, 77 ] ] }, { "pmid": "1978244", "text": "However, the Schilod plots for these antagonists against norepinephrine were curvilinear.", "type": "CHEMICAL", "entities": [ "norepinephrine" ], "offsets": [ [ 57, 71 ] ] }, { "pmid": "1978244", "text": "Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that alpha 1-adrenoceptor populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS)", "type": "CHEMICAL", "entities": [ "WB4101", "5-methyl-urapidil", "WB4101", "5-methyl-urapidil" ], "offsets": [ [ 287, 293 ], [ 324, 341 ], [ 445, 451 ], [ 456, 473 ] ] }, { "pmid": "19920913", "text": "Ambrisentan for the treatment of pulmonary arterial hypertension.\n", "type": "CHEMICAL", "entities": [ "Ambrisentan" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19920913", "text": "Ambrisentan is an endothelin receptor antagonist (ERA) that was recently approved for treatment of pulmonary arterial hypertension (PAH).", "type": "CHEMICAL", "entities": [ "Ambrisentan" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19920913", "text": "ET(A) mediates the vasoconstrictor effect of ET on vascular smooth muscle, whereas ET(B) is expressed primarily on vascular endothelial cells where it induces nitric oxide synthesis and acts to clear ET from the circulation.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 159, 171 ] ] }, { "pmid": "19920913", "text": "Ambrisentan is the first ET(A) selective ERA approved for use in the US.", "type": "CHEMICAL", "entities": [ "Ambrisentan" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "19920913", "text": "It also examines the development process, safety profile and clinical trials that have resulted in ambrisentan being approved for treatment of PAH.", "type": "CHEMICAL", "entities": [ "ambrisentan" ], "offsets": [ [ 99, 110 ] ] }, { "pmid": "19952416", "text": "Design, synthesis, and in-vivo evaluation of 4,5-diaryloxazole as novel nonsteroidal anti-inflammatory drug.\n", "type": "CHEMICAL", "entities": [ "4,5-diaryloxazole" ], "offsets": [ [ 45, 62 ] ] }, { "pmid": "19952416", "text": "A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of oxaprozin.", "type": "CHEMICAL", "entities": [ "oxaprozin", "4,5-diaryloxazole", "oxaprozin" ], "offsets": [ [ 80, 89 ], [ 12, 29 ], [ 224, 233 ] ] }, { "pmid": "19952416", "text": "Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result.", "type": "CHEMICAL", "entities": [ "3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid", "NC-2142" ], "offsets": [ [ 9, 94 ], [ 96, 103 ] ] }, { "pmid": "19952416", "text": "NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice.", "type": "CHEMICAL", "entities": [ "NC-2142" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "19952416", "text": "NC-2142 produced fewer gastric lesions than oxaprozin.", "type": "CHEMICAL", "entities": [ "NC-2142", "oxaprozin" ], "offsets": [ [ 0, 7 ], [ 44, 53 ] ] }, { "pmid": "19952416", "text": "After the aminosulfonyl group was introduced into the benzene ring of oxaprozin, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions.", "type": "CHEMICAL", "entities": [ "oxaprozin", "aminosulfonyl", "benzene" ], "offsets": [ [ 70, 79 ], [ 10, 23 ], [ 54, 61 ] ] }, { "pmid": "19952416", "text": "This provided a feasible method for further structure modification and optimization of oxaprozin.", "type": "CHEMICAL", "entities": [ "oxaprozin" ], "offsets": [ [ 87, 96 ] ] }, { "pmid": "19962254", "text": "Breast cancer and steroid metabolizing enzymes: the role of progestogens.\n", "type": "CHEMICAL", "entities": [ "steroid", "progestogens" ], "offsets": [ [ 18, 25 ], [ 60, 72 ] ] }, { "pmid": "19962254", "text": "It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone.", "type": "CHEMICAL", "entities": [ "estrogens", "androgens", "progesterone" ], "offsets": [ [ 167, 176 ], [ 178, 187 ], [ 192, 204 ] ] }, { "pmid": "19962254", "text": "These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases.", "type": "CHEMICAL", "entities": [ "hydroxysteroid" ], "offsets": [ [ 37, 51 ] ] }, { "pmid": "19962254", "text": "As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and 17beta-hydroxysteroid-dehydrogenase type 1 activities.", "type": "CHEMICAL", "entities": [ "promegestone", "nomegestrol acetate", "norelgestromin", "estradiol", "17beta-hydroxysteroid", "progestogens", "dydrogesterone", "medrogestone" ], "offsets": [ [ 125, 137 ], [ 139, 158 ], [ 163, 177 ], [ 213, 222 ], [ 266, 287 ], [ 37, 49 ], [ 60, 74 ], [ 111, 123 ] ] }, { "pmid": "19962254", "text": "A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 81, 89 ] ] }, { "pmid": "19962254", "text": "Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue.", "type": "CHEMICAL", "entities": [ "Progesterone" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "19962254", "text": "It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis.", "type": "CHEMICAL", "entities": [ "progesterone" ], "offsets": [ [ 55, 67 ] ] }, { "pmid": "19962254", "text": "In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer.", "type": "CHEMICAL", "entities": [ "17beta-hydroxysteroid" ], "offsets": [ [ 78, 99 ] ] }, { "pmid": "20022821", "text": "The purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 84, 90 ] ] }, { "pmid": "20022821", "text": "METHODS: Activation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline.", "type": "CHEMICAL", "entities": [ "ajmaline" ], "offsets": [ [ 239, 247 ] ] }, { "pmid": "20022821", "text": "In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 62, 68 ] ] }, { "pmid": "20022821", "text": "In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 93, 99 ] ] }, { "pmid": "20025554", "text": "Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis.\n", "type": "CHEMICAL", "entities": [ "mitiglinide", "voglibose" ], "offsets": [ [ 25, 36 ], [ 41, 50 ] ] }, { "pmid": "20025554", "text": "Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas.", "type": "CHEMICAL", "entities": [ "sulfonylurea", "Mitiglinide", "sulfonylureas" ], "offsets": [ [ 54, 66 ], [ 0, 11 ], [ 126, 139 ] ] }, { "pmid": "20025554", "text": "The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.", "type": "CHEMICAL", "entities": [ "mitiglinide", "mitiglinide" ], "offsets": [ [ 35, 46 ], [ 212, 223 ] ] }, { "pmid": "20025554", "text": "We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg).", "type": "CHEMICAL", "entities": [ "voglibose" ], "offsets": [ [ 131, 140 ] ] }, { "pmid": "20025554", "text": "The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone.", "type": "CHEMICAL", "entities": [ "mitiglinide", "mitiglinide", "voglibose", "voglibose" ], "offsets": [ [ 80, 91 ], [ 100, 111 ], [ 195, 204 ], [ 277, 286 ] ] }, { "pmid": "20025554", "text": "The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 66, 73 ] ] }, { "pmid": "20025554", "text": "The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.)", "type": "CHEMICAL", "entities": [ "mitiglinide" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "20025554", "text": "Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and Hb(A1c) levels after 8 weeks.", "type": "CHEMICAL", "entities": [ "Mitiglinide", "glucose" ], "offsets": [ [ 0, 11 ], [ 35, 42 ] ] }, { "pmid": "20025554", "text": "Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment.", "type": "CHEMICAL", "entities": [ "Triglyceride", "mitiglinide" ], "offsets": [ [ 0, 12 ], [ 74, 85 ] ] }, { "pmid": "20025554", "text": "This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD.", "type": "CHEMICAL", "entities": [ "mitiglinide", "voglibose" ], "offsets": [ [ 45, 56 ], [ 61, 70 ] ] }, { "pmid": "20025554", "text": "Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.", "type": "CHEMICAL", "entities": [ "mitiglinide" ], "offsets": [ [ 109, 120 ] ] }, { "pmid": "20083608", "text": "Cyan fluorescent protein was fused to the C terminus of the M(2) muscarinic receptor, and a specific binding sequence for the small fluorescent compound fluorescein arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH.", "type": "CHEMICAL", "entities": [ "C", "fluorescein" ], "offsets": [ [ 42, 43 ], [ 153, 164 ] ] }, { "pmid": "20083608", "text": "Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes.", "type": "CHEMICAL", "entities": [ "carbachol", "acetylcholine" ], "offsets": [ [ 35, 44 ], [ 17, 30 ] ] }, { "pmid": "20083608", "text": "The allosteric ligands gallamine and dimethyl-W84 caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors.", "type": "CHEMICAL", "entities": [ "gallamine", "dimethyl-W84" ], "offsets": [ [ 23, 32 ], [ 37, 49 ] ] }, { "pmid": "20083608", "text": "The kinetics of these effects were very rapid, with rate constants of 80-100 ms and approximately 200 ms for saturating concentrations of gallamine and dimethyl-W84, respectively.", "type": "CHEMICAL", "entities": [ "gallamine", "dimethyl-W84" ], "offsets": [ [ 138, 147 ], [ 152, 164 ] ] }, { "pmid": "20083608", "text": "Because these speeds are significantly faster than the responses to antagonists, these data indicate that gallamine and dimethyl-W84 are allosteric ligands and actively induce a conformation of the M(2) receptor with a reduced affinity for its agonists.", "type": "CHEMICAL", "entities": [ "gallamine", "dimethyl-W84" ], "offsets": [ [ 106, 115 ], [ 120, 132 ] ] }, { "pmid": "20089905", "text": "A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.\n", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "20089905", "text": "Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases.", "type": "CHEMICAL", "entities": [ "Ibuprofen" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20089905", "text": "Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "20089905", "text": "In addition, another study suggests that ibuprofen reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "20089905", "text": "The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "20089905", "text": "Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 133, 142 ] ] }, { "pmid": "20089905", "text": "Ibuprofen activates PPARgamma in neuron-like PC12 and B104 cells.", "type": "CHEMICAL", "entities": [ "Ibuprofen" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20089905", "text": "Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors.", "type": "CHEMICAL", "entities": [ "ibuprofen", "ibuprofen" ], "offsets": [ [ 91, 100 ], [ 125, 134 ] ] }, { "pmid": "20089905", "text": "Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "20089905", "text": "These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 105, 114 ] ] }, { "pmid": "20089905", "text": "Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease.", "type": "CHEMICAL", "entities": [ "ibuprofen" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "20135071", "text": "Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development.\n", "type": "CHEMICAL", "entities": [ "dabigatran", "rivaroxaban", "apixaban" ], "offsets": [ [ 65, 75 ], [ 77, 88 ], [ 93, 101 ] ] }, { "pmid": "20135071", "text": "Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure.", "type": "CHEMICAL", "entities": [ "warfarin", "vitamin K" ], "offsets": [ [ 81, 89 ], [ 99, 108 ] ] }, { "pmid": "20135071", "text": "Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade.", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 112, 118 ] ] }, { "pmid": "20135071", "text": "Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe.", "type": "CHEMICAL", "entities": [ "dabigatran", "rivaroxaban" ], "offsets": [ [ 33, 43 ], [ 68, 79 ] ] }, { "pmid": "20135071", "text": "In addition, the factor Xa inhibitor apixaban is in late-stage clinical development.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "20135071", "text": "Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial.", "type": "CHEMICAL", "entities": [ "dabigatran", "rivaroxaban", "apixaban" ], "offsets": [ [ 90, 100 ], [ 126, 137 ], [ 207, 215 ] ] }, { "pmid": "20135071", "text": "However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function.", "type": "CHEMICAL", "entities": [ "rivaroxaban", "apixaban", "dabigatran" ], "offsets": [ [ 24, 35 ], [ 40, 48 ], [ 210, 220 ] ] }, { "pmid": "20135071", "text": "Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.", "type": "CHEMICAL", "entities": [ "dabigatran", "rivaroxaban", "apixaban" ], "offsets": [ [ 62, 72 ], [ 74, 85 ], [ 90, 98 ] ] }, { "pmid": "20184869", "text": "Captopril directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy.\n", "type": "CHEMICAL", "entities": [ "Captopril" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20184869", "text": "We determined whether an angiotensin-converting enzyme (ACE) inhibitor, captopril, inhibits MMP-2 activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the MMP-2-captopril complex.", "type": "CHEMICAL", "entities": [ "angiotensin", "captopril", "captopril" ], "offsets": [ [ 25, 36 ], [ 72, 81 ], [ 198, 207 ] ] }, { "pmid": "20184869", "text": "The inhibitory effect of captopril on MMP-2 activity was measured in peritoneal effluents from 17 patients on CAPD.", "type": "CHEMICAL", "entities": [ "captopril" ], "offsets": [ [ 25, 34 ] ] }, { "pmid": "20184869", "text": "Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization.", "type": "CHEMICAL", "entities": [ "captopril" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "20184869", "text": "Captopril directly inhibited MMP-2 activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that captopril binding to the MMP-2 active site could be formed in each complex model without molecular distortion.", "type": "CHEMICAL", "entities": [ "Captopril", "captopril" ], "offsets": [ [ 0, 9 ], [ 122, 131 ] ] }, { "pmid": "20184869", "text": "ACE inhibitors, such as captopril, may be applied as important compounds for MMP-2 inhibition in inflammation caused by CAPD.", "type": "CHEMICAL", "entities": [ "captopril" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "20188727", "text": "Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel.\n", "type": "CHEMICAL", "entities": [ "Phenformin", "ATP", "potassium" ], "offsets": [ [ 0, 10 ], [ 49, 52 ], [ 63, 72 ] ] }, { "pmid": "20188727", "text": "The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity.", "type": "CHEMICAL", "entities": [ "metformin", "biguanides", "phenformin" ], "offsets": [ [ 31, 40 ], [ 4, 14 ], [ 16, 26 ] ] }, { "pmid": "20188727", "text": "We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs).", "type": "CHEMICAL", "entities": [ "rubidium", "ATP", "K+", "K", "ATP", "K", "ATP" ], "offsets": [ [ 38, 46 ], [ 99, 102 ], [ 113, 115 ], [ 125, 126 ], [ 127, 130 ], [ 194, 195 ], [ 196, 199 ] ] }, { "pmid": "20188727", "text": "Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1).", "type": "CHEMICAL", "entities": [ "Phenformin", "metformin", "K", "ATP" ], "offsets": [ [ 0, 10 ], [ 19, 28 ], [ 62, 63 ], [ 64, 67 ] ] }, { "pmid": "20188727", "text": "The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU", "type": "CHEMICAL", "entities": [ "K", "ATP" ], "offsets": [ [ 74, 75 ], [ 76, 79 ] ] }, { "pmid": "20188727", "text": "37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches.", "type": "CHEMICAL", "entities": [ "phenformin", "Phenformin" ], "offsets": [ [ 22, 32 ], [ 149, 159 ] ] }, { "pmid": "20188727", "text": "These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity.", "type": "CHEMICAL", "entities": [ "phenformin", "sulphonylurea" ], "offsets": [ [ 28, 38 ], [ 107, 120 ] ] }, { "pmid": "20188727", "text": "It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A.", "type": "CHEMICAL", "entities": [ "PNU 37883A" ], "offsets": [ [ 98, 108 ] ] }, { "pmid": "20204178", "text": "Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis.\n", "type": "CHEMICAL", "entities": [ "paricalcitol", "doxercalciferol" ], "offsets": [ [ 45, 57 ], [ 62, 77 ] ] }, { "pmid": "20204178", "text": "Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression.", "type": "CHEMICAL", "entities": [ "Vitamin D" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "20204178", "text": "Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR).", "type": "CHEMICAL", "entities": [ "calcium", "Ca", "Ca", "Ca" ], "offsets": [ [ 64, 71 ], [ 73, 75 ], [ 129, 131 ], [ 172, 174 ] ] }, { "pmid": "20204178", "text": "In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum Ca and PTH, and also the expression of PTH, VDR, and CaSR mRNA.", "type": "CHEMICAL", "entities": [ "doxercalciferol", "Ca", "paricalcitol" ], "offsets": [ [ 59, 74 ], [ 95, 97 ], [ 42, 54 ] ] }, { "pmid": "20204178", "text": "The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks.", "type": "CHEMICAL", "entities": [ "paricalcitol", "doxercalciferol" ], "offsets": [ [ 122, 134 ], [ 139, 154 ] ] }, { "pmid": "20204178", "text": "Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum Ca than doxercalciferol.", "type": "CHEMICAL", "entities": [ "paricalcitol", "Ca", "doxercalciferol" ], "offsets": [ [ 132, 144 ], [ 178, 180 ], [ 186, 201 ] ] }, { "pmid": "20204178", "text": "In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively.", "type": "CHEMICAL", "entities": [ "paricalcitol", "doxercalciferol", "paricalcitol" ], "offsets": [ [ 26, 38 ], [ 62, 77 ], [ 235, 247 ] ] }, { "pmid": "20204178", "text": "The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system.", "type": "CHEMICAL", "entities": [ "Ca", "vitamin D" ], "offsets": [ [ 50, 52 ], [ 165, 174 ] ] }, { "pmid": "20223979", "text": "Identification of a primary target of thalidomide teratogenicity.\n", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "20223979", "text": "Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "20223979", "text": "Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 7, 18 ] ] }, { "pmid": "20223979", "text": "Here, we identified cereblon (CRBN) as a thalidomide-binding protein.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "20223979", "text": "Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity.", "type": "CHEMICAL", "entities": [ "Thalidomide" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "20223979", "text": "This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.", "type": "CHEMICAL", "entities": [ "thalidomide", "thalidomide" ], "offsets": [ [ 31, 42 ], [ 103, 114 ] ] }, { "pmid": "20371872", "text": "In this study we explore the mechanisms by which a double mutation (E59D/D75Y) in cardiac troponin C (CTnC) associated with dilated cardiomyopathy reduces the Ca(2+)-activated maximal tension of cardiac muscle.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 159, 165 ] ] }, { "pmid": "20371872", "text": "Studying the single mutants (i.e. E59D or D75Y) indicates that D75Y, but not E59D, causes a reduction in the calcium affinity of CTnC in troponin complex, regulated thin filaments (RTF), and the Ca(2+) sensitivity of contraction and ATPase in cardiac muscle preparations.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 195, 201 ] ] }, { "pmid": "20407761", "text": "Zolmitriptan and human aggression: interaction with alcohol.\n", "type": "CHEMICAL", "entities": [ "Zolmitriptan", "alcohol" ], "offsets": [ [ 0, 12 ], [ 52, 59 ] ] }, { "pmid": "20407761", "text": "The serotonin 1(B/D) (5-HT1(B/D))", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "20407761", "text": "The 5-HT1(B/D) agonist zolmitriptan's ability to reduce aggressive behavior in humans and its interaction with the well-known aggression-enhancing drug alcohol were examined.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 152, 159 ] ] }, { "pmid": "20407761", "text": "Our objective was to investigate zolmitriptan's potential to modify human aggression in a laboratory paradigm across a range of alcohol doses.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 128, 135 ] ] }, { "pmid": "20407761", "text": "Alcohol has been consistently associated with aggression and violence, thus we hoped to expand current understanding of alcohol's role in aggressive behavior via manipulation of the serotonin (5-HT) system.", "type": "CHEMICAL", "entities": [ "Alcohol", "serotonin", "5-HT" ], "offsets": [ [ 0, 7 ], [ 182, 191 ], [ 193, 197 ] ] }, { "pmid": "20407761", "text": "Subjects were administered 5-mg zolmitriptan and placebo capsules along with alcohol doses of 0.0, 0.4 and 0.8 g/kg in a within-subject, counterbalanced dosing design.", "type": "CHEMICAL", "entities": [ "zolmitriptan", "alcohol" ], "offsets": [ [ 32, 44 ], [ 77, 84 ] ] }, { "pmid": "20407761", "text": "Data were analyzed as the ratio of aggressive/monetary-earning responses, to account for possible changes in overall motor function due to alcohol.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 139, 146 ] ] }, { "pmid": "20407761", "text": "There was a significant alcohol by zolmitriptan interaction on the aggressive/monetary response ratio.", "type": "CHEMICAL", "entities": [ "alcohol", "zolmitriptan" ], "offsets": [ [ 24, 31 ], [ 35, 47 ] ] }, { "pmid": "20407761", "text": "Specifically, compared to placebo, zolmitriptan decreased the aggressive/monetary ratio at the 0.4- and 0.8-g/kg alcohol doses.", "type": "CHEMICAL", "entities": [ "zolmitriptan", "alcohol" ], "offsets": [ [ 35, 47 ], [ 113, 120 ] ] }, { "pmid": "20407761", "text": "A 5-mg dose of zolmitriptan effectively reduced alcohol-related aggression in an acute dosing protocol, demonstrating an interaction of 5-HT and alcohol in human aggressive behavior.", "type": "CHEMICAL", "entities": [ "alcohol", "zolmitriptan", "alcohol", "5-HT" ], "offsets": [ [ 145, 152 ], [ 15, 27 ], [ 48, 55 ], [ 136, 140 ] ] }, { "pmid": "20448797", "text": "New standards in hypertension and cardiovascular risk management: focus on telmisartan.\n", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 75, 86 ] ] }, { "pmid": "20448797", "text": "Blockade of the renin-angiotensin system is an important approach in managing high blood pressure, and has increasingly been shown to affect cardiovascular disease processes mediated by angiotensin II throughout the cardiovascular and renal continua.", "type": "CHEMICAL", "entities": [ "angiotensin II", "angiotensin" ], "offsets": [ [ 186, 200 ], [ 22, 33 ] ] }, { "pmid": "20448797", "text": "Telmisartan is an angiotensin II receptor blocker (ARB) displaying unique pharmacologic properties, including a longer half life than any other ARB, that result in large and sustained reductions of blood pressure.", "type": "CHEMICAL", "entities": [ "Telmisartan", "angiotensin II" ], "offsets": [ [ 0, 11 ], [ 18, 32 ] ] }, { "pmid": "20448797", "text": "In patients with mild-to-moderate hypertension, telmisartan has proved superior to other antihypertensive agents (valsartan, losartan, ramipril, perindopril, and atenolol) in controlling blood pressure particularly towards the end of the dosing interval.", "type": "CHEMICAL", "entities": [ "losartan", "ramipril", "perindopril", "atenolol", "telmisartan", "valsartan" ], "offsets": [ [ 125, 133 ], [ 135, 143 ], [ 145, 156 ], [ 162, 170 ], [ 48, 59 ], [ 114, 123 ] ] }, { "pmid": "20448797", "text": "There is also clinical evidence that telmisartan reduces left ventricular hypertrophy, reduces arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 37, 48 ] ] }, { "pmid": "20448797", "text": "The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study has demonstrated that telmisartan has similar cardiovascular protective effects to ramipril in a large, high-risk patient population but was better tolerated.", "type": "CHEMICAL", "entities": [ "Telmisartan", "Ramipril", "telmisartan", "ramipril" ], "offsets": [ [ 12, 23 ], [ 54, 62 ], [ 124, 135 ], [ 185, 193 ] ] }, { "pmid": "20448797", "text": "The powerful and sustained blood pressure control apparent in clinical trials, together with cardiovascular protection and tolerability demonstrated in ONTARGET means that telmisartan may be a preferred option for patients with hypertension.", "type": "CHEMICAL", "entities": [ "telmisartan" ], "offsets": [ [ 172, 183 ] ] }, { "pmid": "20512796", "text": "Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs.\n", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 67, 75 ] ] }, { "pmid": "20512796", "text": "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy.", "type": "CHEMICAL", "entities": [ "Estrogen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "20512796", "text": "Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth.", "type": "CHEMICAL", "entities": [ "tamoxifen" ], "offsets": [ [ 29, 38 ] ] }, { "pmid": "20512796", "text": "The ER-targeting PROTACs are composed of an estradiol on one end and a hypoxia-inducing factor 1alpha (HIF-1alpha)-derived synthetic pentapeptide on the other.", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 44, 53 ] ] }, { "pmid": "20512796", "text": "Specifically, the pentapeptide is attached at three different locations on estradiol to generate three different PROTAC types.", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 75, 84 ] ] }, { "pmid": "20512796", "text": "With the pentapeptide linked through the C7alpha position of estradiol, the resulting PROTAC shows the most effective ER degradation and highest affinity for the estrogen receptor.", "type": "CHEMICAL", "entities": [ "estradiol", "estrogen" ], "offsets": [ [ 61, 70 ], [ 162, 170 ] ] }, { "pmid": "20512796", "text": "This result provides an opportunity to develop a novel type of ER antagonist that may overcome the resistance of breast tumors to conventional drugs such as tamoxifen and fulvestrant (Faslodex).", "type": "CHEMICAL", "entities": [ "tamoxifen", "fulvestrant", "Faslodex" ], "offsets": [ [ 157, 166 ], [ 171, 182 ], [ 184, 192 ] ] }, { "pmid": "20589617", "text": "C677T polymorphism of the methylenetetrahydrofolate reductase gene does not affect folic acid, vitamin B12, and homocysteine serum levels in Turkish children with neural tube defects.\n", "type": "CHEMICAL", "entities": [ "homocysteine", "methylenetetrahydrofolate", "folic acid", "vitamin B12" ], "offsets": [ [ 112, 124 ], [ 26, 51 ], [ 83, 93 ], [ 95, 106 ] ] }, { "pmid": "20589617", "text": "Association between neural tube defects (NTDs) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was suspected, because the MTHFR gene codes for a key enzyme in folate metabolism.", "type": "CHEMICAL", "entities": [ "methylenetetrahydrofolate", "folate" ], "offsets": [ [ 77, 102 ], [ 190, 196 ] ] }, { "pmid": "20589617", "text": "Its deficiency usually leads to significant reductions in plasma concentrations of folate, vitamin B(12) and methionine, whereas homocysteine levels are increased.", "type": "CHEMICAL", "entities": [ "folate", "vitamin B(12)", "methionine", "homocysteine" ], "offsets": [ [ 83, 89 ], [ 91, 104 ], [ 109, 119 ], [ 129, 141 ] ] }, { "pmid": "20589617", "text": "We examined folate, vitamin B(12) and homocysteine serum concentrations and polymorphism of the C677T MTHFR gene in Turkish children with neural tube defects.", "type": "CHEMICAL", "entities": [ "folate", "vitamin B(12)", "homocysteine" ], "offsets": [ [ 12, 18 ], [ 20, 33 ], [ 38, 50 ] ] }, { "pmid": "20589617", "text": "The levels of folate, vitamin B(12) and homocysteine serum concentrations in NTDs were evaluated and compared, along with information concerning alleles of the MTHFR gene.", "type": "CHEMICAL", "entities": [ "folate", "vitamin B(12)", "homocysteine" ], "offsets": [ [ 14, 20 ], [ 22, 35 ], [ 40, 52 ] ] }, { "pmid": "20589617", "text": "Serum folate and vitamin B(12) concentrations were significantly higher in NTD children than that of controls.", "type": "CHEMICAL", "entities": [ "folate", "vitamin B(12)" ], "offsets": [ [ 6, 12 ], [ 17, 30 ] ] }, { "pmid": "20589617", "text": "Serum homocysteine concentrations were not significantly higher in NTD children and mothers.", "type": "CHEMICAL", "entities": [ "homocysteine" ], "offsets": [ [ 6, 18 ] ] }, { "pmid": "20589617", "text": "We concluded that C677T MTHFR gene polymorphism does not affect folic acid, vitamin B(12) and homocysteine metabolism in Turkish children with NTDs.", "type": "CHEMICAL", "entities": [ "folic acid", "vitamin B(12)", "homocysteine" ], "offsets": [ [ 64, 74 ], [ 76, 89 ], [ 94, 106 ] ] }, { "pmid": "20590599", "text": "Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured.", "type": "CHEMICAL", "entities": [ "[(3)H]-CGP 12177", "[(3)H]-cAMP" ], "offsets": [ [ 135, 151 ], [ 176, 187 ] ] }, { "pmid": "20590599", "text": "Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity.", "type": "CHEMICAL", "entities": [ "salmeterol", "formoterol", "isoprenaline" ], "offsets": [ [ 95, 105 ], [ 110, 120 ], [ 200, 212 ] ] }, { "pmid": "20590599", "text": "However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes.", "type": "CHEMICAL", "entities": [ "salmeterol", "formoterol", "isoprenaline" ], "offsets": [ [ 35, 45 ], [ 47, 57 ], [ 62, 74 ] ] }, { "pmid": "20590599", "text": "Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy.", "type": "CHEMICAL", "entities": [ "salbutamol", "denopamine", "clenbuterol", "AZ 40140d" ], "offsets": [ [ 68, 78 ], [ 20, 30 ], [ 44, 55 ], [ 57, 66 ] ] }, { "pmid": "20600573", "text": "Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity.\n", "type": "CHEMICAL", "entities": [ "Rasagiline", "monoamine" ], "offsets": [ [ 0, 10 ], [ 38, 47 ] ] }, { "pmid": "20600573", "text": "Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug.", "type": "CHEMICAL", "entities": [ "monoamine", "Rasagiline", "N-propargyl-1-(R)-aminoindan" ], "offsets": [ [ 81, 90 ], [ 0, 10 ], [ 12, 40 ] ] }, { "pmid": "20600573", "text": "Rasagiline is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD).", "type": "CHEMICAL", "entities": [ "Rasagiline", "L-Dopa" ], "offsets": [ [ 0, 10 ], [ 53, 59 ] ] }, { "pmid": "20600573", "text": "Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor.", "type": "CHEMICAL", "entities": [ "TVP1022" ], "offsets": [ [ 14, 21 ] ] }, { "pmid": "20600573", "text": "However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins.", "type": "CHEMICAL", "entities": [ "rasagiline", "N-propargyl" ], "offsets": [ [ 186, 196 ], [ 271, 282 ] ] }, { "pmid": "20600573", "text": "Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline.", "type": "CHEMICAL", "entities": [ "1-(R)-aminoindan", "rasagiline", "rasagiline" ], "offsets": [ [ 69, 85 ], [ 206, 216 ], [ 57, 67 ] ] }, { "pmid": "20600573", "text": "This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action.", "type": "CHEMICAL", "entities": [ "rasagiline" ], "offsets": [ [ 77, 87 ] ] }, { "pmid": "20615127", "text": "As the RTH mutant, R316C, was new, the optimum dose of levothyroxine was unclear.", "type": "CHEMICAL", "entities": [ "levothyroxine" ], "offsets": [ [ 55, 68 ] ] }, { "pmid": "20615127", "text": "The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum TSH level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland.", "type": "CHEMICAL", "entities": [ "thyroxine" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "20615127", "text": "Supplementation with levothyroxine at a dose of >350 microg/day did not normalize the serum TSH level; however, the patient showed normal growth and intelligence at 14 years of age.", "type": "CHEMICAL", "entities": [ "levothyroxine" ], "offsets": [ [ 21, 34 ] ] }, { "pmid": "20615127", "text": "Consistent with the results of a computer analysis, the binding of R316C to triiodothyronine (T3) was significantly decreased to 38% that of the wild type.", "type": "CHEMICAL", "entities": [ "T3", "triiodothyronine" ], "offsets": [ [ 94, 96 ], [ 76, 92 ] ] }, { "pmid": "20615127", "text": "However, a glutathione-S-transferase pull-down assay showed reduced binding of R316C with NCoR in the absence of T3 and impaired release in the presence of T3.", "type": "CHEMICAL", "entities": [ "glutathione", "S", "T3", "T3" ], "offsets": [ [ 11, 22 ], [ 23, 24 ], [ 113, 115 ], [ 156, 158 ] ] }, { "pmid": "20615127", "text": "Our findings suggest that R316C causes reduced association with and impaired release of NCoR, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum TSH level with high dose of levothyroxine might be optimum for normal growth.", "type": "CHEMICAL", "entities": [ "levothyroxine" ], "offsets": [ [ 210, 223 ] ] }, { "pmid": "20624420", "text": "In some recent studies, it was shown that lesion of the area tempestas (AT), medial septum (MS), perirhinal cortex (PRC), or posterior piriform cortex (PPC) produces anticonvulsant effects (prevention of convulsions or delayed onset of convulsions) in rats exposed to soman, whereas damage to nucleus accumbens, nucleus basalis magnocellularis, amygdala, hippocampus, or entorhinal cortex does not cause anticonvulsant impact.", "type": "CHEMICAL", "entities": [ "soman" ], "offsets": [ [ 268, 273 ] ] }, { "pmid": "20624420", "text": "Results from microinfusion studies show that anticonvulsant efficacy is obtained by GABA(A) modulators or cholinergic antagonists (M1-M5) in AT, cholinergic antagonists (M1-M5) in MS, combined glutamatergic (NMDA) and cholinergic antagonist (M1-M4), AMPA antagonist, or modulators of metabotropic glutamate receptors (mGluR5, mGluR2/3) in PRC, and cholinergic antagonist (M1-M5) or GABA(A) agonist in PPC.", "type": "CHEMICAL", "entities": [ "GABA", "NMDA", "AMPA", "glutamate" ], "offsets": [ [ 84, 88 ], [ 208, 212 ], [ 250, 254 ], [ 297, 306 ] ] }, { "pmid": "20624420", "text": "Calculation of impact factors for the most potent drugs (percentage of positive effects in the seizure controlling sites) showed that scopolamine and procyclidine were ranking highest (75) followed by muscimol (50), NBQX (33), and caramiphen (33).", "type": "CHEMICAL", "entities": [ "scopolamine", "procyclidine", "muscimol", "NBQX", "caramiphen" ], "offsets": [ [ 134, 145 ], [ 150, 162 ], [ 201, 209 ], [ 216, 220 ], [ 231, 241 ] ] }, { "pmid": "20724158", "text": "Recent epidemiologic and laboratory studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (COX-2).", "type": "CHEMICAL", "entities": [ "steroidal" ], "offsets": [ [ 68, 77 ] ] }, { "pmid": "20724158", "text": "We conducted a case-control study to measure the association between selective cox-2 inhibitors, particularly celecoxib, rofecoxib, valdecoxib and non-specific NSAID subgroups, and breast cancer risk.", "type": "CHEMICAL", "entities": [ "celecoxib", "rofecoxib", "valdecoxib" ], "offsets": [ [ 110, 119 ], [ 121, 130 ], [ 132, 142 ] ] }, { "pmid": "20724158", "text": "Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97).", "type": "CHEMICAL", "entities": [ "Celecoxib" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "20724158", "text": "We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80).", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "20724158", "text": "Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer.", "type": "CHEMICAL", "entities": [ "Acetaminophen" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "20724158", "text": "With exposure to rofecoxib, a selective COX-2 inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective COX-2 inhibitors in breast cancer prophylaxis.", "type": "CHEMICAL", "entities": [ "rofecoxib" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "2087492", "text": "Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide.\n", "type": "CHEMICAL", "entities": [ "SMS 201-995", "ceruletide" ], "offsets": [ [ 35, 46 ], [ 63, 73 ] ] }, { "pmid": "2087492", "text": "Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats.", "type": "CHEMICAL", "entities": [ "somatostatin", "SMS 201-995" ], "offsets": [ [ 76, 88 ], [ 42, 53 ] ] }, { "pmid": "2087492", "text": "Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV).", "type": "CHEMICAL", "entities": [ "ceruletide", "SMS 201-995", "SMS 201-995", "arginine-vasopressin" ], "offsets": [ [ 18, 28 ], [ 105, 116 ], [ 189, 200 ], [ 226, 246 ] ] }, { "pmid": "2087492", "text": "The suppressive effect of ceruletide on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist.", "type": "CHEMICAL", "entities": [ "ceruletide", "MK-329" ], "offsets": [ [ 26, 36 ], [ 88, 94 ] ] }, { "pmid": "2087492", "text": "Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995.", "type": "CHEMICAL", "entities": [ "SMS 201-995" ], "offsets": [ [ 66, 77 ] ] }, { "pmid": "2087492", "text": "These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor.", "type": "CHEMICAL", "entities": [ "SMS 201-995", "ceruletide" ], "offsets": [ [ 93, 104 ], [ 28, 38 ] ] }, { "pmid": "21058326", "text": "Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development.\n", "type": "CHEMICAL", "entities": [ "histamine", "chlorcyclizine" ], "offsets": [ [ 15, 24 ], [ 39, 53 ] ] }, { "pmid": "21058326", "text": "The effects of histamine H1 antagonist chlorcyclizine on rat palate development were characterized following in utero exposure.", "type": "CHEMICAL", "entities": [ "histamine", "chlorcyclizine" ], "offsets": [ [ 15, 24 ], [ 39, 53 ] ] }, { "pmid": "21058326", "text": "METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg chlorcyclizine on Gestation Days 11 to 14.", "type": "CHEMICAL", "entities": [ "chlorcyclizine" ], "offsets": [ [ 117, 131 ] ] }, { "pmid": "21058326", "text": "Fetal palate gene expression was also assessed after 90 mg/kg chlorcyclizine at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR.", "type": "CHEMICAL", "entities": [ "chlorcyclizine" ], "offsets": [ [ 62, 76 ] ] }, { "pmid": "21058326", "text": "The altered genes associated with chlorcyclizine-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold).", "type": "CHEMICAL", "entities": [ "chlorcyclizine" ], "offsets": [ [ 34, 48 ] ] }, { "pmid": "21058326", "text": "CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to chlorcyclizine.", "type": "CHEMICAL", "entities": [ "chlorcyclizine" ], "offsets": [ [ 151, 165 ] ] }, { "pmid": "21194017", "text": "The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of gamma-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia.", "type": "CHEMICAL", "entities": [ "gamma-aminobutyric acid" ], "offsets": [ [ 110, 133 ] ] }, { "pmid": "21194017", "text": "With the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 228, 238 ] ] }, { "pmid": "21194017", "text": "Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane amino acids that were affinity labelled in purified bovine brain GABA(A)-R. Homology protein structural modelling positions these two residues, alphaM1-11' and betaM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the beta/alpha interface.", "type": "CHEMICAL", "entities": [ "amino acids", "etomidate", "R(+)etomidate" ], "offsets": [ [ 110, 121 ], [ 334, 343 ], [ 63, 76 ] ] }, { "pmid": "21194017", "text": "Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols.", "type": "CHEMICAL", "entities": [ "etomidate", "steroids", "barbiturates", "propofol", "alcohols" ], "offsets": [ [ 55, 64 ], [ 131, 139 ], [ 141, 153 ], [ 176, 184 ], [ 194, 202 ] ] }, { "pmid": "21194017", "text": "Residue alpha/betaM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and alpha/betaM1-(-2') is coupled to action of intravenous agents.", "type": "CHEMICAL", "entities": [ "alcohols" ], "offsets": [ [ 113, 121 ] ] }, { "pmid": "2120879", "text": "Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells.\n", "type": "CHEMICAL", "entities": [ "K+", "calcium" ], "offsets": [ [ 134, 136 ], [ 22, 29 ] ] }, { "pmid": "2120879", "text": "The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 147, 149 ] ] }, { "pmid": "2120879", "text": "Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting calmodulin activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion.", "type": "CHEMICAL", "entities": [ "Ca2+", "Ca2+", "verapamil", "trifluoperazine", "chlorpromazine", "pimozide" ], "offsets": [ [ 16, 20 ], [ 31, 35 ], [ 61, 70 ], [ 124, 139 ], [ 152, 166 ], [ 181, 189 ] ] }, { "pmid": "2120879", "text": "The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01).", "type": "CHEMICAL", "entities": [ "Ca2(+)", "W-7" ], "offsets": [ [ 89, 95 ], [ 28, 31 ] ] }, { "pmid": "2120879", "text": "The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion.", "type": "CHEMICAL", "entities": [ "K(+)" ], "offsets": [ [ 47, 51 ] ] }, { "pmid": "2120879", "text": "Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 49, 51 ] ] }, { "pmid": "2120879", "text": "The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH.", "type": "CHEMICAL", "entities": [ "K+" ], "offsets": [ [ 40, 42 ] ] }, { "pmid": "21318872", "text": "Use of (Gyro) Gy and spermine synthase transgenic mice to study functions of spermine.\n", "type": "CHEMICAL", "entities": [ "spermine", "spermine" ], "offsets": [ [ 21, 29 ], [ 77, 85 ] ] }, { "pmid": "21318872", "text": "The polyamines putrescine, spermidine, and spermine are essential for mammalian cell growth, -differentiation, and cell death and have important physiological roles in all tissues.", "type": "CHEMICAL", "entities": [ "putrescine", "spermidine", "polyamines", "spermine" ], "offsets": [ [ 15, 25 ], [ 27, 37 ], [ 4, 14 ], [ 43, 51 ] ] }, { "pmid": "21318872", "text": "Many of the properties of polyamines that can be demonstrated in vitro are common to all three molecules with differences only in potency.", "type": "CHEMICAL", "entities": [ "polyamines" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "21318872", "text": "Loss of any of the enzymes needed to make either putrescine or spermidine (which also -prevent the production of spermine) is lethal, but male mice lacking spermine synthase (SpmS) due to a deletion of part of the X chromosome are viable on the B6C3H background.", "type": "CHEMICAL", "entities": [ "spermine", "putrescine", "spermidine", "spermine" ], "offsets": [ [ 156, 164 ], [ 49, 59 ], [ 63, 73 ], [ 113, 121 ] ] }, { "pmid": "21318872", "text": "They can therefore be used to evaluate the physiological function(s) uniquely provided by spermine.", "type": "CHEMICAL", "entities": [ "spermine" ], "offsets": [ [ 90, 98 ] ] }, { "pmid": "21318872", "text": "An essential control in experiments using Gy mice is to demonstrate that the abnormal phenotypes exhibited by these mice are abolished by providing replacement spermine and this can be accomplished by breeding with CAG-SMS mice that express SpmS from a ubiquitous promoter.", "type": "CHEMICAL", "entities": [ "spermine" ], "offsets": [ [ 160, 168 ] ] }, { "pmid": "21926191", "text": "Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.\n", "type": "CHEMICAL", "entities": [ "Cabozantinib", "XL184" ], "offsets": [ [ 0, 12 ], [ 14, 19 ] ] }, { "pmid": "21926191", "text": "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3.", "type": "CHEMICAL", "entities": [ "Cabozantinib", "XL184", "tyrosine" ], "offsets": [ [ 0, 12 ], [ 14, 19 ], [ 158, 166 ] ] }, { "pmid": "21926191", "text": "Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro.", "type": "CHEMICAL", "entities": [ "cabozantinib" ], "offsets": [ [ 15, 27 ] ] }, { "pmid": "21926191", "text": "In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models.", "type": "CHEMICAL", "entities": [ "cabozantinib" ], "offsets": [ [ 17, 29 ] ] }, { "pmid": "21926191", "text": "Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET.", "type": "CHEMICAL", "entities": [ "cabozantinib" ], "offsets": [ [ 28, 40 ] ] }, { "pmid": "21926191", "text": "Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.", "type": "CHEMICAL", "entities": [ "cabozantinib" ], "offsets": [ [ 38, 50 ] ] }, { "pmid": "21955206", "text": "Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug.\n", "type": "CHEMICAL", "entities": [ "Thiocolchicoside" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "21955206", "text": "To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells.", "type": "CHEMICAL", "entities": [ "thiocolchicoside", "colchicoside" ], "offsets": [ [ 86, 102 ], [ 121, 133 ] ] }, { "pmid": "21955206", "text": "We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells.", "type": "CHEMICAL", "entities": [ "thiocolchicoside" ], "offsets": [ [ 123, 139 ] ] }, { "pmid": "21955206", "text": "Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells.", "type": "CHEMICAL", "entities": [ "Thiocolchicoside" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "21955206", "text": "Inhibition of the NF-kappaB pathway was responsible for this effect since the colchicoside inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by RANKL.", "type": "CHEMICAL", "entities": [ "colchicoside" ], "offsets": [ [ 78, 90 ] ] }, { "pmid": "21955206", "text": "CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-kappaB signalling pathway.", "type": "CHEMICAL", "entities": [ "thiocolchicoside" ], "offsets": [ [ 64, 80 ] ] }, { "pmid": "21955206", "text": "Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss.", "type": "CHEMICAL", "entities": [ "thiocolchicoside" ], "offsets": [ [ 6, 22 ] ] }, { "pmid": "22064666", "text": "Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction.\n", "type": "CHEMICAL", "entities": [ "nitric oxide", "sildenafil" ], "offsets": [ [ 12, 24 ], [ 83, 93 ] ] }, { "pmid": "22064666", "text": "Erectile dysfunction (ED) is usually treated with sildenafil.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "22064666", "text": "Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 50, 62 ] ] }, { "pmid": "22064666", "text": "NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil.", "type": "CHEMICAL", "entities": [ "NO", "sildenafil" ], "offsets": [ [ 0, 2 ], [ 110, 120 ] ] }, { "pmid": "22064666", "text": "The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "22064666", "text": "Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil.", "type": "CHEMICAL", "entities": [ "sildenafil" ], "offsets": [ [ 107, 117 ] ] }, { "pmid": "22080037", "text": "Mercury induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase.\n", "type": "CHEMICAL", "entities": [ "Mercury", "nitric oxide" ], "offsets": [ [ 0, 7 ], [ 65, 77 ] ] }, { "pmid": "22080037", "text": "NF-κB activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS).", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 123, 135 ] ] }, { "pmid": "22080037", "text": "The divalent heavy metal mercury has been used for thousands of years.", "type": "CHEMICAL", "entities": [ "mercury" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "22080037", "text": "Although mercury is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world.", "type": "CHEMICAL", "entities": [ "mercury" ], "offsets": [ [ 6, 13 ] ] }, { "pmid": "22080037", "text": "Here, we report biochemical evidence that mercury alone induces NF-κB activation, resulting in the induced expression of COX-2 and iNOS.", "type": "CHEMICAL", "entities": [ "mercury" ], "offsets": [ [ 39, 46 ] ] }, { "pmid": "22080037", "text": "The results suggest that mercury can induce inflammatory diseases by lowering host defense.", "type": "CHEMICAL", "entities": [ "mercury" ], "offsets": [ [ 21, 28 ] ] }, { "pmid": "22381584", "text": "Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons.\n", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "22381584", "text": "Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking.", "type": "CHEMICAL", "entities": [ "Glutamate", "glutamate", "glutamate" ], "offsets": [ [ 0, 9 ], [ 117, 126 ], [ 187, 196 ] ] }, { "pmid": "22381584", "text": "Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific mGluR agonists and antagonists were examined.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 81, 87 ] ] }, { "pmid": "22381584", "text": "Unexpectedly, both the mGluR(5)specific agonist, CHPG, and the group II mGluR (mGlu(2/3)) agonist, LY379268 (LY), induced a TTX-insensitive outward current/hyperpolarization.", "type": "CHEMICAL", "entities": [ "CHPG", "LY379268", "TTX" ], "offsets": [ [ 49, 53 ], [ 99, 107 ], [ 124, 127 ] ] }, { "pmid": "22381584", "text": "Both outward currents were significantly reduced by the mGluR antagonist MCPG and the CHPG-induced current was blocked by the specific mGluR(5) antagonist MTEP.", "type": "CHEMICAL", "entities": [ "MCPG", "CHPG", "MTEP" ], "offsets": [ [ 73, 77 ], [ 86, 90 ], [ 155, 159 ] ] }, { "pmid": "22381584", "text": "Concurrent Ca(2+)imaging revealed that while CHPG actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "CHPG", "Ca(2+)", "CPA", "thapsigargin" ], "offsets": [ [ 11, 17 ], [ 45, 49 ], [ 81, 87 ], [ 93, 96 ], [ 97, 109 ] ] }, { "pmid": "22381584", "text": "Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance.", "type": "CHEMICAL", "entities": [ "TEA", "potassium", "CHPG" ], "offsets": [ [ 62, 65 ], [ 76, 85 ], [ 5, 9 ] ] }, { "pmid": "22381584", "text": "The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHPG actions.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "potassium", "CHPG" ], "offsets": [ [ 23, 29 ], [ 40, 49 ], [ 96, 100 ] ] }, { "pmid": "22381584", "text": "Consistent with actions on the BK conductance, CHPG enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate.", "type": "CHEMICAL", "entities": [ "CHPG" ], "offsets": [ [ 47, 51 ] ] }, { "pmid": "22381584", "text": "Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at mGluR(5) and mGluR(2/3) on these neurons.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 112, 121 ] ] }, { "pmid": "22381584", "text": "As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate.", "type": "CHEMICAL", "entities": [ "glutamate", "glutamate" ], "offsets": [ [ 159, 168 ], [ 245, 254 ] ] }, { "pmid": "22381584", "text": "This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.", "type": "CHEMICAL", "entities": [ "Glutamate" ], "offsets": [ [ 63, 72 ] ] }, { "pmid": "22391562", "text": "We have examined the effectiveness of two novel Chk1 selective inhibitors, AR323 and AR678, in a panel of melanoma cell lines and normal cell types.", "type": "CHEMICAL", "entities": [ "AR323", "AR678" ], "offsets": [ [ 75, 80 ], [ 85, 90 ] ] }, { "pmid": "22406476", "text": "Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells.\n", "type": "CHEMICAL", "entities": [ "Aspirin", "mTOR", "AMP" ], "offsets": [ [ 0, 7 ], [ 17, 21 ], [ 43, 46 ] ] }, { "pmid": "22406476", "text": "Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms.", "type": "CHEMICAL", "entities": [ "Aspirin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "22406476", "text": "Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation.", "type": "CHEMICAL", "entities": [ "rapamycin", "mTOR" ], "offsets": [ [ 69, 78 ], [ 80, 84 ] ] }, { "pmid": "22406476", "text": "We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells.", "type": "CHEMICAL", "entities": [ "aspirin", "adenosine monophosphate", "mTOR" ], "offsets": [ [ 24, 31 ], [ 40, 63 ], [ 100, 104 ] ] }, { "pmid": "22406476", "text": "The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting.", "type": "CHEMICAL", "entities": [ "aspirin", "mTOR" ], "offsets": [ [ 15, 22 ], [ 26, 30 ] ] }, { "pmid": "22406476", "text": "Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts.", "type": "CHEMICAL", "entities": [ "aspirin", "mTOR" ], "offsets": [ [ 78, 85 ], [ 105, 109 ] ] }, { "pmid": "22406476", "text": "We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 61, 68 ] ] }, { "pmid": "22406476", "text": "Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1.", "type": "CHEMICAL", "entities": [ "mTOR", "Aspirin", "mTOR" ], "offsets": [ [ 62, 66 ], [ 0, 7 ], [ 16, 20 ] ] }, { "pmid": "22406476", "text": "Aspirin changed nucleotide ratios and activated AMPK in CRC cells.", "type": "CHEMICAL", "entities": [ "Aspirin" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "22406476", "text": "mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR.", "type": "CHEMICAL", "entities": [ "mTOR", "aspirin", "aspirin", "mTOR" ], "offsets": [ [ 0, 4 ], [ 28, 35 ], [ 146, 153 ], [ 176, 180 ] ] }, { "pmid": "22406476", "text": "Aspirin induced autophagy, a feature of mTOR inhibition.", "type": "CHEMICAL", "entities": [ "Aspirin", "mTOR" ], "offsets": [ [ 0, 7 ], [ 40, 44 ] ] }, { "pmid": "22406476", "text": "Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells.", "type": "CHEMICAL", "entities": [ "metformin", "mTOR", "Aspirin" ], "offsets": [ [ 12, 21 ], [ 69, 73 ], [ 0, 7 ] ] }, { "pmid": "22406476", "text": "Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6.", "type": "CHEMICAL", "entities": [ "aspirin" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "22406476", "text": "Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism.", "type": "CHEMICAL", "entities": [ "Aspirin", "mTOR" ], "offsets": [ [ 0, 7 ], [ 27, 31 ] ] }, { "pmid": "22410778", "text": "Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration.\n", "type": "CHEMICAL", "entities": [ "cAMP", "forskolin" ], "offsets": [ [ 65, 69 ], [ 86, 95 ] ] }, { "pmid": "22410778", "text": "In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions.", "type": "CHEMICAL", "entities": [ "glucose", "cyclic adenosine monophosphate", "cAMP", "cAMP" ], "offsets": [ [ 130, 137 ], [ 335, 365 ], [ 366, 370 ], [ 397, 401 ] ] }, { "pmid": "22410778", "text": "Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 31, 35 ] ] }, { "pmid": "22410778", "text": "Exogenous stimulation of PKA activity, achieved by forskolin treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels.", "type": "CHEMICAL", "entities": [ "forskolin", "glucose", "adenosine triphosphate", "ATP", "oxygen" ], "offsets": [ [ 51, 60 ], [ 132, 139 ], [ 196, 218 ], [ 220, 223 ], [ 291, 297 ] ] }, { "pmid": "22410778", "text": "These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs.", "type": "CHEMICAL", "entities": [ "glucose", "ATP" ], "offsets": [ [ 39, 46 ], [ 221, 224 ] ] }, { "pmid": "22422627", "text": "Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway.\n", "type": "CHEMICAL", "entities": [ "Berberine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22422627", "text": "The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism.", "type": "CHEMICAL", "entities": [ "berberine" ], "offsets": [ [ 53, 62 ] ] }, { "pmid": "22422627", "text": "NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1.", "type": "CHEMICAL", "entities": [ "berberine" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "22422627", "text": "In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels.", "type": "CHEMICAL", "entities": [ "berberine" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "22475014", "text": "Glaucogenin E, a new C21 steroid from Cynanchum stauntonii.\n", "type": "CHEMICAL", "entities": [ "Glaucogenin E", "C21", "steroid" ], "offsets": [ [ 0, 13 ], [ 21, 24 ], [ 25, 32 ] ] }, { "pmid": "22475014", "text": "Glaucogenin E (1), a new C(21) steroid sapogenin, along with three known ones (2-4) were isolated from the rhizomes of Cynanchum stauntonii (Decne.)", "type": "CHEMICAL", "entities": [ "Glaucogenin E", "C(21)", "steroid" ], "offsets": [ [ 0, 13 ], [ 25, 30 ], [ 31, 38 ] ] }, { "pmid": "22493952", "text": "New triterpenoids from the stem bark of Hypodaphnis zenkeri.\n", "type": "CHEMICAL", "entities": [ "triterpenoids" ], "offsets": [ [ 4, 17 ] ] }, { "pmid": "22493952", "text": "A new pentacyclic triterpenoid and three new derivatives based on the taraxer-14-ene skeleton with a C-28 attached a carboxylic acid group have been isolated from the stem bark of Hypodaphnis zenkeri, together with six known compounds.", "type": "CHEMICAL", "entities": [ "pentacyclic triterpenoid", "taraxer-14-ene", "carboxylic acid" ], "offsets": [ [ 6, 30 ], [ 70, 84 ], [ 117, 132 ] ] }, { "pmid": "22493952", "text": "The new product was identified as 2α,3α-dihydroxytaraxer-14-en-28-oic acid (1).", "type": "CHEMICAL", "entities": [ "2α,3α-dihydroxytaraxer-14-en-28-oic acid" ], "offsets": [ [ 34, 74 ] ] }, { "pmid": "22493952", "text": "Its derivatives, 2α,3α-diacetyltaraxer-14-en-28-oic acid (2), 2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid (3) and 2α,3α-dipropionyltaraxer-14-en-28-oic acid (4) were obtained by semisynthesis.", "type": "CHEMICAL", "entities": [ "2α,3α-dipropionyltaraxer-14-en-28-oic acid", "2α,3α-diacetyltaraxer-14-en-28-oic acid", "2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid" ], "offsets": [ [ 129, 171 ], [ 15, 54 ], [ 60, 120 ] ] }, { "pmid": "22493952", "text": "The known compounds were identified as 3β-hydroxytaraxer-14-en-28-oic acid or aleuritolic acid (5) (McPhail, A.T., McPhail, D.R., Wani, M.C., Wall, M.E. & A.W., Nicholas, A.W. (1989).", "type": "CHEMICAL", "entities": [ "3β-hydroxytaraxer-14-en-28-oic acid", "aleuritolic acid" ], "offsets": [ [ 29, 64 ], [ 68, 84 ] ] }, { "pmid": "22493952", "text": "Identity of maprounic acid with aleuritolic acid.", "type": "CHEMICAL", "entities": [ "maprounic acid", "aleuritolic acid" ], "offsets": [ [ 1, 15 ], [ 21, 37 ] ] }, { "pmid": "22493952", "text": "Revision of the structure of maprounic acid: X-ray crystal structure of p-bromobenzyl acetylmaprounate.", "type": "CHEMICAL", "entities": [ "maprounic acid", "p-bromobenzyl acetylmaprounate" ], "offsets": [ [ 18, 32 ], [ 61, 91 ] ] }, { "pmid": "22493952", "text": "Journal Natural Products, 52, 212), 3α-hydroxytaraxer-14-en-28-oic acid or isoaleuritolic acid (6), 3α-acetyltaraxer-14-en-28-oic acid acetate or aleuritolic acid acetate (7) (Chaudhuri, S.K., Fullas, F., Brown, D.M., Wani, M.C., Wall, M.E., Cai, L., … Kinghorn, A.D. (1995).", "type": "CHEMICAL", "entities": [ "3α-hydroxytaraxer-14-en-28-oic acid", "aleuritolic acid acetate", "isoaleuritolic acid", "3α-acetyltaraxer-14-en-28-oic acid acetate" ], "offsets": [ [ 25, 60 ], [ 135, 159 ], [ 64, 83 ], [ 89, 131 ] ] }, { "pmid": "22493952", "text": "Journal of Natural Products, 58, 1-9), 3-oxo-taraxer-14-ene or taraxerone (8) β-sitosterol (9) and stigmasterol (10) (Kamboj & Saluja, 2011), together with fatty acids.", "type": "CHEMICAL", "entities": [ "3-oxo-taraxer-14-ene", "taraxerone", "β-sitosterol", "stigmasterol" ], "offsets": [ [ 24, 44 ], [ 48, 58 ], [ 63, 75 ], [ 84, 96 ] ] }, { "pmid": "22537580", "text": "Two new C-15 enolic acyl phragmalin-type limonoids from Chukrasia tabularis var. velutina.\n", "type": "CHEMICAL", "entities": [ "enolic acyl phragmalin", "limonoids" ], "offsets": [ [ 13, 35 ], [ 41, 50 ] ] }, { "pmid": "22537580", "text": "Two new C-15 enolic acyl phragmalin-type limonoid orthoesters, chukvelutilide G (1) and chukrasine F (2), were isolated from the stem barks of Chukrasia tabularis var. velutina.", "type": "CHEMICAL", "entities": [ "enolic acyl phragmalin", "limonoid orthoesters", "chukvelutilide G", "chukrasine F" ], "offsets": [ [ 13, 35 ], [ 41, 61 ], [ 63, 79 ], [ 88, 100 ] ] }, { "pmid": "22552008", "text": "Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.\n", "type": "CHEMICAL", "entities": [ "pomalidomide", "lenalidomide" ], "offsets": [ [ 110, 122 ], [ 93, 105 ] ] }, { "pmid": "22552008", "text": "Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies.", "type": "CHEMICAL", "entities": [ "lenalidomide", "Thalidomide" ], "offsets": [ [ 43, 55 ], [ 0, 11 ] ] }, { "pmid": "22552008", "text": "The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 118, 129 ] ] }, { "pmid": "22552008", "text": "Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1", "type": "CHEMICAL", "entities": [ "pomalidomide", "thalidomide", "lenalidomide" ], "offsets": [ [ 90, 102 ], [ 29, 40 ], [ 42, 54 ] ] }, { "pmid": "22552008", "text": "CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells.", "type": "CHEMICAL", "entities": [ "lenalidomide", "pomalidomide", "lenalidomide", "pomalidomide" ], "offsets": [ [ 46, 58 ], [ 63, 75 ], [ 105, 117 ], [ 123, 135 ] ] }, { "pmid": "22552008", "text": "Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA).", "type": "CHEMICAL", "entities": [ "Lenalidomide", "pomalidomide", "thalidomide", "thalidomide" ], "offsets": [ [ 0, 12 ], [ 17, 29 ], [ 95, 106 ], [ 149, 160 ] ] }, { "pmid": "22552008", "text": "Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression.", "type": "CHEMICAL", "entities": [ "pomalidomide" ], "offsets": [ [ 112, 124 ] ] }, { "pmid": "22552008", "text": "Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable.", "type": "CHEMICAL", "entities": [ "lenalidomide", "pomalidomide", "lenalidomide" ], "offsets": [ [ 24, 36 ], [ 162, 174 ], [ 179, 191 ] ] }, { "pmid": "22552008", "text": "Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.", "type": "CHEMICAL", "entities": [ "lenalidomide", "pomalidomide" ], "offsets": [ [ 133, 145 ], [ 150, 162 ] ] }, { "pmid": "22566187", "text": "Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines.", "type": "CHEMICAL", "entities": [ "carbohydrate", "polyphenol" ], "offsets": [ [ 102, 114 ], [ 41, 51 ] ] }, { "pmid": "22566187", "text": "Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals.", "type": "CHEMICAL", "entities": [ "sugar" ], "offsets": [ [ 118, 123 ] ] }, { "pmid": "22566187", "text": "However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 58, 66 ] ] }, { "pmid": "22566187", "text": "Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin.", "type": "CHEMICAL", "entities": [ "warfarin" ], "offsets": [ [ 135, 143 ] ] }, { "pmid": "22566187", "text": "Extract of guava leaf (GvEx) consists of carbohydrate and polyphenols, which are Gvpp, quercetin, and ellagic acid.", "type": "CHEMICAL", "entities": [ "quercetin", "ellagic acid", "carbohydrate", "polyphenols" ], "offsets": [ [ 87, 96 ], [ 102, 114 ], [ 41, 53 ], [ 58, 69 ] ] }, { "pmid": "22566187", "text": "These polyphenols, but not GvEx, showed a certain level of inhibition of human-cDNA-expressed CYPs.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 6, 17 ] ] }, { "pmid": "22566187", "text": "In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1'-hydroxylation than grapefruit juice.", "type": "CHEMICAL", "entities": [ "midazolam" ], "offsets": [ [ 99, 108 ] ] }, { "pmid": "22566187", "text": "When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced.", "type": "CHEMICAL", "entities": [ "warfarin", "warfarin" ], "offsets": [ [ 48, 56 ], [ 104, 112 ] ] }, { "pmid": "22594847", "text": "Crizotinib in the treatment of non-small-cell lung cancer.\n", "type": "CHEMICAL", "entities": [ "Crizotinib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "22594847", "text": "Crizotinib is an oral tyrosine kinase inhibitor (TKI), which silences the protein product of the ALK fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing ALK.", "type": "CHEMICAL", "entities": [ "Crizotinib", "tyrosine" ], "offsets": [ [ 0, 10 ], [ 22, 30 ] ] }, { "pmid": "22594847", "text": "Emerging data suggest that crizotinib may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the MET oncogene, or translocation of the ROS1 oncogene.", "type": "CHEMICAL", "entities": [ "crizotinib" ], "offsets": [ [ 27, 37 ] ] }, { "pmid": "22594847", "text": "It also reviews the pharmacokinetic and pharmacodynamic data on crizotinib and outlines the preclinical and clinical studies leading to the approval of crizotinib.", "type": "CHEMICAL", "entities": [ "crizotinib", "crizotinib" ], "offsets": [ [ 152, 162 ], [ 64, 74 ] ] }, { "pmid": "22594847", "text": "Crizotinib represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations.", "type": "CHEMICAL", "entities": [ "Crizotinib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "22594847", "text": "Crizotinib has demonstrated efficacy against ALK-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer.", "type": "CHEMICAL", "entities": [ "Crizotinib" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "2262902", "text": "Central adenosinergic system involvement in ethanol-induced motor incoordination in mice.\n", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "2262902", "text": "To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod.", "type": "CHEMICAL", "entities": [ "adenosine", "N6-(R-phenylisopropyl)adenosine", "R-PIA", "N6-(S-phenylisopropyl)adenosine", "5'-(N-cyclopropyl)-carboxamidoadenosine", "theophylline", "8-p-(sulfophenyl)theophylline", "enprofylline", "ethanol", "ethanol", "adenosine" ], "offsets": [ [ 171, 180 ], [ 191, 222 ], [ 224, 229 ], [ 232, 263 ], [ 265, 304 ], [ 319, 331 ], [ 336, 365 ], [ 377, 389 ], [ 393, 400 ], [ 49, 56 ], [ 61, 70 ] ] }, { "pmid": "2262902", "text": "Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p.", "type": "CHEMICAL", "entities": [ "Adenosine", "ethanol", "adenosine", "ethanol", "adenosine" ], "offsets": [ [ 0, 9 ], [ 94, 101 ], [ 174, 183 ], [ 213, 220 ], [ 265, 274 ] ] }, { "pmid": "2262902", "text": "Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions.", "type": "CHEMICAL", "entities": [ "adenosine", "Enprofylline", "adenosine", "cyclic AMP", "ethanol" ], "offsets": [ [ 225, 234 ], [ 0, 12 ], [ 21, 30 ], [ 66, 76 ], [ 217, 224 ] ] }, { "pmid": "2262902", "text": "Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype.", "type": "CHEMICAL", "entities": [ "N6-(S-phenylisopropyl)adenosine", "adenosine" ], "offsets": [ [ 23, 54 ], [ 162, 171 ] ] }, { "pmid": "2262902", "text": "However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2.", "type": "CHEMICAL", "entities": [ "5'-(N-cyclopropyl)-carboxamidoadenosine", "adenosine" ], "offsets": [ [ 9, 48 ], [ 165, 174 ] ] }, { "pmid": "2262902", "text": "No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol.", "type": "CHEMICAL", "entities": [ "[3H]R-PIA", "adenosine", "ethanol" ], "offsets": [ [ 49, 58 ], [ 134, 143 ], [ 212, 219 ] ] }, { "pmid": "2262902", "text": "There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS)", "type": "CHEMICAL", "entities": [ "ethanol", "adenosine", "[3H]R-PIA" ], "offsets": [ [ 156, 163 ], [ 164, 173 ], [ 43, 52 ] ] }, { "pmid": "22641218", "text": "Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion.", "type": "CHEMICAL", "entities": [ "Celastrol" ], "offsets": [ [ 56, 65 ] ] }, { "pmid": "22641218", "text": "Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity.", "type": "CHEMICAL", "entities": [ "Celastrol" ], "offsets": [ [ 246, 255 ] ] }, { "pmid": "22641218", "text": "Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression.", "type": "CHEMICAL", "entities": [ "Celastrol" ], "offsets": [ [ 92, 101 ] ] }, { "pmid": "22683935", "text": "At non cytotoxic chemical concentrations 9 sensitizers (2,4-dinitrochlorobenzene, paraphenylendiamine, cinnamaldehyde, isoeugenol, nickel-sulfate, tetramethylthiuram disulfide, eugenol, cinnamic-alcohol, ammonium-hexachloroplatinate) were distinguished from 4 non sensitizers (sodium lauryl sulfate, salicylic acid, phenol, octanoic acid).", "type": "CHEMICAL", "entities": [ "sodium lauryl sulfate", "salicylic acid", "phenol", "octanoic acid", "2,4-dinitrochlorobenzene", "paraphenylendiamine", "cinnamaldehyde", "isoeugenol", "nickel-sulfate", "tetramethylthiuram disulfide", "eugenol", "cinnamic-alcohol", "ammonium-hexachloroplatinate" ], "offsets": [ [ 275, 296 ], [ 298, 312 ], [ 314, 320 ], [ 322, 335 ], [ 54, 78 ], [ 80, 99 ], [ 101, 115 ], [ 117, 127 ], [ 129, 143 ], [ 145, 173 ], [ 175, 182 ], [ 184, 200 ], [ 202, 230 ] ] }, { "pmid": "22708686", "text": "The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors.\n", "type": "CHEMICAL", "entities": [ "mianserin" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "22708686", "text": "We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors.", "type": "CHEMICAL", "entities": [ "tricyclic" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "22708686", "text": "Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors.", "type": "CHEMICAL", "entities": [ "mianserin" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "22708686", "text": "Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation.", "type": "CHEMICAL", "entities": [ "mianserin", "[(35)S]GTPgammaS" ], "offsets": [ [ 11, 20 ], [ 214, 230 ] ] }, { "pmid": "22708686", "text": "Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively.", "type": "CHEMICAL", "entities": [ "Mianserin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22708686", "text": "In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors.", "type": "CHEMICAL", "entities": [ "[(35)S]GTPgammaS", "mianserin" ], "offsets": [ [ 3, 19 ], [ 28, 37 ] ] }, { "pmid": "22708686", "text": "The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI).", "type": "CHEMICAL", "entities": [ "nor-binaltorphimine", "nor-BNI" ], "offsets": [ [ 75, 94 ], [ 96, 103 ] ] }, { "pmid": "22708686", "text": "The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity.", "type": "CHEMICAL", "entities": [ "mianserin", "mirtazapine" ], "offsets": [ [ 4, 13 ], [ 23, 34 ] ] }, { "pmid": "22708686", "text": "Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI.", "type": "CHEMICAL", "entities": [ "Mianserin", "mirtazapine", "nor-BNI" ], "offsets": [ [ 0, 9 ], [ 14, 25 ], [ 158, 165 ] ] }, { "pmid": "22708686", "text": "In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A.", "type": "CHEMICAL", "entities": [ "mianserin", "[35S]GTPgammaS", "nor-BNI", "(-)-U50,488", "dynorphin A" ], "offsets": [ [ 39, 48 ], [ 60, 74 ], [ 88, 95 ], [ 185, 196 ], [ 201, 212 ] ] }, { "pmid": "22708686", "text": "When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS:", "type": "CHEMICAL", "entities": [ "[(35)S]GTPgammaS", "dynorphin A", "mianserin" ], "offsets": [ [ 95, 111 ], [ 189, 200 ], [ 15, 24 ] ] }, { "pmid": "22708686", "text": "In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors.", "type": "CHEMICAL", "entities": [ "mianserin" ], "offsets": [ [ 27, 36 ] ] }, { "pmid": "22718275", "text": "7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3β-hydroxysterol-Δ(7)-reductase (DHCR7).", "type": "CHEMICAL", "entities": [ "3β-hydroxysterol", "7-DHC", "7-Dehydrocholesterol" ], "offsets": [ [ 165, 181 ], [ 22, 27 ], [ 0, 20 ] ] }, { "pmid": "22718275", "text": "We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 oxysterols have been identified as products of oxidation of 7-DHC in solution.", "type": "CHEMICAL", "entities": [ "7-DHC", "oxysterols", "7-DHC" ], "offsets": [ [ 24, 29 ], [ 124, 134 ], [ 184, 189 ] ] }, { "pmid": "22718275", "text": "As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7-KO mouse model of SLOS, including oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively.", "type": "CHEMICAL", "entities": [ "7-DHC", "oxysterols", "isoprostanes", "IsoPs", "neuroprostanes", "NeuroPs", "7-DHC", "arachidonic acid", "docosahexaenoic acid" ], "offsets": [ [ 27, 32 ], [ 186, 196 ], [ 198, 210 ], [ 212, 217 ], [ 224, 238 ], [ 240, 247 ], [ 287, 292 ], [ 294, 310 ], [ 315, 335 ] ] }, { "pmid": "22718275", "text": "In addition to a previously described oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), we provide evidence for the chemical structures of three new oxysterols in the brain and/or liver tissue of Dhcr7-KO mice, two of which were quantified.", "type": "CHEMICAL", "entities": [ "oxysterol", "3β,5α-dihydroxycholest-7-en-6-one", "DHCEO", "oxysterols" ], "offsets": [ [ 36, 45 ], [ 47, 80 ], [ 82, 87 ], [ 151, 161 ] ] }, { "pmid": "22718275", "text": "We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7-KO mice relative to matching WT mice.", "type": "CHEMICAL", "entities": [ "IsoPs", "NeuroPs" ], "offsets": [ [ 19, 24 ], [ 29, 36 ] ] }, { "pmid": "22718275", "text": "While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7-DHC-derived oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress.", "type": "CHEMICAL", "entities": [ "IsoPs", "NeuroPs", "7-DHC", "oxysterols", "IsoPs", "NeuroPs" ], "offsets": [ [ 2, 7 ], [ 12, 19 ], [ 167, 172 ], [ 181, 191 ], [ 231, 236 ], [ 241, 248 ] ] }, { "pmid": "22798249", "text": "Urinary Smad1, fasting plasma glucose (FPG), fasting serum C-Peptide (C-P), hemoglobin A1C (HbA1c), cystatin C, and other chemistry laboratory parameters of T2DM participants and controls were measured.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 30, 37 ] ] }, { "pmid": "22824191", "text": "Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model.\n", "type": "CHEMICAL", "entities": [ "Propranolol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "22824191", "text": "In the present study we tested whether propranolol, a β-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8).", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 39, 50 ] ] }, { "pmid": "22824191", "text": "All these effects were reversed by propranolol treatment.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 33, 44 ] ] }, { "pmid": "22824191", "text": "Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 112, 123 ] ] }, { "pmid": "22824191", "text": "Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 13, 24 ] ] }, { "pmid": "22824191", "text": "Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 105, 116 ] ] }, { "pmid": "22824191", "text": "Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 6, 17 ] ] }, { "pmid": "22835278", "text": "We present two cases in which patients had increased blood levels of testosterone and frank hirsutism.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 69, 81 ] ] }, { "pmid": "22835278", "text": "An androgen producing tumour should be excluded in every woman with evidence of hirsutism or frank virilization and markedly elevated testosterone levels.", "type": "CHEMICAL", "entities": [ "androgen", "testosterone" ], "offsets": [ [ 3, 11 ], [ 134, 146 ] ] }, { "pmid": "22835278", "text": "Adrenal disease with androgen hypersecretion can be suspected by detailed clinical, laboratory and radiologic imaging.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 21, 29 ] ] }, { "pmid": "22835278", "text": "Although DHEAS has a good sensitivity in the detection of adrenal origin of hyperandrogenism (and hence a good negative predictive value) it is not specific (specificity ranging from 85 to 98%).", "type": "CHEMICAL", "entities": [ "DHEAS" ], "offsets": [ [ 9, 14 ] ] }, { "pmid": "22835278", "text": "As these clinical entities represent a diagnostic and therapeutic challenge, oophorectomy should be considered in postmenopausal women with hirsutism and elevated testosterone levels, after the exclusion of adrenal causes.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 163, 175 ] ] }, { "pmid": "22862926", "text": "We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in transcription factor 7-like 2 (TCF7L2) with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 195, 202 ], [ 325, 332 ] ] }, { "pmid": "22862926", "text": "All participants had a 3-h oral glucose tolerance test (OGTT), an intravenous glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 32, 39 ], [ 78, 85 ] ] }, { "pmid": "22862926", "text": "We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon and GLP-1 between the groups.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 50, 57 ], [ 127, 134 ] ] }, { "pmid": "22876943", "text": "Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives.\n", "type": "CHEMICAL", "entities": [ "1, 3-diphenyl-2-propen-1-one" ], "offsets": [ [ 28, 56 ] ] }, { "pmid": "22876943", "text": "Chalcones (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system.", "type": "CHEMICAL", "entities": [ "α, β-unsaturated carbonyl", "Chalcones", "1, 3-Diphenyl-2-propen-1-one", "carbon" ], "offsets": [ [ 75, 100 ], [ 0, 9 ], [ 11, 39 ], [ 68, 74 ] ] }, { "pmid": "22876943", "text": "The biosynthesis of flavonoids and isoflavonoids is initiated by chalcones.", "type": "CHEMICAL", "entities": [ "flavonoids", "isoflavonoids", "chalcones" ], "offsets": [ [ 18, 28 ], [ 33, 46 ], [ 63, 72 ] ] }, { "pmid": "22876943", "text": "Notable pharmacological activities of chalcones and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively.", "type": "CHEMICAL", "entities": [ "chalcones" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "22876943", "text": "Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from chalcones are subjected to extensive consideration.", "type": "CHEMICAL", "entities": [ "chalcones" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "22876943", "text": "This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities.", "type": "CHEMICAL", "entities": [ "chalcone" ], "offsets": [ [ 77, 85 ] ] }, { "pmid": "22876943", "text": "Effect of chalcones on lipid peroxidation, heme oxygenase 1(HO-1), cyclooxygenase (COX), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise.", "type": "CHEMICAL", "entities": [ "chalcones", "heme", "nitric oxide", "NO" ], "offsets": [ [ 8, 17 ], [ 41, 45 ], [ 109, 121 ], [ 123, 125 ] ] }, { "pmid": "22884520", "text": "Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome.\n", "type": "CHEMICAL", "entities": [ "Oxysterol", "cholesterol" ], "offsets": [ [ 0, 9 ], [ 60, 71 ] ] }, { "pmid": "22884520", "text": "Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "cholesterol" ], "offsets": [ [ 188, 199 ], [ 226, 237 ], [ 5, 16 ] ] }, { "pmid": "22884520", "text": "LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles.", "type": "CHEMICAL", "entities": [ "oxysterols", "cholesterol" ], "offsets": [ [ 50, 60 ], [ 90, 101 ] ] }, { "pmid": "22884520", "text": "Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation.", "type": "CHEMICAL", "entities": [ "cholesterol", "sterol", "oxysterol" ], "offsets": [ [ 39, 50 ], [ 101, 107 ], [ 159, 168 ] ] }, { "pmid": "22884520", "text": "This block does not appear to be compensated by oxysterol production in other cell compartments.", "type": "CHEMICAL", "entities": [ "oxysterol" ], "offsets": [ [ 48, 57 ] ] }, { "pmid": "22884520", "text": "The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes.", "type": "CHEMICAL", "entities": [ "oxysterol", "cholesterol", "cholesterol", "oxysterol" ], "offsets": [ [ 67, 76 ], [ 134, 145 ], [ 188, 199 ], [ 256, 265 ] ] }, { "pmid": "22898132", "text": "Embryos were exposed from 4 to 52 h post-fertilization (hpf) to a selection of known embryotoxic/teratogen compounds (valproic acid, retinoic acid, caffeine, sodium salicylate, glucose, hydroxyurea, methoxyacetic acid, boric acid and paraoxon-methyl) over a concentration range.", "type": "CHEMICAL", "entities": [ "valproic acid", "retinoic acid", "caffeine", "sodium salicylate", "glucose", "hydroxyurea", "methoxyacetic acid", "boric acid", "paraoxon-methyl" ], "offsets": [ [ 118, 131 ], [ 133, 146 ], [ 148, 156 ], [ 158, 175 ], [ 177, 184 ], [ 186, 197 ], [ 199, 217 ], [ 219, 229 ], [ 234, 249 ] ] }, { "pmid": "22898132", "text": "In general, the different patterns of the concentration-response curves allowed distinguishing between chemicals that produced growth retardation (valproic and methoxyacetic acid) and chemicals that produced non-growth-delay related malformations.", "type": "CHEMICAL", "entities": [ "valproic and methoxyacetic acid" ], "offsets": [ [ 147, 178 ] ] }, { "pmid": "22898212", "text": "Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase.\n", "type": "CHEMICAL", "entities": [ "Cresyl saligenin phosphate", "histidine", "histidine" ], "offsets": [ [ 0, 26 ], [ 100, 109 ], [ 58, 67 ] ] }, { "pmid": "22898212", "text": "Cresyl saligenin phosphate (CBDP) is a suspected causative agent of \"aerotoxic syndrome\", affecting pilots, crew members and passengers.", "type": "CHEMICAL", "entities": [ "Cresyl saligenin phosphate", "CBDP" ], "offsets": [ [ 0, 26 ], [ 28, 32 ] ] }, { "pmid": "22898212", "text": "CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids.", "type": "CHEMICAL", "entities": [ "CBDP", "tricresyl phosphate", "TCP" ], "offsets": [ [ 0, 4 ], [ 58, 77 ], [ 79, 82 ] ] }, { "pmid": "22898212", "text": "CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198).", "type": "CHEMICAL", "entities": [ "CBDP", "serine", "Ser" ], "offsets": [ [ 0, 4 ], [ 110, 116 ], [ 118, 121 ] ] }, { "pmid": "22898212", "text": "Inhibited BChE undergoes aging to release saligenin and o-cresol.", "type": "CHEMICAL", "entities": [ "saligenin", "o-cresol" ], "offsets": [ [ 42, 51 ], [ 56, 64 ] ] }, { "pmid": "22898212", "text": "The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198.", "type": "CHEMICAL", "entities": [ "histidine", "His", "o-hydroxybenzyl", "Ser" ], "offsets": [ [ 16, 25 ], [ 27, 30 ], [ 65, 80 ], [ 115, 118 ] ] }, { "pmid": "22898212", "text": "Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438.", "type": "CHEMICAL", "entities": [ "CBDP", "Glu", "o-hydroxybenzyl", "lysine", "His" ], "offsets": [ [ 26, 30 ], [ 60, 63 ], [ 76, 91 ], [ 112, 118 ], [ 171, 174 ] ] }, { "pmid": "22898212", "text": "Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins.", "type": "CHEMICAL", "entities": [ "nitrogen", "imidazole", "l-histidine", "CBDP", "o-hydroxybenzyl", "histidine", "CBDP" ], "offsets": [ [ 18, 26 ], [ 34, 43 ], [ 57, 68 ], [ 116, 120 ], [ 136, 151 ], [ 176, 185 ], [ 186, 190 ] ] }, { "pmid": "22898566", "text": "The role of long chain omega-3 polyunsaturated fatty acids in reducing lipid peroxidation among elderly patients with mild cognitive impairment: a case-control study.\n", "type": "CHEMICAL", "entities": [ "omega-3 polyunsaturated fatty acids" ], "offsets": [ [ 23, 58 ] ] }, { "pmid": "22898566", "text": "The present work explores the effect of dietary omega-3 polyunsaturated fatty acids (PUFAs) intake on lipid peroxidation among mild cognitive impairment (MCI) patients.", "type": "CHEMICAL", "entities": [ "PUFAs", "omega-3 polyunsaturated fatty acids" ], "offsets": [ [ 85, 90 ], [ 48, 83 ] ] }, { "pmid": "22898566", "text": "The plasma lipid hydroperoxide (LPO) levels in 67 MCI patients were compared to those of 134 healthy elderly controls.", "type": "CHEMICAL", "entities": [ "hydroperoxide" ], "offsets": [ [ 17, 30 ] ] }, { "pmid": "22898566", "text": "Omega-3 PUFA intake was assessed using an interviewer-administered food frequency questionnaire.", "type": "CHEMICAL", "entities": [ "Omega-3 PUFA" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "22898566", "text": "The influence of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on LPO level was investigated.", "type": "CHEMICAL", "entities": [ "docosahexaenoic acid", "DHA", "eicosapentaenoic acid", "EPA" ], "offsets": [ [ 17, 37 ], [ 39, 42 ], [ 48, 69 ], [ 71, 74 ] ] }, { "pmid": "22898566", "text": "Inverse correlations were found between DHA and EPA intake and LPO level among the MCI group.", "type": "CHEMICAL", "entities": [ "DHA", "EPA" ], "offsets": [ [ 40, 43 ], [ 48, 51 ] ] }, { "pmid": "22898566", "text": "LPO levels decreased significantly with increasing DHA and EPA intake.", "type": "CHEMICAL", "entities": [ "DHA", "EPA" ], "offsets": [ [ 51, 54 ], [ 59, 62 ] ] }, { "pmid": "22898566", "text": "In summary, the findings revealed that DHA and EPA can play a role in alleviating oxidative stress and reducing the risk of neurodegenerative diseases.", "type": "CHEMICAL", "entities": [ "DHA", "EPA" ], "offsets": [ [ 39, 42 ], [ 47, 50 ] ] }, { "pmid": "22902329", "text": "Vitamin E deficiency impairs the somatostatinergic receptor-effector system and leads to phosphotyrosine phosphatase overactivation and cell death in the rat hippocampus.\n", "type": "CHEMICAL", "entities": [ "Vitamin E", "phosphotyrosine" ], "offsets": [ [ 0, 9 ], [ 89, 104 ] ] }, { "pmid": "22902329", "text": "Vitamin E plays an essential role in maintaining the structure and function of the nervous system, and its deficiency, commonly associated with fat malabsorption diseases, may reduce neuronal survival.", "type": "CHEMICAL", "entities": [ "Vitamin E" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "22902329", "text": "We previously demonstrated that the somatostatinergic system, implicated in neuronal survival control, can be modulated by α-tocopherol in the rat dentate gyrus, increasing cyclic adenosine monophosphate response element binding protein phosphorylation.", "type": "CHEMICAL", "entities": [ "α-tocopherol", "cyclic adenosine monophosphate" ], "offsets": [ [ 123, 135 ], [ 173, 203 ] ] }, { "pmid": "22902329", "text": "To gain a better understanding of the molecular actions of tocopherols and examine the link among vitamin E, somatostatin and neuronal survival, we have investigated the effects of a deficiency and subsequent administration of tocopherol on the somatostatin signaling pathway and neuronal survival in the rat hippocampus.", "type": "CHEMICAL", "entities": [ "tocopherols", "vitamin E", "somatostatin", "tocopherol", "somatostatin" ], "offsets": [ [ 58, 69 ], [ 97, 106 ], [ 108, 120 ], [ 226, 236 ], [ 244, 256 ] ] }, { "pmid": "22902329", "text": "No changes in somatostatin expression were detected in vitamin-E-deficient rats.", "type": "CHEMICAL", "entities": [ "somatostatin", "vitamin-E" ], "offsets": [ [ 13, 25 ], [ 54, 63 ] ] }, { "pmid": "22902329", "text": "These rats, however, showed a significant increase in the somatostatin receptor density and dissociation constant, which correlated with a significant increase in the protein levels of somatostatin receptors.", "type": "CHEMICAL", "entities": [ "somatostatin", "somatostatin" ], "offsets": [ [ 57, 69 ], [ 184, 196 ] ] }, { "pmid": "22902329", "text": "Nevertheless, vitamin E deficiency impaired the ability of the somatostatin receptors to couple to the effectors adenylyl cyclase and phosphotyrosine phosphatase by diminishing Gi protein functionality.", "type": "CHEMICAL", "entities": [ "vitamin E", "somatostatin", "adenylyl", "phosphotyrosine" ], "offsets": [ [ 13, 22 ], [ 62, 74 ], [ 112, 120 ], [ 133, 148 ] ] }, { "pmid": "22902329", "text": "Furthermore, vitamin E deficiency significantly increased phosphotyrosine phosphatase activity and PTPη expression, as well as PKCδ activation, and decreased extracellular-signal-regulated kinase phosphorylation.", "type": "CHEMICAL", "entities": [ "vitamin E", "phosphotyrosine" ], "offsets": [ [ 12, 21 ], [ 57, 72 ] ] }, { "pmid": "22902329", "text": "Subsequent α-tocopherol administration partially or completely reversed all these values to control levels.", "type": "CHEMICAL", "entities": [ "α-tocopherol" ], "offsets": [ [ 8, 20 ] ] }, { "pmid": "22902329", "text": "Altogether, our results prove the importance of vitamin E homeostasis in the somatostatin receptor-effector system and suggest a possible mechanism by which this vitamin may regulate the neuronal cell survival in the adult hippocampus.", "type": "CHEMICAL", "entities": [ "vitamin E", "somatostatin" ], "offsets": [ [ 44, 53 ], [ 73, 85 ] ] }, { "pmid": "22918703", "text": "CCAAT/Enhancer-binding protein-homologous protein sensitizes to SU5416 by modulating p21 and PI3K/", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 64, 70 ] ] }, { "pmid": "22918703", "text": "SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells.", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "22918703", "text": "In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 50, 56 ] ] }, { "pmid": "22918703", "text": "Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells.", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 80, 86 ] ] }, { "pmid": "22918703", "text": "After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed.", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 6, 12 ] ] }, { "pmid": "22918703", "text": "Phospho-Akt protein levels were not altered.", "type": "CHEMICAL", "entities": [ "Phospho" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "22918703", "text": "In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002.", "type": "CHEMICAL", "entities": [ "LY294002", "LY294002", "SU5416" ], "offsets": [ [ 117, 125 ], [ 191, 199 ], [ 3, 9 ] ] }, { "pmid": "22918703", "text": "Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA.", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 12, 18 ] ] }, { "pmid": "22918703", "text": "While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels.", "type": "CHEMICAL", "entities": [ "phospho" ], "offsets": [ [ 51, 58 ] ] }, { "pmid": "22918703", "text": "In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 78, 84 ] ] }, { "pmid": "22918703", "text": "Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416.", "type": "CHEMICAL", "entities": [ "SU5416" ], "offsets": [ [ 157, 163 ] ] }, { "pmid": "22926699", "text": "Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors.", "type": "CHEMICAL", "entities": [ "aryl hydrocarbon" ], "offsets": [ [ 93, 109 ] ] }, { "pmid": "22931533", "text": "Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD).", "type": "CHEMICAL", "entities": [ "Morphinans" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "22931533", "text": "Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids.", "type": "CHEMICAL", "entities": [ "Galantamine", "acetylcholine", "morphinan" ], "offsets": [ [ 0, 11 ], [ 127, 140 ], [ 212, 221 ] ] }, { "pmid": "22931533", "text": "The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development.", "type": "CHEMICAL", "entities": [ "codeine", "eseroline", "galantamine" ], "offsets": [ [ 33, 40 ], [ 45, 54 ], [ 61, 72 ] ] }, { "pmid": "22931535", "text": "Adhesion of osteoblasts to a vertically aligned TiO2 nanotube surface.\n", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 48, 52 ] ] }, { "pmid": "22931535", "text": "The adhesion of cells to vertically aligned TiO2 nanotubes is reviewed.", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 44, 48 ] ] }, { "pmid": "22931535", "text": "It is shown that adhesion and spreading of osteoblasts on vertically aligned TiO2 nanotube surfaces depend on the diameter of the nanotubes.", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 77, 81 ] ] }, { "pmid": "22946701", "text": "Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GnRH analogues, Danazol and Levonorgestrel releasing intra uterine system (LNG IUS).", "type": "CHEMICAL", "entities": [ "progestogens", "tranexamic acid", "GnRH", "Danazol", "Levonorgestrel" ], "offsets": [ [ 68, 80 ], [ 130, 145 ], [ 167, 171 ], [ 183, 190 ], [ 195, 209 ] ] }, { "pmid": "22967140", "text": "Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats.\n", "type": "CHEMICAL", "entities": [ "NADPH", "oestrogen" ], "offsets": [ [ 49, 54 ], [ 8, 17 ] ] }, { "pmid": "22967140", "text": "Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain.", "type": "CHEMICAL", "entities": [ "NADPH", "oestradiol", "nitric oxide" ], "offsets": [ [ 70, 75 ], [ 114, 124 ], [ 18, 30 ] ] }, { "pmid": "22967140", "text": "The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation.", "type": "CHEMICAL", "entities": [ "NADPH", "oestradiol", "oestrogen" ], "offsets": [ [ 62, 67 ], [ 91, 101 ], [ 187, 196 ] ] }, { "pmid": "22967140", "text": "Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol).", "type": "CHEMICAL", "entities": [ "DPN", "2,3-bis(4-hydroxyphenyl)-propionitrile", "MPP", "1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol", "1H-pyrazole dihydrochloride", "PHTPP", "4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol", "oestradiol", "PPT", "4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol" ], "offsets": [ [ 228, 231 ], [ 233, 271 ], [ 301, 304 ], [ 306, 372 ], [ 374, 401 ], [ 433, 438 ], [ 440, 512 ], [ 106, 116 ], [ 142, 145 ], [ 147, 201 ] ] }, { "pmid": "22967140", "text": "The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and ERβ ligands induced different effects.", "type": "CHEMICAL", "entities": [ "NADPH" ], "offsets": [ [ 6, 11 ] ] }, { "pmid": "22967140", "text": "These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 93, 102 ] ] }, { "pmid": "22981459", "text": "Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments.", "type": "CHEMICAL", "entities": [ "organophosphorous" ], "offsets": [ [ 7, 24 ] ] }, { "pmid": "22981459", "text": "The residence time of a stoichiometric bioscavenger, human butyrylcholinesterase (huBuChE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (oxime, anti-muscarinic, anticonvulsant).", "type": "CHEMICAL", "entities": [ "oxime" ], "offsets": [ [ 197, 202 ] ] }, { "pmid": "22981459", "text": "A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74mg/kg) to 48h, even when administered on signs of poisoning.", "type": "CHEMICAL", "entities": [ "oxime" ], "offsets": [ [ 44, 49 ] ] }, { "pmid": "22981459", "text": "Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15min and were eliminated rapidly within 4h.", "type": "CHEMICAL", "entities": [ "atropine", "diazepam", "HI-6" ], "offsets": [ [ 54, 62 ], [ 64, 72 ], [ 77, 81 ] ] }, { "pmid": "22982206", "text": "Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner.\n", "type": "CHEMICAL", "entities": [ "Verrucarin A" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "22982206", "text": "Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress.", "type": "CHEMICAL", "entities": [ "verrucarin A" ], "offsets": [ [ 30, 42 ] ] }, { "pmid": "22982206", "text": "Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA.", "type": "CHEMICAL", "entities": [ "salubrinal" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "22982206", "text": "In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 30, 36 ] ] }, { "pmid": "22991293", "text": "X-linked hypophosphatemia (XLH/HYP)-with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses-is caused by mutations in the zinc-metallopeptidase PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome).", "type": "CHEMICAL", "entities": [ "zinc", "phosphate", "phosphate" ], "offsets": [ [ 148, 152 ], [ 181, 190 ], [ 47, 56 ] ] }, { "pmid": "22991293", "text": "Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization-inhibiting, acidic serine- and aspartate-rich motif (ASARM)-containing peptides, which are proteolytically derived from the mineral-binding matrix proteins of the SIBLING family (small, integrin-binding ligand N-linked glycoproteins).", "type": "CHEMICAL", "entities": [ "serine", "aspartate", "N" ], "offsets": [ [ 203, 209 ], [ 215, 224 ], [ 394, 395 ] ] }, { "pmid": "22991447", "text": "Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice.\n", "type": "CHEMICAL", "entities": [ "nitric oxide", "S" ], "offsets": [ [ 33, 45 ], [ 79, 80 ] ] }, { "pmid": "22991447", "text": "Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 44, 45 ] ] }, { "pmid": "22991447", "text": "Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice.", "type": "CHEMICAL", "entities": [ "nitric oxide", "S" ], "offsets": [ [ 40, 52 ], [ 76, 77 ] ] }, { "pmid": "22991447", "text": "Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 36, 37 ] ] }, { "pmid": "22991447", "text": "Conversely, aged iNOS-null mice were protected from S-nitrosation-induced insulin resistance.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 52, 53 ] ] }, { "pmid": "22991447", "text": "Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 99, 100 ] ] }, { "pmid": "22991447", "text": "These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway.", "type": "CHEMICAL", "entities": [ "S" ], "offsets": [ [ 105, 106 ] ] }, { "pmid": "22992330", "text": "Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function.", "type": "CHEMICAL", "entities": [ "catechol", "O" ], "offsets": [ [ 46, 54 ], [ 55, 56 ] ] }, { "pmid": "22996137", "text": "Both microtubule and actin are required for insulin-induced glucose uptake.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "22996137", "text": "Disruption of microtubule prevented insulin-induced actin remodeling and distal insulin signal transduction, with reduction in surface glucose transporter isoform 4 (GLUT4) and glucose uptake.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 135, 142 ], [ 177, 184 ] ] }, { "pmid": "22996137", "text": "Though microtubule mediated actin remodeling through PKCζ, reorganization of microtubule depended on tyrosine phosphorylation of insulin receptor, the mechanism is different from insulin-induced actin remodeling, which relied on the activity of PI3-kinase and PKCζ. We propose that microtubule network is required for insulin-induced signal transduction and actin remodeling in skeletal muscle cells.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 101, 109 ] ] }, { "pmid": "23007560", "text": "The present study was designed to evaluate the effects of chronic fluorosis on the dynamics (including fusion and fission proteins), fragmentation, and distribution of mitochondria in the cortical neurons of the rat brain in an attempt to elucidate molecular mechanisms underlying the brain damage associated with excess accumulation of fluoride.", "type": "CHEMICAL", "entities": [ "fluoride" ], "offsets": [ [ 337, 345 ] ] }, { "pmid": "23007560", "text": "Sixty Sprague-Dawley rats were divided randomly into three groups of 20 each, that is, the untreated control group (drinking water naturally containing <0.5 mg fluoride/l, NaF), the low-fluoride group (whose drinking water was supplemented with 10 mg fluoride/l) and the high-fluoride group (50 mg fluoride/l).", "type": "CHEMICAL", "entities": [ "fluoride", "NaF", "fluoride", "fluoride", "fluoride", "fluoride" ], "offsets": [ [ 160, 168 ], [ 172, 175 ], [ 186, 194 ], [ 251, 259 ], [ 276, 284 ], [ 298, 306 ] ] }, { "pmid": "23015691", "text": "Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse.\n", "type": "CHEMICAL", "entities": [ "steroid", "androstane" ], "offsets": [ [ 96, 103 ], [ 57, 67 ] ] }, { "pmid": "23015691", "text": "The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor.", "type": "CHEMICAL", "entities": [ "androstane" ], "offsets": [ [ 17, 27 ] ] }, { "pmid": "23015691", "text": "The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1).", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 201, 208 ] ] }, { "pmid": "23015691", "text": "Androstanol and androstenol, estrone, 17β-estradiol, TCPOBOP, and CITCO showed compound-specific but similar affinities for both CARs.", "type": "CHEMICAL", "entities": [ "androstenol", "estrone", "17β-estradiol", "TCPOBOP", "CITCO", "Androstanol" ], "offsets": [ [ 16, 27 ], [ 29, 36 ], [ 38, 51 ], [ 53, 60 ], [ 66, 71 ], [ 0, 11 ] ] }, { "pmid": "23017389", "text": "Studies on the antioxidant potential of flavones of Allium vineale isolated from its water-soluble fraction.\n", "type": "CHEMICAL", "entities": [ "flavones" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "23017389", "text": "The water-soluble fraction, containing phenolic compounds, was extracted with ethyl acetate to obtain flavonoids which were separated and purified by repeated column chromatography over Sephadex LH-20, RP C18 and silica gel.", "type": "CHEMICAL", "entities": [ "ethyl acetate", "flavonoids", "silica gel" ], "offsets": [ [ 78, 91 ], [ 102, 112 ], [ 213, 223 ] ] }, { "pmid": "23017389", "text": "The isolated compounds were identified according to their physicochemical properties and spectral data (UV, HPLC-TOF/MS, (1)H NMR, (13)C NMR and 2D NMR).", "type": "CHEMICAL", "entities": [ "(13)C", "(1)H" ], "offsets": [ [ 131, 136 ], [ 121, 125 ] ] }, { "pmid": "23017389", "text": "Three flavonoids were isolated and identified as chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside (1), chrysoeriol (2), and isorhamnetin-3-β-d-glucoside (3).", "type": "CHEMICAL", "entities": [ "chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside", "chrysoeriol", "isorhamnetin-3-β-d-glucoside" ], "offsets": [ [ 49, 96 ], [ 102, 113 ], [ 123, 151 ] ] }, { "pmid": "23017389", "text": "Antioxidant activities were evaluated for total antioxidant activity by the ferric thiocyanate method, ferric ion (Fe(3+)) reducing antioxidant power assay (FRAP), ferrous ion (Fe(2+)) metal chelating activity, and DPPH free radical-scavenging activity.", "type": "CHEMICAL", "entities": [ "ferric thiocyanate", "ferric", "Fe(3+)", "ferrous", "Fe(2+)", "DPPH" ], "offsets": [ [ 72, 90 ], [ 99, 105 ], [ 111, 117 ], [ 160, 167 ], [ 173, 179 ], [ 211, 215 ] ] }, { "pmid": "23017389", "text": "The water-soluble ethyl acetate and methanol extraction methods were also compared using HPLC-TOF/MS.", "type": "CHEMICAL", "entities": [ "ethyl acetate", "methanol" ], "offsets": [ [ 14, 27 ], [ 32, 40 ] ] }, { "pmid": "23017415", "text": "Amino acid composition, antinutrients and allergens in the peanut protein fraction obtained by an aqueous enzymatic process.\n", "type": "CHEMICAL", "entities": [ "Amino acid" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23017415", "text": "The aqueous fraction (AF) obtained by EAE had a better essential amino acid profile than the residues obtained by solvent extraction (Rs) and cold pressing (Rc).", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 65, 75 ] ] }, { "pmid": "23017415", "text": "AF had an extremely low phytate content and was rich in peptides, which could be used as a food supplement.", "type": "CHEMICAL", "entities": [ "phytate" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23022398", "text": "NMDA receptor blockade impairs the muscarinic conversion of sub-threshold transient depression into long-lasting LTD in the hippocampus-prefrontal cortex pathway in vivo: correlation with gamma oscillations.\n", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23022398", "text": "Cortical-evoked responses were recorded in urethane-anesthetized rats for 30 min during baseline and 4 h following LTD.", "type": "CHEMICAL", "entities": [ "urethane" ], "offsets": [ [ 43, 51 ] ] }, { "pmid": "23022398", "text": "In order to test the potentiating effects of pilocarpine (PILO), independent groups of rats received either a microinjection of PILO (40 nmol; i.c.v.) or vehicle, immediately before or 20 min after a sub-threshold LTD protocol (600 pulses, 1 Hz; LFS600).", "type": "CHEMICAL", "entities": [ "PILO", "pilocarpine", "PILO" ], "offsets": [ [ 128, 132 ], [ 45, 56 ], [ 58, 62 ] ] }, { "pmid": "23022398", "text": "Other groups received either an infusion of the selective NMDA receptor antagonist (AP7; 10 nmol; intra-mPFC) or vehicle, 10 min prior to PILO preceding LFS600, or prior to a supra-threshold LTD protocol (900 pulses, 1 Hz; LFS900).", "type": "CHEMICAL", "entities": [ "NMDA", "AP7", "PILO" ], "offsets": [ [ 58, 62 ], [ 84, 87 ], [ 138, 142 ] ] }, { "pmid": "23022398", "text": "Our results show that PILO converts a transient cortical depression induced by LFS600 into a robust LTD, stable for at least 4 h. When applied after LFS600, PILO does not change either mPFC basal neurotransmission or late LTD.", "type": "CHEMICAL", "entities": [ "PILO", "PILO" ], "offsets": [ [ 22, 26 ], [ 157, 161 ] ] }, { "pmid": "23022398", "text": "Our data also indicate that NMDA receptor pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since AP7 microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by PILO.", "type": "CHEMICAL", "entities": [ "NMDA", "AP7", "PILO" ], "offsets": [ [ 28, 32 ], [ 135, 138 ], [ 249, 253 ] ] }, { "pmid": "23022398", "text": "In addition, AP7 effectively blocked the long-lasting LTD induced by LFS900.", "type": "CHEMICAL", "entities": [ "AP7" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23022398", "text": "Therefore, our findings suggest that the glutamatergic co-activation of prefrontal neurons is important for the effects of PILO on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions.", "type": "CHEMICAL", "entities": [ "PILO" ], "offsets": [ [ 123, 127 ] ] }, { "pmid": "23024204", "text": "Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase.\n", "type": "CHEMICAL", "entities": [ "thialysine", "triethylenetetramine", "1,12-diamino-3,6,9-triazadodecane", "spermidine", "spermine" ], "offsets": [ [ 127, 137 ], [ 14, 34 ], [ 39, 72 ], [ 80, 90 ], [ 91, 99 ] ] }, { "pmid": "23024204", "text": "Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine.", "type": "CHEMICAL", "entities": [ "TETA", "Syprine", "Triethylenetetramine", "copper", "polyamine", "spermidine" ], "offsets": [ [ 22, 26 ], [ 28, 35 ], [ 0, 20 ], [ 90, 96 ], [ 139, 148 ], [ 149, 159 ] ] }, { "pmid": "23024204", "text": "We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT).", "type": "CHEMICAL", "entities": [ "spermidine", "spermine", "thialysine", "TETA", "polyamine" ], "offsets": [ [ 83, 93 ], [ 94, 102 ], [ 141, 151 ], [ 24, 28 ], [ 56, 65 ] ] }, { "pmid": "23024204", "text": "The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice.", "type": "CHEMICAL", "entities": [ "TETA" ], "offsets": [ [ 19, 23 ] ] }, { "pmid": "23024204", "text": "However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice.", "type": "CHEMICAL", "entities": [ "TETA" ], "offsets": [ [ 41, 45 ] ] }, { "pmid": "23024204", "text": "Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT.", "type": "CHEMICAL", "entities": [ "TETA" ], "offsets": [ [ 164, 168 ] ] }, { "pmid": "23024204", "text": "By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes.", "type": "CHEMICAL", "entities": [ "1,12-diamino-3,6,9-triazadodecane", "SpmTrien", "spermine" ], "offsets": [ [ 13, 46 ], [ 47, 55 ], [ 77, 85 ] ] }, { "pmid": "23024204", "text": "Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.", "type": "CHEMICAL", "entities": [ "TETA", "SpmTrien", "TETA", "SpmTrien" ], "offsets": [ [ 40, 44 ], [ 49, 57 ], [ 91, 95 ], [ 105, 113 ] ] }, { "pmid": "23030680", "text": "In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan.\n", "type": "CHEMICAL", "entities": [ "elzasonan" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "23030680", "text": "The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP).", "type": "CHEMICAL", "entities": [ "elzasonan" ], "offsets": [ [ 18, 27 ] ] }, { "pmid": "23030680", "text": "Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3).", "type": "CHEMICAL", "entities": [ "N", "elzasonan N-oxide", "5-hydroxyelzasonan" ], "offsets": [ [ 42, 43 ], [ 101, 118 ], [ 128, 146 ] ] }, { "pmid": "23030680", "text": "Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a).", "type": "CHEMICAL", "entities": [ "elzasonan", "indole", "iminium" ], "offsets": [ [ 14, 23 ], [ 74, 80 ], [ 146, 153 ] ] }, { "pmid": "23030680", "text": "The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan.", "type": "CHEMICAL", "entities": [ "elzasonan" ], "offsets": [ [ 170, 179 ] ] }, { "pmid": "23030680", "text": "Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of rCYP.", "type": "CHEMICAL", "entities": [ "5-hydroxyelzasonan" ], "offsets": [ [ 75, 93 ] ] }, { "pmid": "23030766", "text": "The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 amino acid substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131:FcγRIIb).", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 57, 67 ] ] }, { "pmid": "23042728", "text": "Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs.\n", "type": "CHEMICAL", "entities": [ "valproic acid" ], "offsets": [ [ 12, 25 ] ] }, { "pmid": "23042728", "text": "In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects.", "type": "CHEMICAL", "entities": [ "valproic acid", "VPA" ], "offsets": [ [ 21, 34 ], [ 36, 39 ] ] }, { "pmid": "23042728", "text": "Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo.", "type": "CHEMICAL", "entities": [ "Valpromide", "VPD", "amide", "VPA" ], "offsets": [ [ 0, 10 ], [ 12, 15 ], [ 22, 27 ], [ 42, 45 ] ] }, { "pmid": "23042728", "text": "The detailed mechanism of action of VPA as a teratogen is not known.", "type": "CHEMICAL", "entities": [ "VPA" ], "offsets": [ [ 36, 39 ] ] }, { "pmid": "23042728", "text": "The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development.", "type": "CHEMICAL", "entities": [ "VPA" ], "offsets": [ [ 55, 58 ] ] }, { "pmid": "23042728", "text": "Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system.", "type": "CHEMICAL", "entities": [ "VPA", "VPD" ], "offsets": [ [ 72, 75 ], [ 79, 82 ] ] }, { "pmid": "23042728", "text": "VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect.", "type": "CHEMICAL", "entities": [ "VPA" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23042728", "text": "The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA.", "type": "CHEMICAL", "entities": [ "VPA" ], "offsets": [ [ 93, 96 ] ] }, { "pmid": "23042728", "text": "In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes.", "type": "CHEMICAL", "entities": [ "VPD" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23042728", "text": "Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb.", "type": "CHEMICAL", "entities": [ "VPA" ], "offsets": [ [ 6, 9 ] ] }, { "pmid": "23042728", "text": "Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions.", "type": "CHEMICAL", "entities": [ "VPD" ], "offsets": [ [ 99, 102 ] ] }, { "pmid": "23042730", "text": "Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress.\n", "type": "CHEMICAL", "entities": [ "amiodarone" ], "offsets": [ [ 60, 70 ] ] }, { "pmid": "23042730", "text": "Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients.", "type": "CHEMICAL", "entities": [ "Amiodarone", "AMD" ], "offsets": [ [ 0, 10 ], [ 12, 15 ] ] }, { "pmid": "23042730", "text": "We demonstrated previously that tumor necrosis factor-alpha (TNF-α) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress.", "type": "CHEMICAL", "entities": [ "AMD" ], "offsets": [ [ 110, 113 ] ] }, { "pmid": "23042730", "text": "In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity.", "type": "CHEMICAL", "entities": [ "AMD" ], "offsets": [ [ 129, 132 ] ] }, { "pmid": "23042730", "text": "Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity.", "type": "CHEMICAL", "entities": [ "AMD" ], "offsets": [ [ 48, 51 ] ] }, { "pmid": "23042730", "text": "Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment.", "type": "CHEMICAL", "entities": [ "oxygen", "AMD" ], "offsets": [ [ 22, 28 ], [ 112, 115 ] ] }, { "pmid": "23042730", "text": "Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone.", "type": "CHEMICAL", "entities": [ "trolox", "N-acetylcysteine", "glutathione", "ascorbate", "AMD", "AMD" ], "offsets": [ [ 34, 40 ], [ 42, 58 ], [ 60, 71 ], [ 76, 85 ], [ 122, 125 ], [ 187, 190 ] ] }, { "pmid": "23042730", "text": "On the other hand, α-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. α-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity.", "type": "CHEMICAL", "entities": [ "α-tocopherol", "TOCO", "AMD", "AMD", "α-TOCO", "AMD" ], "offsets": [ [ 18, 30 ], [ 32, 36 ], [ 102, 105 ], [ 168, 171 ], [ 189, 195 ], [ 245, 248 ] ] }, { "pmid": "23042730", "text": "In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity.", "type": "CHEMICAL", "entities": [ "AMD", "AMD" ], "offsets": [ [ 171, 174 ], [ 73, 76 ] ] }, { "pmid": "23044488", "text": "Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide.\n", "type": "CHEMICAL", "entities": [ "Amino acid" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23044488", "text": "Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents.", "type": "CHEMICAL", "entities": [ "organophosphate" ], "offsets": [ [ 123, 138 ] ] }, { "pmid": "23044488", "text": "Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs.", "type": "CHEMICAL", "entities": [ "acyl" ], "offsets": [ [ 86, 90 ] ] }, { "pmid": "23053666", "text": "Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and", "type": "CHEMICAL", "entities": [ "cisplatin", "copper" ], "offsets": [ [ 48, 57 ], [ 91, 97 ] ] }, { "pmid": "23053666", "text": "cisplatin influx transporter CTR1.\nClaudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells.", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23053666", "text": "We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP).", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 172, 181 ] ] }, { "pmid": "23053666", "text": "The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells.", "type": "CHEMICAL", "entities": [ "Pt", "Pt", "platinum" ], "offsets": [ [ 34, 36 ], [ 46, 48 ], [ 24, 32 ] ] }, { "pmid": "23053666", "text": "The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP.", "type": "CHEMICAL", "entities": [ "copper" ], "offsets": [ [ 30, 36 ] ] }, { "pmid": "23053666", "text": "Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells.", "type": "CHEMICAL", "entities": [ "copper", "Cu", "Cu", "Cu" ], "offsets": [ [ 9, 15 ], [ 17, 19 ], [ 28, 30 ], [ 43, 45 ] ] }, { "pmid": "23053666", "text": "Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA.", "type": "CHEMICAL", "entities": [ "Cu", "l-DOPA" ], "offsets": [ [ 0, 2 ], [ 131, 137 ] ] }, { "pmid": "23053666", "text": "These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1.", "type": "CHEMICAL", "entities": [ "Cu" ], "offsets": [ [ 155, 157 ] ] }, { "pmid": "23055538", "text": "Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice.", "type": "CHEMICAL", "entities": [ "bisphenol A" ], "offsets": [ [ 102, 113 ] ] }, { "pmid": "23055538", "text": "Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions.", "type": "CHEMICAL", "entities": [ "acetaminophen" ], "offsets": [ [ 171, 184 ] ] }, { "pmid": "23056222", "text": "Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling.\n", "type": "CHEMICAL", "entities": [ "Dimethylfumarate" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23056222", "text": "This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling.", "type": "CHEMICAL", "entities": [ "dimethylfumarate", "DMF" ], "offsets": [ [ 28, 44 ], [ 46, 49 ] ] }, { "pmid": "23056222", "text": "Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F).", "type": "CHEMICAL", "entities": [ "DMF", "DMF" ], "offsets": [ [ 20, 23 ], [ 67, 70 ] ] }, { "pmid": "23056222", "text": "Additionally, DMF and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression.", "type": "CHEMICAL", "entities": [ "DMF" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "23056222", "text": "However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF.", "type": "CHEMICAL", "entities": [ "glutathione", "S", "DMF", "DMF" ], "offsets": [ [ 114, 125 ], [ 126, 127 ], [ 187, 190 ], [ 335, 338 ] ] }, { "pmid": "23056222", "text": "Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively.", "type": "CHEMICAL", "entities": [ "DMF" ], "offsets": [ [ 9, 12 ] ] }, { "pmid": "23056222", "text": "In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.", "type": "CHEMICAL", "entities": [ "DMF", "DMF" ], "offsets": [ [ 12, 15 ], [ 149, 152 ] ] }, { "pmid": "23059626", "text": "Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1).", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 128, 131 ] ] }, { "pmid": "23059626", "text": "mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES.", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 244, 247 ] ] }, { "pmid": "23059626", "text": "The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice.", "type": "CHEMICAL", "entities": [ "Met" ], "offsets": [ [ 168, 171 ] ] }, { "pmid": "23059655", "text": "Nano-graphene in biomedicine: theranostic applications.\n", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 5, 13 ] ] }, { "pmid": "23059655", "text": "Owing to their unique physical and chemical properties, graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (RGO) and GO-nanocomposites have attracted tremendous interest in many different fields including biomedicine in recent years.", "type": "CHEMICAL", "entities": [ "graphene oxide", "reduced graphene oxide", "RGO", "graphene" ], "offsets": [ [ 93, 107 ], [ 114, 136 ], [ 138, 141 ], [ 56, 64 ] ] }, { "pmid": "23059655", "text": "With every atom exposed on its surface, single-layered graphene shows ultra-high surface area available for efficient molecular loading and bioconjugation, and has been widely explored as novel nano-carriers for drug and gene delivery.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 55, 63 ] ] }, { "pmid": "23059655", "text": "Utilizing the intrinsic near-infrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been realized, achieving excellent anti-tumor therapeutic efficacy in animal experiments.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 72, 80 ] ] }, { "pmid": "23059655", "text": "A variety of inorganic nanoparticles can be grown on the surface of nano-graphene, obtaining functional graphene-based nanocomposites with interesting optical and magnetic properties useful for multi-modal imaging and imaging-guided cancer therapy.", "type": "CHEMICAL", "entities": [ "graphene", "graphene" ], "offsets": [ [ 73, 81 ], [ 104, 112 ] ] }, { "pmid": "23059655", "text": "Moreover, significant efforts have also been devoted to study the behaviors and toxicology of functionalized nano-graphene in animals.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 114, 122 ] ] }, { "pmid": "23059655", "text": "It has been uncovered that both surface chemistry and sizes play key roles in controlling the biodistribution, excretion, and toxicity of nano-graphene.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 143, 151 ] ] }, { "pmid": "23059655", "text": "Biocompatibly coated nano-graphene with ultra-small sizes can be cleared out from body after systemic administration, without rendering noticeable toxicity to the treated mice.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 26, 34 ] ] }, { "pmid": "23059655", "text": "In this review article, we will summarize the latest progress in this rapidly growing field, and discuss future prospects and challenges of using graphene-based materials for theranostic applications.", "type": "CHEMICAL", "entities": [ "graphene" ], "offsets": [ [ 146, 154 ] ] }, { "pmid": "23061466", "text": "Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design.\n", "type": "CHEMICAL", "entities": [ "ether" ], "offsets": [ [ 6, 11 ] ] }, { "pmid": "23061466", "text": "The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death.", "type": "CHEMICAL", "entities": [ "ether", "K+" ], "offsets": [ [ 10, 15 ], [ 49, 51 ] ] }, { "pmid": "23061466", "text": "The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and hERG blocking activity.", "type": "CHEMICAL", "entities": [ "matrine", "O=C=N-C-C-C-N", "quinolizidine alkaloids", "oxymatrine", "sophoridine", "sophocarpine" ], "offsets": [ [ 97, 104 ], [ 145, 158 ], [ 4, 27 ], [ 55, 65 ], [ 67, 78 ], [ 80, 92 ] ] }, { "pmid": "23061466", "text": "Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial.", "type": "CHEMICAL", "entities": [ "Acehytisine hydrochloride", "Guangfu base A" ], "offsets": [ [ 0, 25 ], [ 44, 58 ] ] }, { "pmid": "23061466", "text": "The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM).", "type": "CHEMICAL", "entities": [ "isoquinoline alkaloid", "neferine", "Nef" ], "offsets": [ [ 4, 25 ], [ 27, 35 ], [ 37, 40 ] ] }, { "pmid": "23063595", "text": "Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism.\n", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "23063595", "text": "The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease.", "type": "CHEMICAL", "entities": [ "AMP" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "23063595", "text": "Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23063595", "text": "Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value.", "type": "CHEMICAL", "entities": [ "polyphenols" ], "offsets": [ [ 51, 62 ] ] }, { "pmid": "23064031", "text": "Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells.\n", "type": "CHEMICAL", "entities": [ "naphtho[1,2-b]furan-4,5-dione" ], "offsets": [ [ 39, 68 ] ] }, { "pmid": "23064031", "text": "Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity.", "type": "CHEMICAL", "entities": [ "Naphtho[1,2-b]furan-4,5-dione", "NFD" ], "offsets": [ [ 0, 29 ], [ 31, 34 ] ] }, { "pmid": "23064031", "text": "We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion.", "type": "CHEMICAL", "entities": [ "NFD" ], "offsets": [ [ 84, 87 ] ] }, { "pmid": "23064031", "text": "NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity.", "type": "CHEMICAL", "entities": [ "NFD" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23064031", "text": "NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt.", "type": "CHEMICAL", "entities": [ "NFD", "phosphatidylinositol" ], "offsets": [ [ 0, 3 ], [ 69, 89 ] ] }, { "pmid": "23064031", "text": "The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion.", "type": "CHEMICAL", "entities": [ "wortmannin" ], "offsets": [ [ 29, 39 ] ] }, { "pmid": "23064031", "text": "Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/", "type": "CHEMICAL", "entities": [ "AG1478" ], "offsets": [ [ 32, 38 ] ] }, { "pmid": "23064031", "text": "These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/", "type": "CHEMICAL", "entities": [ "NFD" ], "offsets": [ [ 28, 31 ] ] }, { "pmid": "23064031", "text": "These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells.", "type": "CHEMICAL", "entities": [ "NFD" ], "offsets": [ [ 63, 66 ] ] }, { "pmid": "23066090", "text": "Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP.", "type": "CHEMICAL", "entities": [ "cAMP", "cAMP", "cAMP" ], "offsets": [ [ 183, 187 ], [ 39, 43 ], [ 55, 59 ] ] }, { "pmid": "23066090", "text": "Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells.", "type": "CHEMICAL", "entities": [ "3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile", "ESI-09", "nucleotide" ], "offsets": [ [ 61, 143 ], [ 145, 151 ], [ 172, 182 ] ] }, { "pmid": "23066988", "text": "Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells.\n", "type": "CHEMICAL", "entities": [ "Metformin", "AMP" ], "offsets": [ [ 0, 9 ], [ 54, 57 ] ] }, { "pmid": "23066988", "text": "The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals.", "type": "CHEMICAL", "entities": [ "Metformin" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "23066988", "text": "Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin.", "type": "CHEMICAL", "entities": [ "Metformin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23066988", "text": "To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined.", "type": "CHEMICAL", "entities": [ "Metformin", "Metformin", "adenosine monophosphate" ], "offsets": [ [ 16, 25 ], [ 102, 111 ], [ 194, 217 ] ] }, { "pmid": "23066988", "text": "Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion.", "type": "CHEMICAL", "entities": [ "Metformin", "compound C", "5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide", "AICAR" ], "offsets": [ [ 0, 9 ], [ 158, 168 ], [ 202, 253 ], [ 255, 260 ] ] }, { "pmid": "23066988", "text": "Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK.", "type": "CHEMICAL", "entities": [ "Metformin" ], "offsets": [ [ 8, 17 ] ] }, { "pmid": "23066988", "text": "Our results show that Metformin directly inhibits stomach ghrelin production and secretion through AMPK.", "type": "CHEMICAL", "entities": [ "Metformin" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "23066988", "text": "This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss.", "type": "CHEMICAL", "entities": [ "Metformin" ], "offsets": [ [ 71, 80 ] ] }, { "pmid": "23081912", "text": "Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway.\n", "type": "CHEMICAL", "entities": [ "prochloraz", "arylhydrocarbon", "dioxin" ], "offsets": [ [ 10, 20 ], [ 127, 142 ], [ 49, 55 ] ] }, { "pmid": "23081912", "text": "The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood.", "type": "CHEMICAL", "entities": [ "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD", "imidazole", "prochloraz" ], "offsets": [ [ 69, 104 ], [ 106, 110 ], [ 127, 136 ], [ 147, 157 ] ] }, { "pmid": "23081912", "text": "Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed \"dioxin response elements\" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland.", "type": "CHEMICAL", "entities": [ "dioxin", "aryl hydrocarbon" ], "offsets": [ [ 110, 116 ], [ 56, 72 ] ] }, { "pmid": "23081912", "text": "As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells.", "type": "CHEMICAL", "entities": [ "TCDD", "prochloraz" ], "offsets": [ [ 88, 92 ], [ 97, 107 ] ] }, { "pmid": "23081912", "text": "TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion.", "type": "CHEMICAL", "entities": [ "TCDD", "prochloraz", "Hoechst H33342" ], "offsets": [ [ 0, 4 ], [ 8, 18 ], [ 42, 56 ] ] }, { "pmid": "23081912", "text": "This effect was almost completely reversed by specific ABCG2 inhibitor Ko143.", "type": "CHEMICAL", "entities": [ "Ko143" ], "offsets": [ [ 71, 76 ] ] }, { "pmid": "23081912", "text": "Receptor binding was significantly reduced by specific AhR antagonist salicyl amide.", "type": "CHEMICAL", "entities": [ "salicyl amide" ], "offsets": [ [ 70, 83 ] ] }, { "pmid": "23081912", "text": "Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels.", "type": "CHEMICAL", "entities": [ "TCDD", "prochloraz" ], "offsets": [ [ 20, 24 ], [ 29, 39 ] ] }, { "pmid": "23081912", "text": "Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products.", "type": "CHEMICAL", "entities": [ "prochloraz", "dioxin" ], "offsets": [ [ 76, 86 ], [ 91, 97 ] ] }, { "pmid": "23085295", "text": "Furthermore, antibodies to DNA show localized binding to these microstructures, which also react positively with DNA intercalating stains propidium iodide (PI) and 4',6'-diamidino-2-phenylindole dihydrochloride (DAPI).", "type": "CHEMICAL", "entities": [ "propidium iodide", "4',6'-diamidino-2-phenylindole dihydrochloride", "DAPI" ], "offsets": [ [ 138, 154 ], [ 164, 210 ], [ 212, 216 ] ] }, { "pmid": "23086748", "text": "Effects of silver nanoparticles on the liver and hepatocytes in vitro.\n", "type": "CHEMICAL", "entities": [ "silver" ], "offsets": [ [ 11, 17 ] ] }, { "pmid": "23086748", "text": "Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments.", "type": "CHEMICAL", "entities": [ "Silver", "Ag" ], "offsets": [ [ 0, 6 ], [ 8, 10 ] ] }, { "pmid": "23086748", "text": "Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of Ag NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that Ag NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release.", "type": "CHEMICAL", "entities": [ "Ag", "lactate", "Ag" ], "offsets": [ [ 504, 506 ], [ 556, 563 ], [ 250, 252 ] ] }, { "pmid": "23086748", "text": "At sublethal concentrations with normal cell or tissue morphology, Ag NPs were detected in cytoplasm and nuclei of hepatocytes.", "type": "CHEMICAL", "entities": [ "Ag" ], "offsets": [ [ 65, 67 ] ] }, { "pmid": "23086748", "text": "We observed similar effects of Ag NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro.", "type": "CHEMICAL", "entities": [ "Ag" ], "offsets": [ [ 29, 31 ] ] }, { "pmid": "23086748", "text": "This article presents evidence of the potential toxicity and inflammogenic potential of Ag NPs in the liver following ingestion.", "type": "CHEMICAL", "entities": [ "Ag" ], "offsets": [ [ 85, 87 ] ] }, { "pmid": "23087260", "text": "Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor.\n", "type": "CHEMICAL", "entities": [ "GTP", "prostaglandin" ], "offsets": [ [ 32, 35 ], [ 55, 68 ] ] }, { "pmid": "23087260", "text": "Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2))", "type": "CHEMICAL", "entities": [ "PGE(2)", "prostaglandin E(2)" ], "offsets": [ [ 76, 82 ], [ 56, 74 ] ] }, { "pmid": "23087260", "text": "E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS).", "type": "CHEMICAL", "entities": [ "E-prostanoid", "guanosine 5[prime]-O-(3-thio)triphosphate", "GTPγS" ], "offsets": [ [ 0, 12 ], [ 102, 143 ], [ 145, 150 ] ] }, { "pmid": "23087260", "text": "We report the identification of mutations that confer GTPγS sensitivity to agonist binding.", "type": "CHEMICAL", "entities": [ "GTPγS" ], "offsets": [ [ 53, 58 ] ] }, { "pmid": "23087260", "text": "Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding.", "type": "CHEMICAL", "entities": [ "GTP" ], "offsets": [ [ 137, 140 ] ] }, { "pmid": "23087260", "text": "Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP.", "type": "CHEMICAL", "entities": [ "[(3)H]PGE(2)", "GTP", "GTP" ], "offsets": [ [ 186, 198 ], [ 255, 258 ], [ 131, 134 ] ] }, { "pmid": "23087260", "text": "The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM).", "type": "CHEMICAL", "entities": [ "[(3)H]PGE(2)", "GTPγS" ], "offsets": [ [ 2, 14 ], [ 95, 100 ] ] }, { "pmid": "23087260", "text": "Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding.", "type": "CHEMICAL", "entities": [ "GTP", "GTP" ], "offsets": [ [ 63, 66 ], [ 116, 119 ] ] }, { "pmid": "23087260", "text": "This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 136, 146 ] ] }, { "pmid": "23091169", "text": "Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo.", "type": "CHEMICAL", "entities": [ "phenobarbital" ], "offsets": [ [ 112, 125 ] ] }, { "pmid": "23091169", "text": "PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs.", "type": "CHEMICAL", "entities": [ "glutamine" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "23091169", "text": "The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways.", "type": "CHEMICAL", "entities": [ "androstane" ], "offsets": [ [ 129, 139 ] ] }, { "pmid": "23092877", "text": "In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone.", "type": "CHEMICAL", "entities": [ "steroid", "nandrolone" ], "offsets": [ [ 120, 127 ], [ 128, 138 ] ] }, { "pmid": "23092877", "text": "Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for 10 consecutive days.", "type": "CHEMICAL", "entities": [ "nandrolone decanoate" ], "offsets": [ [ 26, 46 ] ] }, { "pmid": "23092877", "text": "In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals.", "type": "CHEMICAL", "entities": [ "nandrolone" ], "offsets": [ [ 124, 134 ] ] }, { "pmid": "23092877", "text": "In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration.", "type": "CHEMICAL", "entities": [ "nandrolone" ], "offsets": [ [ 34, 44 ] ] }, { "pmid": "23092877", "text": "In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 120, 127 ] ] }, { "pmid": "23093023", "text": "Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days.", "type": "CHEMICAL", "entities": [ "O(2)", "CO(2)", "O(2)", "CO(2)" ], "offsets": [ [ 76, 80 ], [ 84, 89 ], [ 97, 101 ], [ 105, 110 ] ] }, { "pmid": "23093023", "text": "Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012", "type": "CHEMICAL", "entities": [ "OSU-03012" ], "offsets": [ [ 85, 94 ] ] }, { "pmid": "23097088", "text": "Interestingly, ICAM2 was found to associate with β1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 98, 106 ] ] }, { "pmid": "23097088", "text": "Following CdCl₂ treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ICAM2 by 6-16 h. Interestingly, there was a loss in the binding of ICAM2 to actin during CdCl₂-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring.", "type": "CHEMICAL", "entities": [ "CdCl₂", "CdCl₂" ], "offsets": [ [ 265, 270 ], [ 9, 14 ] ] }, { "pmid": "23098818", "text": "The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study.\n", "type": "CHEMICAL", "entities": [ "serotonin", "5-methoxytryptamine" ], "offsets": [ [ 64, 73 ], [ 79, 98 ] ] }, { "pmid": "23098818", "text": "Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 6, 15 ] ] }, { "pmid": "23098818", "text": "The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain.", "type": "CHEMICAL", "entities": [ "serotonin", "serotonin", "O", "5-methoxytryptamine" ], "offsets": [ [ 141, 150 ], [ 204, 213 ], [ 99, 100 ], [ 118, 137 ] ] }, { "pmid": "23098818", "text": "Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6.", "type": "CHEMICAL", "entities": [ "O", "5-methoxytryptamine", "serotonin" ], "offsets": [ [ 90, 91 ], [ 109, 128 ], [ 132, 141 ] ] }, { "pmid": "23098818", "text": "Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin.", "type": "CHEMICAL", "entities": [ "5-methoxytryptamine", "serotonin" ], "offsets": [ [ 69, 88 ], [ 92, 101 ] ] }, { "pmid": "23098818", "text": "The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine.", "type": "CHEMICAL", "entities": [ "quinine", "fluoxetine" ], "offsets": [ [ 60, 67 ], [ 72, 82 ] ] }, { "pmid": "23098818", "text": "Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones.", "type": "CHEMICAL", "entities": [ "5-methoxytryptamine", "serotonin" ], "offsets": [ [ 59, 78 ], [ 82, 91 ] ] }, { "pmid": "23098818", "text": "The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain.", "type": "CHEMICAL", "entities": [ "serotonin", "5-methoxytryptamine", "serotonin" ], "offsets": [ [ 86, 95 ], [ 101, 120 ], [ 181, 190 ] ] }, { "pmid": "23103568", "text": "Estrogen receptor signaling as a target for novel breast cancer therapeutics.\n", "type": "CHEMICAL", "entities": [ "Estrogen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23103568", "text": "In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors.", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 64, 73 ] ] }, { "pmid": "23103568", "text": "Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC.", "type": "CHEMICAL", "entities": [ "estrogens", "estrogen" ], "offsets": [ [ 3, 12 ], [ 84, 92 ] ] }, { "pmid": "23103568", "text": "In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors.", "type": "CHEMICAL", "entities": [ "lapatinib" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "23103568", "text": "These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 4, 12 ] ] }, { "pmid": "23103568", "text": "The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "23103568", "text": "These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 167, 175 ] ] }, { "pmid": "23111283", "text": "Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells.\n", "type": "CHEMICAL", "entities": [ "Toosendanin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23111283", "text": "Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb.", "type": "CHEMICAL", "entities": [ "Toosendanin", "TSN", "triterpenoid" ], "offsets": [ [ 0, 11 ], [ 13, 16 ], [ 21, 33 ] ] }, { "pmid": "23111283", "text": "However, the mechanism how TSN induces apoptosis remains poorly understood.", "type": "CHEMICAL", "entities": [ "TSN" ], "offsets": [ [ 27, 30 ] ] }, { "pmid": "23111283", "text": "In this study, we examined the effects of TSN on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells.", "type": "CHEMICAL", "entities": [ "TSN" ], "offsets": [ [ 42, 45 ] ] }, { "pmid": "23111283", "text": "Cell apoptosis induced by TSN was confirmed by Annexin V-FITC/propidium iodide staining.", "type": "CHEMICAL", "entities": [ "TSN", "FITC", "propidium iodide" ], "offsets": [ [ 26, 29 ], [ 57, 61 ], [ 62, 78 ] ] }, { "pmid": "23111283", "text": "Western blot analysis indicated that TSN inhibits the CDC42/MEKK1/JNK pathway.", "type": "CHEMICAL", "entities": [ "TSN" ], "offsets": [ [ 37, 40 ] ] }, { "pmid": "23111283", "text": "Taken together, our study suggested, for the first time, that the pro-apoptotic effects of TSN on HL-60 cells were mediated through JNK signaling pathway.", "type": "CHEMICAL", "entities": [ "TSN" ], "offsets": [ [ 91, 94 ] ] }, { "pmid": "23115221", "text": "Novel insights on the effect of nicotine in a murine colitis model.\n", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 32, 40 ] ] }, { "pmid": "23115221", "text": "Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 20, 28 ] ] }, { "pmid": "23115221", "text": "In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model.", "type": "CHEMICAL", "entities": [ "nicotine", "sodium sulfate" ], "offsets": [ [ 48, 56 ], [ 123, 137 ] ] }, { "pmid": "23115221", "text": "We also investigated the effects of cotinine, a major metabolite of nicotine, in the model.", "type": "CHEMICAL", "entities": [ "nicotine", "cotinine" ], "offsets": [ [ 68, 76 ], [ 36, 44 ] ] }, { "pmid": "23115221", "text": "The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model.", "type": "CHEMICAL", "entities": [ "nicotine", "cotinine" ], "offsets": [ [ 13, 21 ], [ 26, 34 ] ] }, { "pmid": "23115221", "text": "In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols.", "type": "CHEMICAL", "entities": [ "nicotine", "cotinine" ], "offsets": [ [ 45, 53 ], [ 58, 66 ] ] }, { "pmid": "23115221", "text": "Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-α.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23115221", "text": "However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 39, 47 ] ] }, { "pmid": "23115221", "text": "Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect.", "type": "CHEMICAL", "entities": [ "nicotine", "cotinine" ], "offsets": [ [ 30, 38 ], [ 43, 51 ] ] }, { "pmid": "23115221", "text": "Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis.", "type": "CHEMICAL", "entities": [ "cotinine" ], "offsets": [ [ 12, 20 ] ] }, { "pmid": "23115221", "text": "These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "23117207", "text": "Keap1 is expressed in differentiating osteoclast-like cells and the S349T mutation selectively impairs the SQSTM1-Keap1 interaction in co-immunoprecipitations, which molecular modelling indicates results from effects on critical hydrogen bonds required to stabilise the KIR-Keap1 complex.", "type": "CHEMICAL", "entities": [ "hydrogen" ], "offsets": [ [ 227, 235 ] ] }, { "pmid": "23117790", "text": "Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "23117790", "text": "Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 12, 19 ], [ 210, 217 ] ] }, { "pmid": "23117790", "text": "We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 58, 65 ] ] }, { "pmid": "23117790", "text": "Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus.", "type": "CHEMICAL", "entities": [ "SB334867", "N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea" ], "offsets": [ [ 51, 59 ], [ 61, 118 ] ] }, { "pmid": "23117790", "text": "Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 143, 150 ] ] }, { "pmid": "23117790", "text": "The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown.", "type": "CHEMICAL", "entities": [ "SB334867" ], "offsets": [ [ 206, 214 ] ] }, { "pmid": "23117790", "text": "These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 55, 62 ] ] }, { "pmid": "23146664", "text": "Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.\n", "type": "CHEMICAL", "entities": [ "Mesalamine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23146664", "text": "Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon.", "type": "CHEMICAL", "entities": [ "Mesalamine", "5-ASA" ], "offsets": [ [ 0, 10 ], [ 12, 17 ] ] }, { "pmid": "23146664", "text": "Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 54, 59 ] ] }, { "pmid": "23146664", "text": "We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 55, 60 ] ] }, { "pmid": "23146664", "text": "Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29).", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 56, 61 ] ] }, { "pmid": "23146664", "text": "Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 81, 86 ] ] }, { "pmid": "23146664", "text": "PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 37, 42 ] ] }, { "pmid": "23146664", "text": "We further investigated the effect of 5-ASA on cell adhesion.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 37, 42 ] ] }, { "pmid": "23146664", "text": "Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 9, 14 ] ] }, { "pmid": "23146664", "text": "PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 50, 55 ] ] }, { "pmid": "23146664", "text": "Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis.", "type": "CHEMICAL", "entities": [ "mesalamine" ], "offsets": [ [ 55, 65 ] ] }, { "pmid": "23146664", "text": "We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 47, 52 ] ] }, { "pmid": "23146664", "text": "The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action.", "type": "CHEMICAL", "entities": [ "5-ASA" ], "offsets": [ [ 97, 102 ] ] }, { "pmid": "23146761", "text": "Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2.\n", "type": "CHEMICAL", "entities": [ "epigallocatechin gallate" ], "offsets": [ [ 22, 46 ] ] }, { "pmid": "23146761", "text": "Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported.", "type": "CHEMICAL", "entities": [ "EGCG", "Epigallocatechin gallate" ], "offsets": [ [ 26, 30 ], [ 0, 24 ] ] }, { "pmid": "23146761", "text": "Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats.", "type": "CHEMICAL", "entities": [ "EGCG", "bile acid" ], "offsets": [ [ 115, 119 ], [ 137, 146 ] ] }, { "pmid": "23146761", "text": "Compared to controls, EGCG treatment decreased bile flow by 23%.", "type": "CHEMICAL", "entities": [ "EGCG" ], "offsets": [ [ 22, 26 ] ] }, { "pmid": "23146761", "text": "Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%.", "type": "CHEMICAL", "entities": [ "bile acid", "EGCG", "glutathione" ], "offsets": [ [ 46, 55 ], [ 86, 90 ], [ 119, 130 ] ] }, { "pmid": "23146761", "text": "Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "23146761", "text": "EGCG administration also doubled plasma bile acid levels compared to controls.", "type": "CHEMICAL", "entities": [ "EGCG", "bile acid" ], "offsets": [ [ 0, 4 ], [ 40, 49 ] ] }, { "pmid": "23146761", "text": "While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG.", "type": "CHEMICAL", "entities": [ "bile acid", "bile acid", "EGCG" ], "offsets": [ [ 41, 50 ], [ 112, 121 ], [ 172, 176 ] ] }, { "pmid": "23146761", "text": "Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one.", "type": "CHEMICAL", "entities": [ "bile acid", "7α-hydroxy-4-cholesten-3-one" ], "offsets": [ [ 9, 18 ], [ 103, 131 ] ] }, { "pmid": "23146761", "text": "In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum.", "type": "CHEMICAL", "entities": [ "EGCG", "bile acid" ], "offsets": [ [ 12, 16 ], [ 46, 55 ] ] }, { "pmid": "23146761", "text": "When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis.", "type": "CHEMICAL", "entities": [ "EGCG", "ethinylestradiol" ], "offsets": [ [ 3, 7 ], [ 32, 48 ] ] }, { "pmid": "23146761", "text": "This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow.", "type": "CHEMICAL", "entities": [ "bile acid", "EGCG", "bile acid" ], "offsets": [ [ 176, 185 ], [ 26, 30 ], [ 47, 56 ] ] }, { "pmid": "23146761", "text": "In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis.", "type": "CHEMICAL", "entities": [ "EGCG" ], "offsets": [ [ 64, 68 ] ] }, { "pmid": "23147987", "text": "Effects-based marine ecological risk assessment at a polychlorinated biphenyl-contaminated site in Saglek, Labrador, Canada.\n", "type": "CHEMICAL", "entities": [ "polychlorinated biphenyl" ], "offsets": [ [ 53, 77 ] ] }, { "pmid": "23147987", "text": "Although the presence and distribution of polychlorinated biphenyls (PCBs) in Arctic marine environments has been well documented, the implications for the health of biota are poorly understood.", "type": "CHEMICAL", "entities": [ "polychlorinated biphenyls", "PCBs" ], "offsets": [ [ 42, 67 ], [ 69, 73 ] ] }, { "pmid": "23147987", "text": "In the present study, multiple lines of evidence, including site-specific effects data, were used to assess PCB-related risks to marine biota at a contaminated military site in Saglek Bay, Labrador, Canada, from 1997 to 1999.", "type": "CHEMICAL", "entities": [ "PCB" ], "offsets": [ [ 108, 111 ] ] }, { "pmid": "23147987", "text": "Average sediment PCB concentrations exceeded the Canadian interim sediment quality guideline level by 41-fold.", "type": "CHEMICAL", "entities": [ "PCB" ], "offsets": [ [ 17, 20 ] ] }, { "pmid": "23147987", "text": "In contrast, shorthorn sculpin and black guillemot PCB exposures (measured as sum of 55 congeners) were elevated enough to pose risks to survival or reproduction.", "type": "CHEMICAL", "entities": [ "PCB" ], "offsets": [ [ 51, 54 ] ] }, { "pmid": "23147987", "text": "Based on the collective evidence, the authors estimated that risks were posed by sediment PCB concentrations greater than 77 ng/g dry weight for black guillemots and 750 ng/g dry weight for shorthorn sculpins.", "type": "CHEMICAL", "entities": [ "PCB" ], "offsets": [ [ 90, 93 ] ] }, { "pmid": "23147987", "text": "This ecological risk assessment describes the steps and rationale taken to evaluate the risk posed by an area of PCB-contaminated marine sediments in an otherwise relatively pristine northern coastal environment.", "type": "CHEMICAL", "entities": [ "PCB" ], "offsets": [ [ 109, 112 ] ] }, { "pmid": "23150495", "text": "Consistent with an adult-onset isolated GHD model, mutant animals are hypoglycemic and display increased insulin sensitivity and glucose clearance.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 129, 136 ] ] }, { "pmid": "23150495", "text": "This latter phenotype is in contrast to the glucose intolerance observed in another early-onset GHD model.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "23150495", "text": "Surprisingly, increased insulin sensitivity is not accompanied by a modified balance between fat and lean tissues, but by reduced metabolic adaptability between glucose and lipid oxidation conditions.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 161, 168 ] ] }, { "pmid": "23150495", "text": "In conclusion, our mutant may be a valuable genetic model with which to study the effects of long-term GH deficiency, in conditions of normal pancreatic function and unaffected balance between fat and glucose metabolism.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 201, 208 ] ] }, { "pmid": "23155201", "text": "Scintigraphic images were obtained at 5th min (blood pool or early phase) and starting at 3 h (late phase) after (after tracer injection) intravenous administration of technetium-99m (99mTc)-methylendiphosphonate (MDP).", "type": "CHEMICAL", "entities": [ "technetium-99m", "99mTc", "methylendiphosphonate", "MDP" ], "offsets": [ [ 167, 181 ], [ 183, 188 ], [ 190, 211 ], [ 213, 216 ] ] }, { "pmid": "23157629", "text": "Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology.\n", "type": "CHEMICAL", "entities": [ "Serotonin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23157629", "text": "The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop.", "type": "CHEMICAL", "entities": [ "5-HT", "C", "serotonin", "5-HT" ], "offsets": [ [ 15, 19 ], [ 160, 161 ], [ 4, 13 ], [ 84, 88 ] ] }, { "pmid": "23157629", "text": "A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution.", "type": "CHEMICAL", "entities": [ "catecholamines" ], "offsets": [ [ 103, 117 ] ] }, { "pmid": "23159887", "text": "Expression of cAMP-responsive element binding proteins (CREBs) in fast- and slow-twitch muscles: A signaling pathway to account for the synaptic expression of collagen-tailed subunit (ColQ) of acetylcholinesterase at the rat neuromuscular junction.\n", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 14, 18 ] ] }, { "pmid": "23159887", "text": "is expressed at the neuromuscular junction (NMJ) in fast-twitch muscle, and this expression depends on trophic factors supplied by motor neurons signaling via a cAMP-dependent pathway in muscle.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 161, 165 ] ] }, { "pmid": "23159887", "text": "To further elucidate the molecular basis of ColQ-1a's synaptic expression, here we investigated the expression and localization of cAMP-responsive element binding protein (CREB) at the synaptic and extra-synaptic regions of fast- and slow-twitch muscles from adult rats.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 131, 135 ] ] }, { "pmid": "23159887", "text": "These results reveal, for the first time, the differential distribution of P-CREB in fast- and slow-twitch muscles, which might support the crucial role of cAMP-dependent signaling in controlling the synapse-specific expression of ColQ-1a in fast-twitch muscles.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 156, 160 ] ] }, { "pmid": "23159888", "text": "Analysis of mammalian alcohol dehydrogenase 5 (ADH5): characterisation of rat ADH5 with comparisons to the corresponding human variant.\n", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 22, 29 ] ] }, { "pmid": "23159888", "text": "Alcohol dehydrogenase 5 (ADH5) is a member of the mammalian alcohol dehydrogenase family of yet undefined functions.", "type": "CHEMICAL", "entities": [ "Alcohol", "alcohol" ], "offsets": [ [ 0, 7 ], [ 60, 67 ] ] }, { "pmid": "23159888", "text": "A rat alcohol dehydrogenase structure of similar type has been isolated at the cDNA level using human ADH5 as a screening probe, where the rat cDNA structure displayed several atypical properties.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 6, 13 ] ] }, { "pmid": "23159888", "text": "However, no soluble ADH5 protein could be heterologously expressed in Escherichia coli cells with expression systems successfully used for other mammalian ADHs, including fused to glutathione-S-transferase.", "type": "CHEMICAL", "entities": [ "glutathione", "S" ], "offsets": [ [ 180, 191 ], [ 192, 193 ] ] }, { "pmid": "23161844", "text": "SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 259, 268 ] ] }, { "pmid": "23164921", "text": "Catalpol inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures.\n", "type": "CHEMICAL", "entities": [ "Catalpol" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23164921", "text": "Our previous studies described the neuroprotective effects of catalpol in lipopolysaccharide (LPS)-induced inflammatory models, in which catalpol was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals.", "type": "CHEMICAL", "entities": [ "catalpol", "catalpol" ], "offsets": [ [ 61, 69 ], [ 136, 144 ] ] }, { "pmid": "23164921", "text": "To further investigate the protective effect and underlying mechanism of catalpol, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) catalpol for 1h prior to LPS plus interferon-γ stimulation.", "type": "CHEMICAL", "entities": [ "catalpol", "catalpol" ], "offsets": [ [ 72, 80 ], [ 148, 156 ] ] }, { "pmid": "23164921", "text": "Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by catalpol.", "type": "CHEMICAL", "entities": [ "NO", "catalpol" ], "offsets": [ [ 31, 33 ], [ 101, 109 ] ] }, { "pmid": "23164921", "text": "Data at transcriptional level also demonstrated that catalpol potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and TLR4.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23164921", "text": "In addition, our exploration further revealed that the suppressive action of catalpol on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 75, 83 ] ] }, { "pmid": "23164921", "text": "Collectively, these results suggest that catalpol can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 37, 45 ] ] }, { "pmid": "23164921", "text": "Therefore, catalpol may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation.", "type": "CHEMICAL", "entities": [ "catalpol" ], "offsets": [ [ 6, 14 ] ] }, { "pmid": "23172229", "text": "Cardiolipin-dependent reconstitution of respiratory supercomplexes from purified Saccharomyces cerevisiae complexes III and IV.\n", "type": "CHEMICAL", "entities": [ "Cardiolipin" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23172229", "text": "Complex III contained eight molecules of cardiolipin, and complex IV contained two molecules of cardiolipin, as determined by electrospray ionization-mass spectrometry.", "type": "CHEMICAL", "entities": [ "cardiolipin", "cardiolipin" ], "offsets": [ [ 41, 52 ], [ 96, 107 ] ] }, { "pmid": "23172229", "text": "No supercomplexes were formed upon mixing of the purified complexes, and low amounts of the supercomplex trimer III(2)IV(1) were formed after reconstitution into proteoliposomes containing only phosphatidylcholine and phosphatidylethanolamine.", "type": "CHEMICAL", "entities": [ "phosphatidylcholine", "phosphatidylethanolamine" ], "offsets": [ [ 194, 213 ], [ 218, 242 ] ] }, { "pmid": "23172229", "text": "No other anionic phospholipid was as effective as cardiolipin in supporting tetramer formation.", "type": "CHEMICAL", "entities": [ "cardiolipin" ], "offsets": [ [ 50, 61 ] ] }, { "pmid": "23172229", "text": "Phospholipase treatment of complex IV prevented trimer formation in the absence of cardiolipin.", "type": "CHEMICAL", "entities": [ "cardiolipin" ], "offsets": [ [ 83, 94 ] ] }, { "pmid": "23172229", "text": "Both trimer and tetramer formations were restored by cardiolipin.", "type": "CHEMICAL", "entities": [ "cardiolipin" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "23172229", "text": "In conclusion, although some trimer formation occurred dependent only on tightly bound cardiolipin, tetramer formation required additional cardiolipin.", "type": "CHEMICAL", "entities": [ "cardiolipin", "cardiolipin" ], "offsets": [ [ 87, 98 ], [ 139, 150 ] ] }, { "pmid": "23172229", "text": "This is consistent with the high cardiolipin content in the native tetramer.", "type": "CHEMICAL", "entities": [ "cardiolipin" ], "offsets": [ [ 33, 44 ] ] }, { "pmid": "23172229", "text": "The dependence on cardiolipin for supercomplex formation suggests that changes in cardiolipin levels resulting from changes in physiological conditions may control the equilibrium between individual respiratory complexes and supercomplexes in vivo.", "type": "CHEMICAL", "entities": [ "cardiolipin", "cardiolipin" ], "offsets": [ [ 18, 29 ], [ 82, 93 ] ] }, { "pmid": "23177789", "text": "Protein tyrosine phosphatase 1B inhibitory effect by dammarane-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum saponins.\n", "type": "CHEMICAL", "entities": [ "saponins", "dammarane", "triterpenes", "tyrosine" ], "offsets": [ [ 130, 138 ], [ 53, 62 ], [ 68, 79 ], [ 8, 16 ] ] }, { "pmid": "23177789", "text": "Protein tyrosine phosphatase 1B (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 8, 16 ] ] }, { "pmid": "23177789", "text": "Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum.", "type": "CHEMICAL", "entities": [ "triterpenes", "saponins" ], "offsets": [ [ 131, 142 ], [ 193, 201 ] ] }, { "pmid": "23182946", "text": "Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride.\n", "type": "CHEMICAL", "entities": [ "diphenyl ditelluride" ], "offsets": [ [ 125, 145 ] ] }, { "pmid": "23182946", "text": "In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards.", "type": "CHEMICAL", "entities": [ "(PhTe)(2)", "diphenyl ditelluride" ], "offsets": [ [ 89, 98 ], [ 68, 88 ] ] }, { "pmid": "23182946", "text": "The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities.", "type": "CHEMICAL", "entities": [ "cAMP" ], "offsets": [ [ 358, 362 ] ] }, { "pmid": "23182946", "text": "Also, reactive astrogliosis takes part of the early responses to the insult with (PhTe)(2), evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis.", "type": "CHEMICAL", "entities": [ "(PhTe)(2)" ], "offsets": [ [ 80, 89 ] ] }, { "pmid": "23182946", "text": "Six days after (PhTe)(2) injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to (PhTe)(2) progressed to neuronal death.", "type": "CHEMICAL", "entities": [ "(PhTe)(2)", "propidium iodide", "(PhTe)(2)" ], "offsets": [ [ 14, 23 ], [ 78, 94 ], [ 252, 261 ] ] }, { "pmid": "23182946", "text": "Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in (PhTe)(2) injected rat.", "type": "CHEMICAL", "entities": [ "[(3)H]glutamate", "Ser", "(PhTe)(2)" ], "offsets": [ [ 44, 59 ], [ 128, 131 ], [ 153, 162 ] ] }, { "pmid": "23182946", "text": "Therefore, the present results show that the earlier cerebellar responses to (PhTe)(2) include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis.", "type": "CHEMICAL", "entities": [ "(PhTe)(2)" ], "offsets": [ [ 75, 84 ] ] }, { "pmid": "23182946", "text": "The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 203, 212 ] ] }, { "pmid": "23182946", "text": "The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by (PhTe)(2) in rat cerebellum.", "type": "CHEMICAL", "entities": [ "(PhTe)(2)" ], "offsets": [ [ 122, 131 ] ] }, { "pmid": "23194529", "text": "The presence of D-fagomine in the human diet from buckwheat-based foodstuffs.\n", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 16, 26 ] ] }, { "pmid": "23194529", "text": "Buckwheat (Fagopyrum esculentum Moench) groats contain the iminosugar D-fagomine as a minor component that might contribute to the alleged health benefits of this pseudo-cereal.", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "23194529", "text": "This study presents analysis of D-fagomine in buckwheat-based foodstuffs by liquid chromatography coupled to mass spectrometry and an estimation of its presence in the human diet based on a published population-based cross-sectional nutrition survey.", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 32, 42 ] ] }, { "pmid": "23194529", "text": "D-fagomine is present in common buckwheat-based foodstuffs in amounts ranging from 1 to 25 mg/kg or mg/L, it is stable during boiling, baking, frying and fermentation, and it is biosynthesised upon sprouting.", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23194529", "text": "The estimated total intake of D-fagomine resulting from a diet that includes such foodstuffs would be between 3 and 17 mg per day (mean for both genders; range from P5 to P95).", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 30, 40 ] ] }, { "pmid": "23194529", "text": "A diet rich in buckwheat products would provide a daily amount of D-fagomine that may in part explain the beneficial properties traditionally attributed to buckwheat consumption.", "type": "CHEMICAL", "entities": [ "D-fagomine" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "23198810", "text": "Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate.", "type": "CHEMICAL", "entities": [ "naphthalimide", "quinone" ], "offsets": [ [ 112, 125 ], [ 166, 173 ] ] }, { "pmid": "23198810", "text": "Fluorescence of the reporter dye is turned on by rapid removal of the quinone quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted quinone substrate by the cancer-associated human NAD(P)H:quinone oxidoreductase isozyme 1 (hNQO1).", "type": "CHEMICAL", "entities": [ "quinone", "quinone", "quinone" ], "offsets": [ [ 223, 230 ], [ 280, 287 ], [ 70, 77 ] ] }, { "pmid": "23199028", "text": "Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo.\n", "type": "CHEMICAL", "entities": [ "glycyrrhizin" ], "offsets": [ [ 60, 72 ] ] }, { "pmid": "23199028", "text": "Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30.", "type": "CHEMICAL", "entities": [ "carbohydrate", "glycyrrhizin", "amine", "amino acid" ], "offsets": [ [ 127, 139 ], [ 6, 18 ], [ 89, 94 ], [ 98, 108 ] ] }, { "pmid": "23200253", "text": "This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab.", "type": "CHEMICAL", "entities": [ "TBPB", "VU0357017" ], "offsets": [ [ 85, 89 ], [ 94, 103 ] ] }, { "pmid": "23200253", "text": "Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site.", "type": "CHEMICAL", "entities": [ "TPBP", "piperidine" ], "offsets": [ [ 7, 11 ], [ 79, 89 ] ] }, { "pmid": "23200253", "text": "Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism.", "type": "CHEMICAL", "entities": [ "VU0357017" ], "offsets": [ [ 60, 69 ] ] }, { "pmid": "23205514", "text": "Effects of single or repeated silymarin administration on pharmacokinetics of risperidone and its major metabolite, 9-hydroxyrisperidone in rats.\n", "type": "CHEMICAL", "entities": [ "9-hydroxyrisperidone", "risperidone" ], "offsets": [ [ 116, 136 ], [ 78, 89 ] ] }, { "pmid": "23205514", "text": "2. The objective of this article is to examine the effects of single and repeated administrations of silymarin on pharmacokinetics of a P-gp substrate, risperidone, and its major metabolite, 9-hydroxyrisperidone, in rats.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 150, 161 ], [ 189, 209 ] ] }, { "pmid": "23205514", "text": "3. To determine the plasma levels of risperidone and 9-hydroxyrisperidone in rats, a HPLC method was developed using a liquid-liquid acid back extraction.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 33, 44 ], [ 49, 69 ] ] }, { "pmid": "23205514", "text": "When risperidone (6 mg/kg) was co-administered with silymarin (40 mg/kg) to rats orally, the C(max) of 9-hydroxyrisperidone was significantly increased to1.3-fold (p < 0.05), while the other pharmacokinetic parameters did not show any significant differences.", "type": "CHEMICAL", "entities": [ "9-hydroxyrisperidone" ], "offsets": [ [ 97, 117 ] ] }, { "pmid": "23205514", "text": "Expanding the experiment where rats were repeatedly administered with silymarin for 5 days prior to giving risperidone, the C(max) of risperidone and 9-hydroxyrisperidone were significantly increased to 2.4-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively, and the AUC(0-t), as well to 1.7-fold (p < 0.05) and 2.1-fold (p < 0.01), respectively.", "type": "CHEMICAL", "entities": [ "risperidone", "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 97, 108 ], [ 124, 135 ], [ 140, 160 ] ] }, { "pmid": "23205514", "text": "4. The repeated exposures of silymarin, compared to single administration of silymarin, increased oral bioavailability and affected the pharmacokinetics of risperidone and 9-hydroxyrisperidone, by inhibiting P-gp.", "type": "CHEMICAL", "entities": [ "risperidone", "9-hydroxyrisperidone" ], "offsets": [ [ 146, 157 ], [ 162, 182 ] ] }, { "pmid": "23205571", "text": "Design, synthesis and structure-activity relationship of new arginine vasopressin analogues containing proline derivatives in position 2.\n", "type": "CHEMICAL", "entities": [ "proline", "arginine vasopressin" ], "offsets": [ [ 103, 110 ], [ 61, 81 ] ] }, { "pmid": "23205571", "text": "In this study, we present the synthesis and pharmacological properties of new analogues of arginine vasopressin modified in the N-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid.", "type": "CHEMICAL", "entities": [ "arginine vasopressin", "N", "proline", "indoline-2-carboxylic acid", "Ica", "(2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid" ], "offsets": [ [ 91, 111 ], [ 128, 129 ], [ 165, 172 ], [ 186, 212 ], [ 214, 217 ], [ 223, 286 ] ] }, { "pmid": "23205571", "text": "We also determined their binding affinity to the human oxytocin receptor.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 55, 63 ] ] }, { "pmid": "23205571", "text": "The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and", "type": "CHEMICAL", "entities": [ "Ica", "[Mpa(1), Ica(2), D-Arg(8)]VP" ], "offsets": [ [ 4, 7 ], [ 93, 121 ] ] }, { "pmid": "23205571", "text": "[Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively).", "type": "CHEMICAL", "entities": [ "[Mpa(1),Ica(2),Val(4),D-Arg(8)]VP" ], "offsets": [ [ 0, 33 ] ] }, { "pmid": "23205571", "text": "On the other hand, peptides modified with (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to arginine vasopressin.", "type": "CHEMICAL", "entities": [ "(2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid", "arginine vasopressin" ], "offsets": [ [ 42, 105 ], [ 217, 237 ] ] }, { "pmid": "23205571", "text": "The results of this study provide useful information about the structure-activity relationship of arginine vasopressin analogues and can help to design compounds with desired biological properties.", "type": "CHEMICAL", "entities": [ "arginine vasopressin" ], "offsets": [ [ 98, 118 ] ] }, { "pmid": "23211426", "text": "Liver X Receptors and female reproduction: when cholesterol meets fertility!\n", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 48, 59 ] ] }, { "pmid": "23211426", "text": "The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 12, 23 ] ] }, { "pmid": "23211426", "text": "Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility.", "type": "CHEMICAL", "entities": [ "Cholesterol", "steroid" ], "offsets": [ [ 0, 11 ], [ 40, 47 ] ] }, { "pmid": "23211426", "text": "In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol" ], "offsets": [ [ 15, 26 ], [ 106, 117 ] ] }, { "pmid": "23211426", "text": "Liver X Receptor (LXR) α and LXR β are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol.", "type": "CHEMICAL", "entities": [ "oxysterols", "cholesterol" ], "offsets": [ [ 70, 80 ], [ 106, 117 ] ] }, { "pmid": "23211426", "text": "Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 55, 66 ] ] }, { "pmid": "23211426", "text": "Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 11, 22 ] ] }, { "pmid": "23211426", "text": "This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 79, 90 ] ] }, { "pmid": "23211523", "text": "β-catenin regulates GnRH-induced FSHβ gene expression.\n", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 20, 24 ] ] }, { "pmid": "23211523", "text": "The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 42, 46 ] ] }, { "pmid": "23211523", "text": "For example, involvement of β-catenin in LHβ induction by GnRH has been discovered.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 56, 60 ] ] }, { "pmid": "23211523", "text": "We examined the role of β-catenin in FSHβ gene expression in LβT2 gonadotrope cells.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 81, 85 ] ] }, { "pmid": "23211523", "text": "GnRH caused a sustained increase in nuclear β-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 96, 97 ] ] }, { "pmid": "23211523", "text": "Small interfering RNA-mediated knockdown of β-catenin mRNA demonstrated that induction of FSHβ mRNA by GnRH depended on β-catenin and that regulation of FSHβ by β-catenin occurred independently of the JNK-c-jun pathway.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 95, 99 ] ] }, { "pmid": "23211523", "text": "In LβT2 cells transfected with FSHβ promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by β-catenin knockdown.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 60, 64 ] ] }, { "pmid": "23211523", "text": "However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 112, 116 ] ] }, { "pmid": "23211523", "text": "Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSHβ expression.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 35, 39 ] ] }, { "pmid": "23211523", "text": "Thus, our findings indicate that the expression of Brms1L depends on β-catenin activity and contributes to FSHβ induction by GnRH.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 101, 105 ] ] }, { "pmid": "23220037", "text": "Doxorubicin decreases paraquat accumulation and toxicity in Caco-2 cells.\n", "type": "CHEMICAL", "entities": [ "Doxorubicin", "paraquat" ], "offsets": [ [ 0, 11 ], [ 22, 30 ] ] }, { "pmid": "23220037", "text": "P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 57, 60 ] ] }, { "pmid": "23220037", "text": "The herbicide paraquat (PQ) is a P-gp substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote.", "type": "CHEMICAL", "entities": [ "paraquat" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "23220037", "text": "The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known P-gp inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario.", "type": "CHEMICAL", "entities": [ "doxorubicin", "DOX" ], "offsets": [ [ 101, 112 ], [ 114, 117 ] ] }, { "pmid": "23220037", "text": "Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS).", "type": "CHEMICAL", "entities": [ "MTT" ], "offsets": [ [ 34, 37 ] ] }, { "pmid": "23220037", "text": "Also, the DOX modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline.", "type": "CHEMICAL", "entities": [ "DOX", "choline", "[³H]-choline" ], "offsets": [ [ 10, 13 ], [ 35, 42 ], [ 107, 119 ] ] }, { "pmid": "23220037", "text": "The results show that DOX exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide.", "type": "CHEMICAL", "entities": [ "DOX" ], "offsets": [ [ 21, 24 ] ] }, { "pmid": "23220037", "text": "In fact, DOX also efficiently inhibited the choline transport system that influences PQ cellular uptake.", "type": "CHEMICAL", "entities": [ "DOX", "choline" ], "offsets": [ [ 8, 11 ], [ 43, 50 ] ] }, { "pmid": "23220037", "text": "In conclusion, in this cellular model, DOX effectively protects against PQ toxicity by inducing P-gp and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications.", "type": "CHEMICAL", "entities": [ "DOX", "choline" ], "offsets": [ [ 38, 41 ], [ 137, 144 ] ] }, { "pmid": "23220641", "text": "Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of NAD(+)-dependent protein N(ε)-acetyl-lysine (AcK) deacetylases.", "type": "CHEMICAL", "entities": [ "AcK", "NAD(+)", "N(ε)-acetyl-lysine" ], "offsets": [ [ 119, 122 ], [ 74, 80 ], [ 99, 117 ] ] }, { "pmid": "23220742", "text": "The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia.\n", "type": "CHEMICAL", "entities": [ "P505-15", "PRT062607", "fludarabine" ], "offsets": [ [ 28, 35 ], [ 37, 46 ], [ 137, 148 ] ] }, { "pmid": "23220742", "text": "B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 58, 66 ] ] }, { "pmid": "23220742", "text": "P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50)", "type": "CHEMICAL", "entities": [ "P505-15", "PRT062607" ], "offsets": [ [ 0, 7 ], [ 23, 32 ] ] }, { "pmid": "23220742", "text": "We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL.", "type": "CHEMICAL", "entities": [ "P505-15" ], "offsets": [ [ 48, 55 ] ] }, { "pmid": "23220742", "text": "P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL.", "type": "CHEMICAL", "entities": [ "P505-15" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23220742", "text": "In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations.", "type": "CHEMICAL", "entities": [ "P505-15", "fludarabine" ], "offsets": [ [ 61, 68 ], [ 74, 85 ] ] }, { "pmid": "23220742", "text": "Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies.", "type": "CHEMICAL", "entities": [ "P505-15" ], "offsets": [ [ 48, 55 ] ] }, { "pmid": "23223234", "text": "The fidelity of RNA synthesis depends on both accurate template-mediated nucleotide selection and proper maintenance of register between template and RNA.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 73, 83 ] ] }, { "pmid": "23223234", "text": "Alleles of RPB1 (RPO21) with elevated slippage rates were identified among 6-azauracil-sensitive mutants and were also isolated using a slippage-dependent reporter gene.", "type": "CHEMICAL", "entities": [ "6-azauracil" ], "offsets": [ [ 75, 86 ] ] }, { "pmid": "23223414", "text": "Effect of nuclear vibrations, temperature, co-adsorbed water, and dye orientation on light absorption, charge injection and recombination conditions in organic dyes on TiO2.\n", "type": "CHEMICAL", "entities": [ "TiO2" ], "offsets": [ [ 168, 172 ] ] }, { "pmid": "23223414", "text": "We study the effect of nuclear motions at different temperatures, including the effect of a dye molecule's orientation with respect to the oxide surface, on factors determining the performance of dye sensitized solar cells: light absorption, electron injection, and back-donation.", "type": "CHEMICAL", "entities": [ "oxide" ], "offsets": [ [ 139, 144 ] ] }, { "pmid": "23223414", "text": "We perform ab initio molecular dynamics simulations of aminophenyl acid dyes NK1 and NK7, differing by the electron donating group, in a vacuum and adsorbed in mono- and bi-dentate modes on a dry and a water-covered anatase (101) surface of TiO(2), at 300 and 350 K. Nuclear vibrations and an increase of temperature cause a red shift in the absorption spectra of free dyes.", "type": "CHEMICAL", "entities": [ "aminophenyl acid", "NK1", "NK7", "anatase (101)", "TiO(2)" ], "offsets": [ [ 55, 71 ], [ 77, 80 ], [ 85, 88 ], [ 216, 229 ], [ 241, 247 ] ] }, { "pmid": "23223414", "text": "This effect is preserved in dyes on dry TiO(2) but largely disappears in the presence of water.", "type": "CHEMICAL", "entities": [ "TiO(2)" ], "offsets": [ [ 40, 46 ] ] }, { "pmid": "23223414", "text": "It depends on the adsorption mode and the presence of H(2)O but is almost the same for 300 and 350 K. Recombination to the dye cation is expected to be much enhanced by the approach of the dye oxidation equivalent hole to the surface during dye wagging around TiO(2).", "type": "CHEMICAL", "entities": [ "H(2)O", "TiO(2)" ], "offsets": [ [ 53, 58 ], [ 259, 265 ] ] }, { "pmid": "23223414", "text": "The dynamics of ΔG(t) are explained by uncorrelated evolution of the energies of the dye excited state and the conduction band minimum of the oxide due to their respective vibrations, and are almost independent of dye orientation.", "type": "CHEMICAL", "entities": [ "oxide" ], "offsets": [ [ 141, 146 ] ] }, { "pmid": "23224291", "text": "Connexin43 expression was suppressed by means of RNA interference technology, and the overall outcome of this treatment on the hepatocellular proteome and metabolome was investigated using tandem mass tag-based differential protein profiling and (1)H NMR spectroscopy, respectively.", "type": "CHEMICAL", "entities": [ "(1)H" ], "offsets": [ [ 246, 250 ] ] }, { "pmid": "23224291", "text": "Global protein profiling revealed a number of targets of the connexin43 knock-down procedure, including mitochondrial proteins (heat shock protein 60, glucose-regulated protein 75, thiosulphate sulphurtransferase and adenosine triphosphate synthase) and detoxifying enzymes (glutathione S-transferase μ 2 and cytochrome P450 2C70).", "type": "CHEMICAL", "entities": [ "adenosine triphosphate", "glutathione", "S", "glucose", "thiosulphate" ], "offsets": [ [ 217, 239 ], [ 275, 286 ], [ 287, 288 ], [ 151, 158 ], [ 181, 193 ] ] }, { "pmid": "23224291", "text": "At the metabolomic level, connexin43 silencing caused no overt changes, though there was some evidence for a subtle increase in intracellular glycine quantities.", "type": "CHEMICAL", "entities": [ "glycine" ], "offsets": [ [ 141, 148 ] ] }, { "pmid": "23229511", "text": "Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells.\n", "type": "CHEMICAL", "entities": [ "Aryl hydrocarbon", "17-Allylamino-17-demethoxygeldanamycin" ], "offsets": [ [ 0, 16 ], [ 41, 79 ] ] }, { "pmid": "23229511", "text": "We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD).", "type": "CHEMICAL", "entities": [ "aryl hydrocarbon" ], "offsets": [ [ 26, 42 ] ] }, { "pmid": "23229511", "text": "17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials.", "type": "CHEMICAL", "entities": [ "17-Allylamino-17-demethoxygeldanamycin", "17-AAG" ], "offsets": [ [ 0, 38 ], [ 40, 46 ] ] }, { "pmid": "23229511", "text": "Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy.", "type": "CHEMICAL", "entities": [ "17-AAG" ], "offsets": [ [ 49, 55 ] ] }, { "pmid": "23229511", "text": "Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators.", "type": "CHEMICAL", "entities": [ "17-AAG" ], "offsets": [ [ 23, 29 ] ] }, { "pmid": "23229511", "text": "Although treatment with 17-AAG reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG.", "type": "CHEMICAL", "entities": [ "17-AAG", "17-AAG" ], "offsets": [ [ 24, 30 ], [ 150, 156 ] ] }, { "pmid": "23229511", "text": "In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells.", "type": "CHEMICAL", "entities": [ "17-AAG" ], "offsets": [ [ 13, 19 ] ] }, { "pmid": "23229511", "text": "NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells.", "type": "CHEMICAL", "entities": [ "NAD(P)H", "quinone", "17-AAG" ], "offsets": [ [ 0, 7 ], [ 8, 15 ], [ 111, 117 ] ] }, { "pmid": "23229511", "text": "Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells.", "type": "CHEMICAL", "entities": [ "17-AAG" ], "offsets": [ [ 82, 88 ] ] }, { "pmid": "23229511", "text": "We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells.", "type": "CHEMICAL", "entities": [ "17-AAG", "17-AAG" ], "offsets": [ [ 78, 84 ], [ 127, 133 ] ] }, { "pmid": "23230131", "text": "Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase.\n", "type": "CHEMICAL", "entities": [ "deoxycytidine", "gemcitabine", "cytidine" ], "offsets": [ [ 110, 123 ], [ 20, 31 ], [ 87, 95 ] ] }, { "pmid": "23230131", "text": "Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear.", "type": "CHEMICAL", "entities": [ "cytidine", "Gemcitabine", "deoxycytidine", "dFdC", "2',2'-difluorodeoxycytidine" ], "offsets": [ [ 66, 74 ], [ 0, 11 ], [ 95, 108 ], [ 13, 17 ], [ 19, 46 ] ] }, { "pmid": "23230131", "text": "Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates.", "type": "CHEMICAL", "entities": [ "Ara-C", "dFdC", "2',2'-difluorodeoxyuridine", "dFdU", "cytarabine" ], "offsets": [ [ 222, 227 ], [ 230, 234 ], [ 255, 281 ], [ 283, 287 ], [ 210, 220 ] ] }, { "pmid": "23230131", "text": "All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination.", "type": "CHEMICAL", "entities": [ "Ara-C", "dFdC", "Ara-C" ], "offsets": [ [ 58, 63 ], [ 68, 72 ], [ 167, 172 ] ] }, { "pmid": "23230131", "text": "All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05).", "type": "CHEMICAL", "entities": [ "Ara-C", "dFdC", "dFdC" ], "offsets": [ [ 64, 69 ], [ 74, 78 ], [ 214, 218 ] ] }, { "pmid": "23230131", "text": "DCK did not significantly contribute to dFdU monophosphorylation.", "type": "CHEMICAL", "entities": [ "dFdU" ], "offsets": [ [ 40, 44 ] ] }, { "pmid": "23230131", "text": "In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine.", "type": "CHEMICAL", "entities": [ "dFdC", "gemcitabine" ], "offsets": [ [ 93, 97 ], [ 180, 191 ] ] }, { "pmid": "23230131", "text": "The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response.", "type": "CHEMICAL", "entities": [ "dFdC", "dFdC" ], "offsets": [ [ 60, 64 ], [ 104, 108 ] ] }, { "pmid": "23232060", "text": "Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors.\n", "type": "CHEMICAL", "entities": [ "4-phenyl-2-phenylaminopyridine" ], "offsets": [ [ 13, 43 ] ] }, { "pmid": "23232060", "text": "A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described.", "type": "CHEMICAL", "entities": [ "4-phenyl-2-phenylaminopyridine" ], "offsets": [ [ 33, 63 ] ] }, { "pmid": "23234537", "text": "Hybrid carbon nanotube networks as efficient hole extraction layers for organic photovoltaics.\n", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 7, 13 ] ] }, { "pmid": "23234537", "text": "Transparent, highly percolated networks of regioregular poly(3-hexylthiophene) (rr-P3HT)-wrapped semiconducting single-walled carbon nanotubes (s-SWNTs) are deposited, and the charge transfer processes of these nanohybrids are studied using spectroscopic and electrical measurements.", "type": "CHEMICAL", "entities": [ "carbon", "poly(3-hexylthiophene)", "P3HT" ], "offsets": [ [ 126, 132 ], [ 56, 78 ], [ 83, 87 ] ] }, { "pmid": "23234537", "text": "Through controlled fabrication, high- to low-density nanohybrid networks are achieved, with low-density hybrid carbon nanotube networks tested as hole transport layers (HTLs) for bulk heterojunction (BHJ) organic photovoltaics (OPV).", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 111, 117 ] ] }, { "pmid": "23234537", "text": "OPVs incorporating these rr-P3HT/s-SWNT networks as the HTL demonstrate the best large area (70 mm(2)) carbon nanotube incorporated organic solar cells to date with a power conversion efficiency of 7.6%.", "type": "CHEMICAL", "entities": [ "P3HT", "carbon" ], "offsets": [ [ 28, 32 ], [ 103, 109 ] ] }, { "pmid": "23238236", "text": "Sterols, triterpenes, organic acids, fatty acids and volatile compounds were determined by different chromatographic methods.", "type": "CHEMICAL", "entities": [ "Sterols", "triterpenes", "fatty acids" ], "offsets": [ [ 0, 7 ], [ 9, 20 ], [ 37, 48 ] ] }, { "pmid": "23238236", "text": "The antioxidant activity was assessed against DPPH(·), superoxide and nitric oxide radicals.", "type": "CHEMICAL", "entities": [ "DPPH(·)", "superoxide", "nitric oxide" ], "offsets": [ [ 46, 53 ], [ 55, 65 ], [ 70, 82 ] ] }, { "pmid": "23239555", "text": "Boron-based inhibitors of acyl protein thioesterases 1 and 2.\n", "type": "CHEMICAL", "entities": [ "Boron", "acyl" ], "offsets": [ [ 0, 5 ], [ 26, 30 ] ] }, { "pmid": "23239555", "text": "Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle.", "type": "CHEMICAL", "entities": [ "acyl" ], "offsets": [ [ 46, 50 ] ] }, { "pmid": "23239555", "text": "Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors.", "type": "CHEMICAL", "entities": [ "boronic", "borinic acid" ], "offsets": [ [ 16, 23 ], [ 28, 40 ] ] }, { "pmid": "23239592", "text": "Three-Dimensional CdS-Titanate Composite Nanomaterials for Enhanced Visible-Light-Driven Hydrogen Evolution.\n", "type": "CHEMICAL", "entities": [ "CdS", "Titanate", "Hydrogen" ], "offsets": [ [ 18, 21 ], [ 22, 30 ], [ 89, 97 ] ] }, { "pmid": "23239592", "text": "3D Hierarchical echinus-like titanate spheres (HETSs), serving as the supporting material for CdS nanoparticles, are synthesized via a fast one-step hydrothermal method.", "type": "CHEMICAL", "entities": [ "titanate", "CdS" ], "offsets": [ [ 29, 37 ], [ 94, 97 ] ] }, { "pmid": "23239592", "text": "The obtained 3D CdS-HETS composite materials show enhanced H2 generation under visible light irradiation.", "type": "CHEMICAL", "entities": [ "CdS", "H2" ], "offsets": [ [ 16, 19 ], [ 59, 61 ] ] }, { "pmid": "23246428", "text": "UPLC-Q-TOF/HSMS/MS(E)-based metabonomics for adenine-induced changes in metabolic profiles of rat faeces and intervention effects of ergosta-4,6,8(14),22-tetraen-3-one.\n", "type": "CHEMICAL", "entities": [ "ergosta-4,6,8(14),22-tetraen-3-one", "adenine" ], "offsets": [ [ 133, 167 ], [ 45, 52 ] ] }, { "pmid": "23246428", "text": "Ergosta-4,6,8(14),22-tetraen-3-one (ergone), isolated from the medicinal fungus Polyporus umbellatus, has been proven to prevent the progression of renal injury and the subsequent renal fibrosis.", "type": "CHEMICAL", "entities": [ "Ergosta-4,6,8(14),22-tetraen-3-one", "ergone" ], "offsets": [ [ 0, 34 ], [ 36, 42 ] ] }, { "pmid": "23246428", "text": "data collection technique was employed to investigate metabonomic characters of chronic renal failure (CRF) induced adenine and the protective effects of ergosta-4,6,8(14),22-tetraen-3-one (ergone).", "type": "CHEMICAL", "entities": [ "adenine", "ergosta-4,6,8(14),22-tetraen-3-one", "ergone" ], "offsets": [ [ 116, 123 ], [ 154, 188 ], [ 190, 196 ] ] }, { "pmid": "23246428", "text": "Coupled with blood biochemistry and kidney histopathology results, the significant difference in metabolic profiling between adenine-induced CRF group and ergone-treated CRF group by using pattern recognition analysis indicated that changes in global faecal metabolites were occurred.", "type": "CHEMICAL", "entities": [ "adenine", "ergone" ], "offsets": [ [ 125, 132 ], [ 155, 161 ] ] }, { "pmid": "23246428", "text": "These biochemical changes in faecal metabolites are related to the perturbations of bile acid metabolism and phospholipid metabolism, which may be helpful to further understand the CRF and therapeutic mechanisms of ergone.", "type": "CHEMICAL", "entities": [ "bile acid", "ergone" ], "offsets": [ [ 84, 93 ], [ 215, 221 ] ] }, { "pmid": "23252799", "text": "An integral asymmetric membrane was fabricated in a fast and one-step process by combining the self-assembly of an amphiphilic block copolymer (PS-b-P4VP) with nonsolvent-induced phase separation.", "type": "CHEMICAL", "entities": [ "PS-b-P4VP" ], "offsets": [ [ 144, 153 ] ] }, { "pmid": "23254196", "text": "Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling.\n", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "23254196", "text": "The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear.", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "23254196", "text": "Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability.", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "23254196", "text": "Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs).", "type": "CHEMICAL", "entities": [ "Ser", "Thr" ], "offsets": [ [ 144, 147 ], [ 152, 155 ] ] }, { "pmid": "23254196", "text": "Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 39, 45 ] ] }, { "pmid": "23254196", "text": "Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein.", "type": "CHEMICAL", "entities": [ "nitric oxide", "estrogen", "genistein" ], "offsets": [ [ 41, 53 ], [ 66, 74 ], [ 123, 132 ] ] }, { "pmid": "23254196", "text": "RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs.", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "23254196", "text": "Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs.", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 56, 65 ] ] }, { "pmid": "23254196", "text": "Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein.", "type": "CHEMICAL", "entities": [ "cAMP", "genistein" ], "offsets": [ [ 32, 36 ], [ 95, 104 ] ] }, { "pmid": "23254196", "text": "These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling.", "type": "CHEMICAL", "entities": [ "genistein" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "23256446", "text": "The main outcome measures were serum glucose, lipids, and C-peptide, and anthropometric measurements.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 37, 44 ] ] }, { "pmid": "23256446", "text": "The intervention resulted in significant decreases in subscapular skin fold thickness (SSFT; P=.002), fasting serum glucose (FSG; P=.001), total cholesterol (P=.0001), serum triglycerides (TG; P=.0001), and low-density lipoprotein (P=.0009), and significant increases in fasting C-peptide (FCP; P=.0004) and 2-h postprandial C-peptide (PCP; P=.002).", "type": "CHEMICAL", "entities": [ "glucose", "cholesterol", "triglycerides" ], "offsets": [ [ 116, 123 ], [ 145, 156 ], [ 174, 187 ] ] }, { "pmid": "23256446", "text": "As possible long-term effects of honey after its withdrawal, statistically significant reductions in midarm circumference (P=.000), triceps skin fold thickness (P=.006), SSFT (P=.003), FSG (P=.005), 2-h postprandial serum glucose (P=.000), TG (P=.003), and HbA1C (P=.043), and significant increases in FCP (P=.002) and PCP (P=.003) were observed.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 222, 229 ] ] }, { "pmid": "23256625", "text": "Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design.\n", "type": "CHEMICAL", "entities": [ "GSK1292263" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "23256625", "text": "1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin.", "type": "CHEMICAL", "entities": [ "GSK1292263", "simvastatin", "rosuvastatin" ], "offsets": [ [ 60, 70 ], [ 134, 145 ], [ 150, 162 ] ] }, { "pmid": "23256625", "text": "2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose).", "type": "CHEMICAL", "entities": [ "GSK1292263", "simvastatin", "rosuvastatin", "GSK1292263" ], "offsets": [ [ 158, 168 ], [ 216, 227 ], [ 252, 264 ], [ 81, 91 ] ] }, { "pmid": "23256625", "text": "3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2.", "type": "CHEMICAL", "entities": [ "GSK1292263" ], "offsets": [ [ 3, 13 ] ] }, { "pmid": "23256625", "text": "4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4.", "type": "CHEMICAL", "entities": [ "simvastatin", "rosuvastatin", "GSK1292263" ], "offsets": [ [ 50, 61 ], [ 109, 121 ], [ 205, 215 ] ] }, { "pmid": "23256625", "text": "In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)].", "type": "CHEMICAL", "entities": [ "simvastatin", "GSK1292263" ], "offsets": [ [ 65, 76 ], [ 149, 159 ] ] }, { "pmid": "23256625", "text": "5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain.", "type": "CHEMICAL", "entities": [ "simvastatin", "rosuvastain" ], "offsets": [ [ 32, 43 ], [ 48, 59 ] ] }, { "pmid": "23256625", "text": "This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.", "type": "CHEMICAL", "entities": [ "GSK1292263" ], "offsets": [ [ 88, 98 ] ] }, { "pmid": "23256719", "text": "Thiol compounts such as N-acetyl-L-cysteine (NAC), carbocysteine, erdosteine, and fudosteine have been extensively studied.", "type": "CHEMICAL", "entities": [ "Thiol", "N-acetyl-L-cysteine", "NAC", "carbocysteine", "erdosteine", "fudosteine" ], "offsets": [ [ 0, 5 ], [ 24, 43 ], [ 45, 48 ], [ 51, 64 ], [ 66, 76 ], [ 82, 92 ] ] }, { "pmid": "23256719", "text": "Although some results remain controversial, NAC and carbocysteine seem to have beneficial effect in patients not receiving inhaled corticosteroids who suffer from frequent exacerbations.", "type": "CHEMICAL", "entities": [ "carbocysteine", "corticosteroids", "NAC" ], "offsets": [ [ 52, 65 ], [ 131, 146 ], [ 44, 47 ] ] }, { "pmid": "23256719", "text": "In addition, other antioxidants like superoxide dismutase (SOD) mimetics and nuclear factor-erythroid 2 related factor 2 (Nrf2) are shown to decrease markers of oxidative stress in patients with emphysema, while others like glutathione peroxidase (GPx) mimetics and NO synthase (iNOS) can prevent both inflammation and oxidative stress in clinical trials in vivo (or in mouse models).", "type": "CHEMICAL", "entities": [ "superoxide", "glutathione", "NO" ], "offsets": [ [ 37, 47 ], [ 224, 235 ], [ 266, 268 ] ] }, { "pmid": "23257178", "text": "Steroid toxicity and detoxification in ascomycetous fungi.\n", "type": "CHEMICAL", "entities": [ "Steroid" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23257178", "text": "A major interest into fungal steroid action has been provoked since research has proven that steroid hormones are toxic to fungi and affect the host/fungus relationship.", "type": "CHEMICAL", "entities": [ "steroid", "steroid" ], "offsets": [ [ 93, 100 ], [ 29, 36 ] ] }, { "pmid": "23257178", "text": "Steroid hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae.", "type": "CHEMICAL", "entities": [ "Steroid" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23257178", "text": "Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone.", "type": "CHEMICAL", "entities": [ "androstenedione", "testosterone" ], "offsets": [ [ 117, 132 ], [ 137, 149 ] ] }, { "pmid": "23257178", "text": "For their protection, fungi use several mechanisms to lower the toxic effects of steroids.", "type": "CHEMICAL", "entities": [ "steroids" ], "offsets": [ [ 81, 89 ] ] }, { "pmid": "23257178", "text": "The efficiency of biotransformation in detoxification depended on the microorganism and steroid substrate used.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 88, 95 ] ] }, { "pmid": "23257178", "text": "In addition to biotransformation, steroid extrusion out of the cells contributed to the lowering of the active intracellular steroid concentration.", "type": "CHEMICAL", "entities": [ "steroid", "steroid" ], "offsets": [ [ 34, 41 ], [ 125, 132 ] ] }, { "pmid": "23257178", "text": "Proteins Aus1 and Dan1 were not found to be involved in steroid import.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 56, 63 ] ] }, { "pmid": "23257178", "text": "The research of possible targets of steroid hormone action in fungi suggests that steroid hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii.", "type": "CHEMICAL", "entities": [ "steroid", "steroid", "ergosterol" ], "offsets": [ [ 36, 43 ], [ 82, 89 ], [ 107, 117 ] ] }, { "pmid": "23257178", "text": "Results of this inhibition caused changes in the sterol content of the cellular membrane.", "type": "CHEMICAL", "entities": [ "sterol" ], "offsets": [ [ 49, 55 ] ] }, { "pmid": "23257178", "text": "The presence of steroid hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import.", "type": "CHEMICAL", "entities": [ "steroid", "tryptophan" ], "offsets": [ [ 16, 23 ], [ 109, 119 ] ] }, { "pmid": "23261051", "text": "Disruption of the cell-cycle boxes also affected growth in a DNA polymerase-defective strain background where mismatch repair is essential, particularly in the presence of the DNA damaging agent methyl methane sulfonate (MMS).", "type": "CHEMICAL", "entities": [ "methyl methane sulfonate", "MMS" ], "offsets": [ [ 193, 217 ], [ 219, 222 ] ] }, { "pmid": "23261051", "text": "Promoter replacements conferring constitutive expression of MSH2 revealed that the transcriptional induction in response to MMS is required to maintain induced levels of Msh2.", "type": "CHEMICAL", "entities": [ "MMS" ], "offsets": [ [ 122, 125 ] ] }, { "pmid": "23261051", "text": "Turnover experiments confirmed an elevated rate of degradation in the presence of MMS.", "type": "CHEMICAL", "entities": [ "MMS" ], "offsets": [ [ 80, 83 ] ] }, { "pmid": "23261528", "text": "Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin.\n", "type": "CHEMICAL", "entities": [ "icariin", "flavonoid" ], "offsets": [ [ 175, 182 ], [ 155, 164 ] ] }, { "pmid": "23261528", "text": "However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 81, 88 ] ] }, { "pmid": "23261528", "text": "In the present study we found that icariin, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium.", "type": "CHEMICAL", "entities": [ "icariin", "sulfate", "sodium" ], "offsets": [ [ 35, 42 ], [ 184, 191 ], [ 192, 198 ] ] }, { "pmid": "23261528", "text": "Oral administration of icariin significantly attenuated the disease progression and alleviated the pathological changes of colitis.", "type": "CHEMICAL", "entities": [ "icariin" ], "offsets": [ [ 23, 30 ] ] }, { "pmid": "23261528", "text": "Further study showed that icariin dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells.", "type": "CHEMICAL", "entities": [ "icariin" ], "offsets": [ [ 26, 33 ] ] }, { "pmid": "23261528", "text": "Moreover, icariin treatment inhibited the phosphorylations of STAT1 and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively.", "type": "CHEMICAL", "entities": [ "icariin" ], "offsets": [ [ 10, 17 ] ] }, { "pmid": "23261528", "text": "Taken together, these results indicate that icariin is a potential therapeutic agent for IBD.", "type": "CHEMICAL", "entities": [ "icariin" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "23261705", "text": "The present study examined the effect of insulin-mediated activation of the mammalian target of rapamycin complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 96, 105 ] ] }, { "pmid": "23261705", "text": "Pharmacological inhibition of MTORC1 with rapamycin abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 42, 51 ] ] }, { "pmid": "23261705", "text": "Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by rapamycin.", "type": "CHEMICAL", "entities": [ "rapamycin" ], "offsets": [ [ 150, 159 ] ] }, { "pmid": "23263989", "text": "Plant homeodomain (PHD)-type zinc fingers play an important role in recognizing chromatin modifications and recruiting regulatory proteins to specific genes.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 29, 33 ] ] }, { "pmid": "23263989", "text": "AF10 has mostly been studied in the context of the leukemic MLL-AF10 fusion protein, which lacks the N-terminal PHD fingers of AF10.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 101, 102 ] ] }, { "pmid": "23263989", "text": "In this study, we used genetic and biochemical approaches to examine the PHD1-PHD2 region of the Caenorhabditis elegans ortholog of AF10, zinc finger protein 1 (ZFP-1).", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 138, 142 ] ] }, { "pmid": "23263989", "text": "We demonstrate that the PHD1-PHD2 region is essential for viability and that the first PHD finger contributes to the preferred binding of PHD1-PHD2 to lysine 4-methylated histone H3 tails.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 151, 157 ] ] }, { "pmid": "23265873", "text": "Novel limonene and citral based 2,5-disubstituted-1,3,4-oxadiazoles: a natural product coupled approach to semicarbazones for antiepileptic activity.\n", "type": "CHEMICAL", "entities": [ "semicarbazones", "citral", "2,5-disubstituted-1,3,4-oxadiazoles", "limonene" ], "offsets": [ [ 107, 121 ], [ 19, 25 ], [ 32, 67 ], [ 6, 14 ] ] }, { "pmid": "23265873", "text": "Two novel series of N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity.", "type": "CHEMICAL", "entities": [ "N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide", "N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide" ], "offsets": [ [ 149, 259 ], [ 20, 144 ] ] }, { "pmid": "23265873", "text": "The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models.", "type": "CHEMICAL", "entities": [ "pentylenetrtrazole", "strychnine" ], "offsets": [ [ 120, 138 ], [ 164, 174 ] ] }, { "pmid": "23265873", "text": "Some of the selected active compounds were subjected to GABA assay to confirm their mode of action.", "type": "CHEMICAL", "entities": [ "GABA" ], "offsets": [ [ 56, 60 ] ] }, { "pmid": "23265901", "text": "Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility.\n", "type": "CHEMICAL", "entities": [ "8-oxoadenine" ], "offsets": [ [ 28, 40 ] ] }, { "pmid": "23265901", "text": "We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety.", "type": "CHEMICAL", "entities": [ "tertiary amines", "N", "adenine", "8-oxoadenines" ], "offsets": [ [ 141, 156 ], [ 166, 167 ], [ 187, 194 ], [ 80, 93 ] ] }, { "pmid": "23265901", "text": "The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity.", "type": "CHEMICAL", "entities": [ "amino" ], "offsets": [ [ 24, 29 ] ] }, { "pmid": "23265901", "text": "In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility.", "type": "CHEMICAL", "entities": [ "DSR-6434" ], "offsets": [ [ 27, 35 ] ] }, { "pmid": "23265904", "text": "Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1).\n", "type": "CHEMICAL", "entities": [ "stearoyl-CoA" ], "offsets": [ [ 42, 54 ] ] }, { "pmid": "23265904", "text": "Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model.", "type": "CHEMICAL", "entities": [ "stearoyl-coenzyme A", "CoA", "benzo-fused spirocyclic oxazepine" ], "offsets": [ [ 85, 104 ], [ 106, 109 ], [ 22, 55 ] ] }, { "pmid": "23265904", "text": "Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties.", "type": "CHEMICAL", "entities": [ "oxazepine", "benzylic", "piperidine" ], "offsets": [ [ 58, 67 ], [ 77, 85 ], [ 123, 133 ] ] }, { "pmid": "23265904", "text": "After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles.", "type": "CHEMICAL", "entities": [ "amides", "thiazoles", "piperidine", "nitrogen", "glycine amides" ], "offsets": [ [ 203, 209 ], [ 215, 224 ], [ 69, 79 ], [ 80, 88 ], [ 168, 182 ] ] }, { "pmid": "23265904", "text": "An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.", "type": "CHEMICAL", "entities": [ "5-carboxy-2-thiazole", "spirocyclic piperidine" ], "offsets": [ [ 32, 52 ], [ 82, 104 ] ] }, { "pmid": "23266452", "text": "N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver.\n", "type": "CHEMICAL", "entities": [ "N-acetylgalactosamine" ], "offsets": [ [ 0, 21 ] ] }, { "pmid": "23266452", "text": "Here, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixed micellar nanoparticles (Gal-MNP), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration.", "type": "CHEMICAL", "entities": [ "N-acetylgalactosamine" ], "offsets": [ [ 77, 98 ] ] }, { "pmid": "23266452", "text": "The Gal-MNP were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-b-poly(ε-caprolactone) and cationic poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated.", "type": "CHEMICAL", "entities": [ "N-acetylgalactosamine", "poly(ethylene glycol)-b-poly(ε-caprolactone)", "poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate)", "PCL-b-PPEEA", "poly(ethylene glycol)" ], "offsets": [ [ 58, 79 ], [ 95, 139 ], [ 153, 213 ], [ 215, 226 ], [ 321, 342 ] ] }, { "pmid": "23266732", "text": "Compared to the HC group, aqueous Mate tea extract significantly reduced endothelin (ET) and thromboxane B(2) (TXB(2)) levels and increased nitric oxide (NO) and 6-keto prostaglandin F(1α) (6-keto-PGF(1α))", "type": "CHEMICAL", "entities": [ "NO", "6-keto prostaglandin F(1α)", "6-keto-PGF(1α)", "thromboxane B(2)", "TXB(2)", "nitric oxide" ], "offsets": [ [ 154, 156 ], [ 162, 188 ], [ 190, 204 ], [ 93, 109 ], [ 111, 117 ], [ 140, 152 ] ] }, { "pmid": "23267767", "text": "Development of hypoxia-inducible factor (HIF)-1α inhibitors: effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia.\n", "type": "CHEMICAL", "entities": [ "ortho-carborane" ], "offsets": [ [ 71, 86 ] ] }, { "pmid": "23267767", "text": "A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI(50)) using the MTT assay.", "type": "CHEMICAL", "entities": [ "ortho-carboranylphenoxyacetanilides", "MTT" ], "offsets": [ [ 23, 58 ], [ 421, 424 ] ] }, { "pmid": "23267767", "text": "The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC(50): 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC(50): 10.9 ± 0.63 μM).", "type": "CHEMICAL", "entities": [ "malate", "ETB" ], "offsets": [ [ 13, 19 ], [ 201, 204 ] ] }, { "pmid": "23270704", "text": "Apocynin and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes.\n", "type": "CHEMICAL", "entities": [ "Apocynin", "raisanberine", "testosterone" ], "offsets": [ [ 0, 8 ], [ 13, 25 ], [ 98, 110 ] ] }, { "pmid": "23270704", "text": "We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis.", "type": "CHEMICAL", "entities": [ "APO", "apocynin", "raisanberine", "calcium", "NADPH" ], "offsets": [ [ 114, 117 ], [ 119, 127 ], [ 153, 165 ], [ 174, 181 ], [ 82, 87 ] ] }, { "pmid": "23270704", "text": "Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d.", "type": "CHEMICAL", "entities": [ "APO" ], "offsets": [ [ 89, 92 ] ] }, { "pmid": "23270704", "text": "Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 49, 53 ] ] }, { "pmid": "23270704", "text": "Hypoxic rats displayed lower serum testosterone and higher LH and FSH.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 33, 45 ] ] }, { "pmid": "23270805", "text": "Coming full circle: contributions of central and peripheral oxytocin actions to energy balance.\n", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23270805", "text": "The neuropeptide oxytocin has emerged as an important anorexigen in the regulation of energy balance.", "type": "CHEMICAL", "entities": [ "oxytocin", "anorexigen" ], "offsets": [ [ 17, 25 ], [ 54, 64 ] ] }, { "pmid": "23270805", "text": "Pharmacologic and pair-feeding studies indicate that its ability to reduce body mass extends beyond that of food intake, affecting multiple factors that determine energy balance such as energy expenditure, lipolysis, and glucose regulation.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 221, 228 ] ] }, { "pmid": "23270805", "text": "Systemic administration of oxytocin recapitulates many of its effects when administered centrally, raising the questions of whether and to what extent circulating oxytocin contributes to energy regulation.", "type": "CHEMICAL", "entities": [ "oxytocin", "oxytocin" ], "offsets": [ [ 27, 35 ], [ 163, 171 ] ] }, { "pmid": "23270805", "text": "Its therapeutic potential to treat metabolic conditions remains to be determined, but data from diet-induced and genetically obese rodent models as well as application of oxytocin in humans in other areas of research have revealed promising results thus far.", "type": "CHEMICAL", "entities": [ "oxytocin" ], "offsets": [ [ 171, 179 ] ] }, { "pmid": "23271742", "text": "Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein.\nTranscription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53.", "type": "CHEMICAL", "entities": [ "Arsenic" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23271742", "text": "Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners.", "type": "CHEMICAL", "entities": [ "arsenic trioxide" ], "offsets": [ [ 14, 30 ] ] }, { "pmid": "23271742", "text": "In addition, we found that arsenic trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript.", "type": "CHEMICAL", "entities": [ "arsenic trioxide" ], "offsets": [ [ 21, 37 ] ] }, { "pmid": "23271742", "text": "Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression.", "type": "CHEMICAL", "entities": [ "arsenic trioxide" ], "offsets": [ [ 19, 35 ] ] }, { "pmid": "23271742", "text": "Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 103, 110 ] ] }, { "pmid": "23271742", "text": "Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 125, 132 ] ] }, { "pmid": "23271742", "text": "Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death.", "type": "CHEMICAL", "entities": [ "arsenic", "arsenic" ], "offsets": [ [ 23, 30 ], [ 170, 177 ] ] }, { "pmid": "23274058", "text": "Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation.\n", "type": "CHEMICAL", "entities": [ "Jaceosidin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23274058", "text": "Jaceosidin, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood.", "type": "CHEMICAL", "entities": [ "Jaceosidin", "flavonoid", "jaceosidin" ], "offsets": [ [ 0, 10 ], [ 14, 23 ], [ 201, 211 ] ] }, { "pmid": "23274058", "text": "In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells.", "type": "CHEMICAL", "entities": [ "jaceosidin" ], "offsets": [ [ 99, 109 ] ] }, { "pmid": "23274058", "text": "We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells.", "type": "CHEMICAL", "entities": [ "jaceosidin", "cisplatin" ], "offsets": [ [ 21, 31 ], [ 79, 88 ] ] }, { "pmid": "23274058", "text": "In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin.", "type": "CHEMICAL", "entities": [ "jaceosidin", "cisplatin" ], "offsets": [ [ 13, 23 ], [ 106, 115 ] ] }, { "pmid": "23274058", "text": "Jaceosidin induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells.", "type": "CHEMICAL", "entities": [ "Jaceosidin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23274058", "text": "Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition.", "type": "CHEMICAL", "entities": [ "jaceosidin" ], "offsets": [ [ 59, 69 ] ] }, { "pmid": "23274058", "text": "Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part.", "type": "CHEMICAL", "entities": [ "jaceosidin", "jaceosidin" ], "offsets": [ [ 45, 55 ], [ 171, 181 ] ] }, { "pmid": "23274058", "text": "Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin.", "type": "CHEMICAL", "entities": [ "jaceosidin", "PD98059", "jaceosidin" ], "offsets": [ [ 10, 20 ], [ 108, 115 ], [ 154, 164 ] ] }, { "pmid": "23274058", "text": "These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells.", "type": "CHEMICAL", "entities": [ "jaceosidin" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "23274893", "text": "EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia.\n", "type": "CHEMICAL", "entities": [ "glutamine", "glutamate" ], "offsets": [ [ 119, 128 ], [ 129, 138 ] ] }, { "pmid": "23274893", "text": "Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate counterregulatory hormone release as well.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 71, 78 ] ] }, { "pmid": "23274893", "text": "Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic-hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or overexpression of ephrinA5 using an adenoassociated viral construct.", "type": "CHEMICAL", "entities": [ "glucose", "glutamine", "glutamate" ], "offsets": [ [ 129, 136 ], [ 30, 39 ], [ 40, 49 ] ] }, { "pmid": "23274893", "text": "Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia.", "type": "CHEMICAL", "entities": [ "glutamate", "glutamine" ], "offsets": [ [ 57, 66 ], [ 166, 175 ] ] }, { "pmid": "23274893", "text": "Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling.", "type": "CHEMICAL", "entities": [ "glucose", "glucose", "glutamate", "glutamine" ], "offsets": [ [ 65, 72 ], [ 127, 134 ], [ 240, 249 ], [ 250, 259 ] ] }, { "pmid": "23274898", "text": "Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells.\n", "type": "CHEMICAL", "entities": [ "ATP", "Glucose" ], "offsets": [ [ 27, 30 ], [ 67, 74 ] ] }, { "pmid": "23274898", "text": "Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 15, 22 ] ] }, { "pmid": "23274898", "text": "ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 154, 161 ] ] }, { "pmid": "23274898", "text": "Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin).", "type": "CHEMICAL", "entities": [ "2-NBD-Glucose", "2-NBDG", "ATP", "2-NBDG", "adenosine-phosphate", "suramin", "ATP" ], "offsets": [ [ 67, 80 ], [ 82, 88 ], [ 154, 157 ], [ 168, 174 ], [ 200, 219 ], [ 269, 276 ], [ 23, 26 ] ] }, { "pmid": "23274898", "text": "Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin.", "type": "CHEMICAL", "entities": [ "ATP", "suramin" ], "offsets": [ [ 57, 60 ], [ 138, 145 ] ] }, { "pmid": "23274898", "text": "Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation.", "type": "CHEMICAL", "entities": [ "ATP", "ATP", "2-NBDG" ], "offsets": [ [ 9, 12 ], [ 148, 151 ], [ 162, 168 ] ] }, { "pmid": "23274898", "text": "ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240.", "type": "CHEMICAL", "entities": [ "AS605240", "2-NBDG", "ATP" ], "offsets": [ [ 163, 171 ], [ 13, 19 ], [ 173, 176 ] ] }, { "pmid": "23274898", "text": "ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise.", "type": "CHEMICAL", "entities": [ "ATP", "2-NBDG" ], "offsets": [ [ 231, 234 ], [ 246, 252 ] ] }, { "pmid": "23274898", "text": "Hence, the ATP-induced pathway may be tapped to bypass insulin resistance.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 3, 6 ] ] }, { "pmid": "23275442", "text": "The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability.", "type": "CHEMICAL", "entities": [ "carboxyl", "amino", "amino acids" ], "offsets": [ [ 41, 49 ], [ 54, 59 ], [ 109, 120 ] ] }, { "pmid": "23279865", "text": "Structure-based design, synthesis and evaluation of novel anthra[1,2-d]imidazole-6,11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology.\n", "type": "CHEMICAL", "entities": [ "anthra[1,2-d]imidazole-6,11-dione" ], "offsets": [ [ 58, 91 ] ] }, { "pmid": "23279865", "text": "A series of anthra[1,2-d]imidazole-6,11-dione derivatives were synthesized and evaluated for telomerase inhibition, hTERT expression and suppression of cancer cell growth in vitro.", "type": "CHEMICAL", "entities": [ "anthra[1,2-d]imidazole-6,11-dione" ], "offsets": [ [ 12, 45 ] ] }, { "pmid": "23282999", "text": "Zinc sulphate and vitamin E alleviate reproductive toxicity caused by aluminium sulphate in male albino rats.\n", "type": "CHEMICAL", "entities": [ "Zinc sulphate", "vitamin E", "aluminium sulphate" ], "offsets": [ [ 0, 13 ], [ 18, 27 ], [ 70, 88 ] ] }, { "pmid": "23282999", "text": "This study was designed to investigate the reproductive toxicity of aluminium sulphate and the therapeutic effects of administration of zinc sulphate and vitamin E individually or in combination against the toxic effect caused by aluminium (Al) in male albino rats.", "type": "CHEMICAL", "entities": [ "aluminium", "Al", "aluminium sulphate", "zinc sulphate", "vitamin E" ], "offsets": [ [ 230, 239 ], [ 241, 243 ], [ 68, 86 ], [ 136, 149 ], [ 154, 163 ] ] }, { "pmid": "23282999", "text": "The animals were divided into five groups: group 1 received distilled water and served as control; group 2 received only aluminium sulphate (50 mg/kg body weight (b.w.)); group 3 received aluminium sulphate (50 mg/kg b.w.) plus zinc sulphate (50 mg/kg b.w.); group 4 received aluminium sulphate (50 mg/kg b.w.) and vitamin E (15 mg/kg b.w.); group 5 received aluminium sulphate plus a combination of zinc sulphate and vitamin E in similar doses as above.", "type": "CHEMICAL", "entities": [ "aluminium sulphate", "aluminium sulphate", "zinc sulphate", "aluminium sulphate", "vitamin E", "aluminium sulphate", "zinc sulphate", "vitamin E" ], "offsets": [ [ 121, 139 ], [ 188, 206 ], [ 228, 241 ], [ 276, 294 ], [ 315, 324 ], [ 359, 377 ], [ 400, 413 ], [ 418, 427 ] ] }, { "pmid": "23282999", "text": "The results revealed that aluminium sulphate induced significant decrease in body weight gain and testis weight and significant increase in Al level in both serum and testes of male rats.", "type": "CHEMICAL", "entities": [ "aluminium sulphate", "Al" ], "offsets": [ [ 26, 44 ], [ 140, 142 ] ] }, { "pmid": "23282999", "text": "Biochemical analysis showed significant decrease in serum total protein and phospholipids levels, while serum total lipid was significantly elevated post Al treatment.", "type": "CHEMICAL", "entities": [ "Al" ], "offsets": [ [ 154, 156 ] ] }, { "pmid": "23282999", "text": "In addition, significant decrease in total protein, phospholipids and cholesterol levels in the testes of Al-treated rats was recorded.", "type": "CHEMICAL", "entities": [ "cholesterol", "Al" ], "offsets": [ [ 70, 81 ], [ 106, 108 ] ] }, { "pmid": "23282999", "text": "The data also showed significant decrease in the levels of serum testosterone, leutinizing hormone and follicle stimulating hormone and significant increase in the level of serum prolactin in Al-intoxicated rats.", "type": "CHEMICAL", "entities": [ "testosterone", "Al" ], "offsets": [ [ 65, 77 ], [ 192, 194 ] ] }, { "pmid": "23282999", "text": "Moreover, histological examination showed that aluminium sulphate caused apparent alterations in the testicular structure of the treated animals.", "type": "CHEMICAL", "entities": [ "aluminium sulphate" ], "offsets": [ [ 47, 65 ] ] }, { "pmid": "23282999", "text": "Treatment with zinc sulphate and vitamin E individually or in combination ameliorated the harmful effects of Al, which was proved histopathologically by the noticeable improvement in the testicular tissues.", "type": "CHEMICAL", "entities": [ "vitamin E", "Al", "zinc sulphate" ], "offsets": [ [ 33, 42 ], [ 109, 111 ], [ 15, 28 ] ] }, { "pmid": "23282999", "text": "We can conclude that the tested dose of aluminium sulphate induced toxic effect on the reproductive system of male albino rats and the treatment with zinc sulphate and/or vitamin E alleviated these toxic effects.", "type": "CHEMICAL", "entities": [ "aluminium sulphate", "zinc sulphate", "vitamin E" ], "offsets": [ [ 40, 58 ], [ 150, 163 ], [ 171, 180 ] ] }, { "pmid": "23282999", "text": "In some cases, vitamin E exerted a more potent effect, while in other cases, the more potent effect is related to zinc sulphate and the combination of both at most of the recorded data.", "type": "CHEMICAL", "entities": [ "vitamin E", "zinc sulphate" ], "offsets": [ [ 15, 24 ], [ 114, 127 ] ] }, { "pmid": "23284002", "text": "Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling.\n", "type": "CHEMICAL", "entities": [ "Trichostatin A", "oxygen" ], "offsets": [ [ 0, 14 ], [ 70, 76 ] ] }, { "pmid": "23284002", "text": "Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 15, 18 ] ] }, { "pmid": "23284002", "text": "The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro.", "type": "CHEMICAL", "entities": [ "TSA", "oxygen" ], "offsets": [ [ 96, 99 ], [ 61, 67 ] ] }, { "pmid": "23284002", "text": "Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA.", "type": "CHEMICAL", "entities": [ "TSA", "NAD(P)H", "diphenyleneiodonium", "DPI", "N-acetyl-cysteine", "NAC", "sulforaphane" ], "offsets": [ [ 79, 82 ], [ 88, 95 ], [ 114, 133 ], [ 135, 138 ], [ 157, 174 ], [ 176, 179 ], [ 259, 271 ] ] }, { "pmid": "23284002", "text": "ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH" ], "offsets": [ [ 23, 34 ], [ 36, 39 ] ] }, { "pmid": "23284002", "text": "Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC.", "type": "CHEMICAL", "entities": [ "TSA", "DPI", "NAC" ], "offsets": [ [ 9, 12 ], [ 156, 159 ], [ 163, 166 ] ] }, { "pmid": "23284002", "text": "Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity.", "type": "CHEMICAL", "entities": [ "TSA", "H(2)O(2)", "GSH" ], "offsets": [ [ 6, 9 ], [ 42, 50 ], [ 116, 119 ] ] }, { "pmid": "23284002", "text": "In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation.", "type": "CHEMICAL", "entities": [ "TSA", "TSA" ], "offsets": [ [ 5, 8 ], [ 187, 190 ] ] }, { "pmid": "23284002", "text": "In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling.", "type": "CHEMICAL", "entities": [ "TSA" ], "offsets": [ [ 63, 66 ] ] }, { "pmid": "23287700", "text": "Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists.\n", "type": "CHEMICAL", "entities": [ "Cannabinoid" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23287700", "text": "Cannabinoid receptor 1 (CB(1))", "type": "CHEMICAL", "entities": [ "Cannabinoid" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23287700", "text": "inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications.", "type": "CHEMICAL", "entities": [ "rimonabant" ], "offsets": [ [ 24, 34 ] ] }, { "pmid": "23287700", "text": "In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054.", "type": "CHEMICAL", "entities": [ "AM4113", "AM4054", "SR141716A", "rimonabant" ], "offsets": [ [ 106, 112 ], [ 285, 291 ], [ 50, 59 ], [ 61, 71 ] ] }, { "pmid": "23287700", "text": "Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054.", "type": "CHEMICAL", "entities": [ "AM4054", "Δ(9)-tetrahydrocannabinol", "rimonabant", "AM4113", "AM4054", "AM4054" ], "offsets": [ [ 22, 28 ], [ 165, 190 ], [ 221, 231 ], [ 259, 265 ], [ 311, 317 ], [ 427, 433 ] ] }, { "pmid": "23287700", "text": "Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9).", "type": "CHEMICAL", "entities": [ "rimonabant", "AM4113" ], "offsets": [ [ 33, 43 ], [ 48, 54 ] ] }, { "pmid": "23292170", "text": "Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women.\n", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "23292170", "text": "The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 40, 47 ] ] }, { "pmid": "23292170", "text": "We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "23292170", "text": "Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 62, 69 ] ] }, { "pmid": "23292170", "text": "[ISOGTT] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUCins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 177, 184 ] ] }, { "pmid": "23292752", "text": "New oral anticoagulants: comparative pharmacology with vitamin K antagonists.\n", "type": "CHEMICAL", "entities": [ "vitamin K" ], "offsets": [ [ 55, 64 ] ] }, { "pmid": "23292752", "text": "These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences.", "type": "CHEMICAL", "entities": [ "vitamin K" ], "offsets": [ [ 56, 65 ] ] }, { "pmid": "23292752", "text": "FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa.", "type": "CHEMICAL", "entities": [ "rivaroxaban", "apixaban" ], "offsets": [ [ 21, 32 ], [ 37, 45 ] ] }, { "pmid": "23292752", "text": "Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers.", "type": "CHEMICAL", "entities": [ "rivaroxaban", "apixaban" ], "offsets": [ [ 48, 59 ], [ 64, 72 ] ] }, { "pmid": "23292752", "text": "Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists.", "type": "CHEMICAL", "entities": [ "argatroban", "dabigatran" ], "offsets": [ [ 68, 78 ], [ 144, 154 ] ] }, { "pmid": "23292752", "text": "Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI.", "type": "CHEMICAL", "entities": [ "Dabigatran etexilate", "dabigatran" ], "offsets": [ [ 0, 20 ], [ 137, 147 ] ] }, { "pmid": "23292752", "text": "Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin.", "type": "CHEMICAL", "entities": [ "Dabigatran" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23292752", "text": "The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin.", "type": "CHEMICAL", "entities": [ "dabigatran" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "23292752", "text": "Dabigatran shows a very low potential for drug-drug interactions.", "type": "CHEMICAL", "entities": [ "Dabigatran" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23292752", "text": "However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk.", "type": "CHEMICAL", "entities": [ "dabigatran etexilate" ], "offsets": [ [ 30, 50 ] ] }, { "pmid": "23292752", "text": "Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia.", "type": "CHEMICAL", "entities": [ "dabigatran", "rivaroxaban", "apixaban", "dabigatran", "dabigatran" ], "offsets": [ [ 245, 255 ], [ 270, 281 ], [ 286, 294 ], [ 307, 317 ], [ 370, 380 ] ] }, { "pmid": "23292752", "text": "The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran.", "type": "CHEMICAL", "entities": [ "rivaroxaban", "apixaban", "dabigatran" ], "offsets": [ [ 89, 100 ], [ 103, 111 ], [ 114, 124 ] ] }, { "pmid": "23293126", "text": "Results revealed that cholesterol, low-density lipoprotein (LDL) and glutathion peroxidase (GPx) enzyme were significantly higher in the 38 smoker sprayers than in the 42 nonsmoker sprayers.", "type": "CHEMICAL", "entities": [ "cholesterol", "glutathion" ], "offsets": [ [ 22, 33 ], [ 69, 79 ] ] }, { "pmid": "23293126", "text": "Cholesterol and LDL were correlated with smoking index and high-density lipoprotein (HDL), superoxide dismutase (SOD) enzyme and zinc (Zn) were inversely correlated with duration of pesticides' exposure.", "type": "CHEMICAL", "entities": [ "Cholesterol", "superoxide", "zinc", "Zn" ], "offsets": [ [ 0, 11 ], [ 91, 101 ], [ 129, 133 ], [ 135, 137 ] ] }, { "pmid": "23293126", "text": "In nonsmokers, LDL and cholesterol were negatively correlated with SOD and correlated with malondialdehyde (MDA), and cholesterol was negatively correlated with Zn. HDL was negatively correlated with MDA in all the sprayers, but was correlated with GPx in smokers and with Zn in nonsmokers.", "type": "CHEMICAL", "entities": [ "cholesterol", "malondialdehyde", "MDA", "cholesterol", "Zn", "MDA", "Zn" ], "offsets": [ [ 23, 34 ], [ 91, 106 ], [ 108, 111 ], [ 118, 129 ], [ 161, 163 ], [ 200, 203 ], [ 273, 275 ] ] }, { "pmid": "23293126", "text": "In smokers, LDL was negatively correlated with GPx, HDL was negatively correlated with MDA and triglycerides and very-low-density lipoprotein were negatively correlated with Zn.", "type": "CHEMICAL", "entities": [ "MDA", "triglycerides", "Zn" ], "offsets": [ [ 87, 90 ], [ 95, 108 ], [ 174, 176 ] ] }, { "pmid": "23293126", "text": "MDA was negatively correlated with SOD, GPx and Zn.", "type": "CHEMICAL", "entities": [ "MDA", "Zn" ], "offsets": [ [ 0, 3 ], [ 48, 50 ] ] }, { "pmid": "23295229", "text": "Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1.\n", "type": "CHEMICAL", "entities": [ "magnesium", "NADH", "aldehyde" ], "offsets": [ [ 45, 54 ], [ 74, 78 ], [ 88, 96 ] ] }, { "pmid": "23295229", "text": "Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids.", "type": "CHEMICAL", "entities": [ "Aldehyde", "aldehydes", "carboxylic acids" ], "offsets": [ [ 0, 8 ], [ 68, 77 ], [ 81, 97 ] ] }, { "pmid": "23295229", "text": "Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme.", "type": "CHEMICAL", "entities": [ "NADH", "Mg(2+)" ], "offsets": [ [ 80, 84 ], [ 22, 28 ] ] }, { "pmid": "23295229", "text": "By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns).", "type": "CHEMICAL", "entities": [ "NADH", "NADH" ], "offsets": [ [ 105, 109 ], [ 154, 158 ] ] }, { "pmid": "23295229", "text": "We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis.", "type": "CHEMICAL", "entities": [ "Mg(2+)", "NADH" ], "offsets": [ [ 49, 55 ], [ 76, 80 ] ] }, { "pmid": "23295229", "text": "From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively.", "type": "CHEMICAL", "entities": [ "NADH", "NADH", "Mg(2+)" ], "offsets": [ [ 29, 33 ], [ 82, 86 ], [ 148, 154 ] ] }, { "pmid": "23295229", "text": "The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal.", "type": "CHEMICAL", "entities": [ "NADH", "Mg(2+)", "Mg(2+)", "NAD(+)", "NADH", "NADH" ], "offsets": [ [ 43, 47 ], [ 88, 94 ], [ 115, 121 ], [ 159, 165 ], [ 195, 199 ], [ 228, 232 ] ] }, { "pmid": "23295229", "text": "During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH.", "type": "CHEMICAL", "entities": [ "NAD(+)", "butyraldehyde", "NADH", "NADH", "NADH" ], "offsets": [ [ 34, 40 ], [ 45, 58 ], [ 95, 99 ], [ 144, 148 ], [ 216, 220 ] ] }, { "pmid": "23295229", "text": "As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+).", "type": "CHEMICAL", "entities": [ "Mg(2+)", "NADH", "magnesium", "NADH", "Mg(2+)", "Mg(2+)" ], "offsets": [ [ 157, 163 ], [ 259, 263 ], [ 342, 351 ], [ 385, 389 ], [ 460, 466 ], [ 125, 131 ] ] }, { "pmid": "23295229", "text": "This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket.", "type": "CHEMICAL", "entities": [ "Mg(2+)", "NADH" ], "offsets": [ [ 38, 44 ], [ 136, 140 ] ] }, { "pmid": "23295229", "text": "The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization.", "type": "CHEMICAL", "entities": [ "magnesium", "NADH" ], "offsets": [ [ 51, 60 ], [ 85, 89 ] ] }, { "pmid": "23296102", "text": "Acrolein induces Alzheimer's disease-like pathologies in vitro and in vivo.\n", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23296102", "text": "Acrolein, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23296102", "text": "Here, we examined the effects of Acrolein on the AD pathologies in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 33, 41 ] ] }, { "pmid": "23296102", "text": "We found Acrolein induced HT22 cells death in concentration- and time-dependent manners.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "23296102", "text": "Interestingly, Acrolein increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "23296102", "text": "In vivo, chronic oral exposure to Acrolein (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 32, 40 ] ] }, { "pmid": "23296102", "text": "The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain.", "type": "CHEMICAL", "entities": [ "superoxide", "malondialdehyde" ], "offsets": [ [ 14, 24 ], [ 73, 88 ] ] }, { "pmid": "23296102", "text": "Moreover, Acrolein resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 8, 16 ] ] }, { "pmid": "23296102", "text": "Taken together, our findings suggest that exposure to Acrolein induces AD-like pathology in vitro and in vivo.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 52, 60 ] ] }, { "pmid": "23296102", "text": "Scavenging Acrolein might be beneficial for the therapy of AD.", "type": "CHEMICAL", "entities": [ "Acrolein" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "23296142", "text": "Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons.\n", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 19, 28 ] ] }, { "pmid": "23296142", "text": "Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus.", "type": "CHEMICAL", "entities": [ "estradiol", "estrogen" ], "offsets": [ [ 37, 46 ], [ 74, 82 ] ] }, { "pmid": "23296142", "text": "Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane.", "type": "CHEMICAL", "entities": [ "estradiol", "estradiol" ], "offsets": [ [ 107, 116 ], [ 67, 76 ] ] }, { "pmid": "23296142", "text": "Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS).", "type": "CHEMICAL", "entities": [ "ICI 182,780", "bisindolylmaleimide", "BIS" ], "offsets": [ [ 39, 50 ], [ 104, 123 ], [ 125, 128 ] ] }, { "pmid": "23296142", "text": "Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium.", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 45, 54 ] ] }, { "pmid": "23296142", "text": "These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol.", "type": "CHEMICAL", "entities": [ "estradiol" ], "offsets": [ [ 84, 93 ] ] }, { "pmid": "23296837", "text": "Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease.\n", "type": "CHEMICAL", "entities": [ "MPTP" ], "offsets": [ [ 78, 82 ] ] }, { "pmid": "23296837", "text": "One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation.", "type": "CHEMICAL", "entities": [ "eicosanoyl-5-hydroxytryptamide", "EHT" ], "offsets": [ [ 26, 56 ], [ 58, 61 ] ] }, { "pmid": "23296837", "text": "Here, we sought to investigate if EHT has an effect in the MPTP model of PD.", "type": "CHEMICAL", "entities": [ "EHT", "MPTP" ], "offsets": [ [ 33, 36 ], [ 58, 62 ] ] }, { "pmid": "23296837", "text": "Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed.", "type": "CHEMICAL", "entities": [ "EHT", "MPTP" ], "offsets": [ [ 26, 29 ], [ 124, 128 ] ] }, { "pmid": "23296837", "text": "Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment.", "type": "CHEMICAL", "entities": [ "dopamine", "tyrosine", "EHT" ], "offsets": [ [ 22, 30 ], [ 35, 43 ], [ 95, 98 ] ] }, { "pmid": "23296837", "text": "The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT.", "type": "CHEMICAL", "entities": [ "MPTP", "EHT" ], "offsets": [ [ 33, 37 ], [ 148, 151 ] ] }, { "pmid": "23296837", "text": "In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production.", "type": "CHEMICAL", "entities": [ "EHT", "nitric oxide" ], "offsets": [ [ 45, 48 ], [ 181, 193 ] ] }, { "pmid": "23296837", "text": "Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT.", "type": "CHEMICAL", "entities": [ "MPP(+)", "EHT" ], "offsets": [ [ 30, 36 ], [ 201, 204 ] ] }, { "pmid": "23296837", "text": "These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.", "type": "CHEMICAL", "entities": [ "EHT", "MPTP" ], "offsets": [ [ 57, 60 ], [ 69, 73 ] ] }, { "pmid": "23297346", "text": "Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases.\n", "type": "CHEMICAL", "entities": [ "Hydrogen sulfide" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23297346", "text": "Hydrogen sulfide (H(2)S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide.", "type": "CHEMICAL", "entities": [ "nitric oxide", "Hydrogen sulfide", "carbon monoxide", "H(2)S" ], "offsets": [ [ 86, 98 ], [ 0, 16 ], [ 103, 118 ], [ 18, 23 ] ] }, { "pmid": "23297346", "text": "It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase.", "type": "CHEMICAL", "entities": [ "cystathionine", "cystathionine", "3-mercaptopyruvate" ], "offsets": [ [ 35, 48 ], [ 58, 71 ], [ 88, 106 ] ] }, { "pmid": "23297346", "text": "Substantial evidence shows that H(2)S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho.", "type": "CHEMICAL", "entities": [ "H(2)S" ], "offsets": [ [ 30, 35 ] ] }, { "pmid": "23297346", "text": "Moreover, H(2)S has been shown to have therapeutic potential in age-associated diseases.", "type": "CHEMICAL", "entities": [ "H(2)S" ], "offsets": [ [ 8, 13 ] ] }, { "pmid": "23297346", "text": "This article provides an overview of the physiological functions and effects of H(2)S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H(2)S.", "type": "CHEMICAL", "entities": [ "H(2)S", "H(2)S" ], "offsets": [ [ 78, 83 ], [ 184, 189 ] ] }, { "pmid": "23298677", "text": "Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice.\n", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 61, 68 ] ] }, { "pmid": "23298677", "text": "We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions.", "type": "CHEMICAL", "entities": [ "heme" ], "offsets": [ [ 26, 30 ] ] }, { "pmid": "23298677", "text": "We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 24, 31 ] ] }, { "pmid": "23298677", "text": "The induction of HO-1 by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002.", "type": "CHEMICAL", "entities": [ "SB203580", "SP600125", "PD98059", "LY294002" ], "offsets": [ [ 42, 50 ], [ 62, 70 ], [ 72, 79 ], [ 85, 93 ] ] }, { "pmid": "23298677", "text": "Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a HO-1 inhibitor.", "type": "CHEMICAL", "entities": [ "creatinine" ], "offsets": [ [ 107, 117 ] ] }, { "pmid": "23307185", "text": "More robust FV secretion and microparticle generation with PAR4-AP was attributable to stronger and more sustained phosphorylation of myosin light chain at serine 19 and threonine 18.", "type": "CHEMICAL", "entities": [ "serine", "threonine" ], "offsets": [ [ 156, 162 ], [ 170, 179 ] ] }, { "pmid": "23311608", "text": "Diels-Alder mediated controlled release from a poly(ethylene glycol) based hydrogel.\n", "type": "CHEMICAL", "entities": [ "poly(ethylene glycol)" ], "offsets": [ [ 47, 68 ] ] }, { "pmid": "23311608", "text": "A synthetic amino acid bearing a furan functionality was developed and incorporated into peptide sequences using solid phase synthesis.", "type": "CHEMICAL", "entities": [ "amino acid", "furan" ], "offsets": [ [ 12, 22 ], [ 33, 38 ] ] }, { "pmid": "23311608", "text": "Peptides expressing the furan moiety were attached to poly(ethylene glycol) (PEG) hydrogels through a thermally reversible covalent bond formed by a Diels-Alder reaction.", "type": "CHEMICAL", "entities": [ "furan", "poly(ethylene glycol)", "PEG" ], "offsets": [ [ 24, 29 ], [ 54, 75 ], [ 77, 80 ] ] }, { "pmid": "23311608", "text": "Reactions of thiol and maleimide PEG macromers in an off-stoichiometric Michael addition were performed, such that the maleimide moiety was in excess, to create hydrogel networks with pendant Diels-Alder compatible tethering sites, that is, the maleimide.", "type": "CHEMICAL", "entities": [ "maleimide", "maleimide", "thiol", "maleimide PEG" ], "offsets": [ [ 119, 128 ], [ 245, 254 ], [ 13, 18 ], [ 23, 36 ] ] }, { "pmid": "23311608", "text": "This concept was demonstrated by incorporating a fluorescently labeled furan-RGDS sequence into a hydrogel possessing excess maleimide functionalities and monitoring the subsequent liberation of RGDS at various temperatures, illustrating a Diels-Alder mediated release mechanism.", "type": "CHEMICAL", "entities": [ "furan", "maleimide" ], "offsets": [ [ 71, 76 ], [ 125, 134 ] ] }, { "pmid": "23311608", "text": "Increasing the amount of free maleimide and, therefore, the number of potential Diels-Alder reaction sites, effectively slowed the release of peptide from the polymer.", "type": "CHEMICAL", "entities": [ "maleimide" ], "offsets": [ [ 28, 37 ] ] }, { "pmid": "23311608", "text": "For instance, doubling the amount of maleimide sites present in the hydrogel system decreased the amount of peptide released from approximately 60% to about 40% in the same span of time.", "type": "CHEMICAL", "entities": [ "maleimide" ], "offsets": [ [ 35, 44 ] ] }, { "pmid": "23312283", "text": "Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation.\n", "type": "CHEMICAL", "entities": [ "Trimethylamine-N-oxide" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "23312283", "text": "Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis.", "type": "CHEMICAL", "entities": [ "trimethylamine-N-oxide", "TMAO" ], "offsets": [ [ 12, 34 ], [ 36, 40 ] ] }, { "pmid": "23312283", "text": "We now examine genetic, dietary, and hormonal factors regulating TMAO levels.", "type": "CHEMICAL", "entities": [ "TMAO" ], "offsets": [ [ 65, 69 ] ] }, { "pmid": "23312283", "text": "We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO.", "type": "CHEMICAL", "entities": [ "flavin", "trimethylamine", "TMA", "choline", "TMAO" ], "offsets": [ [ 24, 30 ], [ 85, 99 ], [ 101, 104 ], [ 144, 151 ], [ 156, 160 ] ] }, { "pmid": "23312283", "text": "FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels.", "type": "CHEMICAL", "entities": [ "TMAO", "TMAO" ], "offsets": [ [ 102, 106 ], [ 59, 63 ] ] }, { "pmid": "23312283", "text": "In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 81, 90 ] ] }, { "pmid": "23312283", "text": "FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor.", "type": "CHEMICAL", "entities": [ "bile acids", "bile acid" ], "offsets": [ [ 38, 48 ], [ 112, 121 ] ] }, { "pmid": "23312283", "text": "Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis.", "type": "CHEMICAL", "entities": [ "TMAO", "TMAO" ], "offsets": [ [ 91, 95 ], [ 130, 134 ] ] }, { "pmid": "23313270", "text": "Tricycloalternarenes F-H: three new mixed terpenoids produced by an endolichenic fungus Ulocladium sp. using OSMAC method.\n", "type": "CHEMICAL", "entities": [ "Tricycloalternarenes F-H", "terpenoids" ], "offsets": [ [ 0, 24 ], [ 42, 52 ] ] }, { "pmid": "23313270", "text": "Three new mixed terpenoids, tricycloalternarenes (TCAs) F-H (1-3), together with ten known tricycloalternarenes (4-13), were isolated from the Czapek's culture of an endophytic fungus Ulocladium sp.", "type": "CHEMICAL", "entities": [ "terpenoids", "tricycloalternarenes", "TCAs", "tricycloalternarenes" ], "offsets": [ [ 16, 26 ], [ 28, 48 ], [ 50, 54 ], [ 91, 111 ] ] }, { "pmid": "23313270", "text": "TCA 1b (5) showed weak activity against the Bacille Calmette-Guerin strain with the MIC of 125μg/mL. TCA 9b (10) exhibited strong cytotoxic activity against Hela cell line with IC50 of 8.58μM.", "type": "CHEMICAL", "entities": [ "TCA", "TCA" ], "offsets": [ [ 0, 3 ], [ 101, 104 ] ] }, { "pmid": "23313336", "text": "What are the physiological estrogens?\nEstradiol (E2) is the principal physiological estrogen in mammals.", "type": "CHEMICAL", "entities": [ "Estradiol", "estrogens" ], "offsets": [ [ 38, 47 ], [ 27, 36 ] ] }, { "pmid": "23313336", "text": "E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group.", "type": "CHEMICAL", "entities": [ "estrone", "estriol", "progesterone", "testosterone", "cortisol", "aldosterone", "ketone", "methyl" ], "offsets": [ [ 31, 38 ], [ 43, 50 ], [ 97, 109 ], [ 111, 123 ], [ 125, 133 ], [ 138, 149 ], [ 188, 194 ], [ 218, 224 ] ] }, { "pmid": "23313336", "text": "Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 31, 39 ] ] }, { "pmid": "23313336", "text": "However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and ERβ.", "type": "CHEMICAL", "entities": [ "steroids", "Δ(5)-androstenediol", "5α-androstanediol", "27-hydroxycholesterol", "3β-hydroxyl", "methyl", "estrogen" ], "offsets": [ [ 14, 22 ], [ 34, 53 ], [ 55, 72 ], [ 77, 98 ], [ 143, 154 ], [ 165, 171 ], [ 235, 243 ] ] }, { "pmid": "23313336", "text": "Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 13, 21 ] ] }, { "pmid": "23313336", "text": "Our understanding of the physiological responses mediated by these \"alternative\" estrogens is in its infancy.", "type": "CHEMICAL", "entities": [ "estrogens" ], "offsets": [ [ 72, 81 ] ] }, { "pmid": "23313336", "text": "Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities.", "type": "CHEMICAL", "entities": [ "steroids" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "23313637", "text": "Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.\n", "type": "CHEMICAL", "entities": [ "quinoline" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "23313637", "text": "Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain.", "type": "CHEMICAL", "entities": [ "cGMP" ], "offsets": [ [ 60, 64 ] ] }, { "pmid": "23313637", "text": "Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory.", "type": "CHEMICAL", "entities": [ "nitric oxide", "cGMP", "cAMP" ], "offsets": [ [ 55, 67 ], [ 68, 72 ], [ 73, 77 ] ] }, { "pmid": "23313637", "text": "To explore this possibility, a series of quinoline derivatives were synthesized and evaluated.", "type": "CHEMICAL", "entities": [ "quinoline" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "23313637", "text": "Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.", "type": "CHEMICAL", "entities": [ "Quinoline" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23314054", "text": "Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors.\n", "type": "CHEMICAL", "entities": [ "N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide" ], "offsets": [ [ 63, 124 ] ] }, { "pmid": "23314054", "text": "We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1).", "type": "CHEMICAL", "entities": [ "3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile" ], "offsets": [ [ 82, 148 ] ] }, { "pmid": "23314054", "text": "By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment.", "type": "CHEMICAL", "entities": [ "2-hydroxypyridine" ], "offsets": [ [ 54, 71 ] ] }, { "pmid": "23314054", "text": "A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained.", "type": "CHEMICAL", "entities": [ "N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide" ], "offsets": [ [ 25, 83 ] ] }, { "pmid": "23315216", "text": "Transaldolase deficiency is a recently described inborn error of pentose phosphate pathway.", "type": "CHEMICAL", "entities": [ "pentose phosphate" ], "offsets": [ [ 65, 82 ] ] }, { "pmid": "23317163", "text": "Our findings by combined analyses of gene polymorphisms of two separate genes present evidences that such is the case with human body in a clinical setting: 1) an integrated effect of epidermal growth factor receptor (EGFR) and protease activated receptor-1 (PAR-1) on susceptibility to airway hyperresponsiveness (AHR), and 2) a crosstalk effect between muscarinic acetylcholine receptor (mAChRs) and β(2) adrenoceptor (β(2)AR) on bronchodilatory response to anticholinergic agents in patients with COPD.", "type": "CHEMICAL", "entities": [ "acetylcholine" ], "offsets": [ [ 366, 379 ] ] }, { "pmid": "23318685", "text": "Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration.\n", "type": "CHEMICAL", "entities": [ "Peginesatide" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23318685", "text": "Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis.", "type": "CHEMICAL", "entities": [ "Peginesatide", "polyethylene glycol", "PEG" ], "offsets": [ [ 0, 12 ], [ 16, 35 ], [ 37, 40 ] ] }, { "pmid": "23318685", "text": "Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose.", "type": "CHEMICAL", "entities": [ "peginesatide" ], "offsets": [ [ 137, 149 ] ] }, { "pmid": "23318685", "text": "The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life.", "type": "CHEMICAL", "entities": [ "peginesatide" ], "offsets": [ [ 18, 30 ] ] }, { "pmid": "23318685", "text": "The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis.", "type": "CHEMICAL", "entities": [ "peginesatide" ], "offsets": [ [ 4, 16 ] ] }, { "pmid": "23318685", "text": "Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg.", "type": "CHEMICAL", "entities": [ "peginesatide" ], "offsets": [ [ 74, 86 ] ] }, { "pmid": "23318685", "text": "The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.", "type": "CHEMICAL", "entities": [ "peginesatide" ], "offsets": [ [ 40, 52 ] ] }, { "pmid": "23319584", "text": "Calcium binding to thin filaments is a major element controlling active force generation in striated muscles.", "type": "CHEMICAL", "entities": [ "Calcium" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23319584", "text": "Recent evidence suggests that processes other than Ca(2+) binding, such as phosphorylation of myosin regulatory light chain (RLC) also controls contraction of vertebrate striated muscle (Cooke, R. (2011) Biophys.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 51, 57 ] ] }, { "pmid": "23319584", "text": "Electron paramagnetic resonance (EPR) studies using nucleotide analog spin label probes showed that dephosphorylated myosin heads are highly ordered in the relaxed fibers and have very low ATPase activity.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "23319584", "text": "We find that: (i) relaxed cross-bridges, but not active ones, are statistically better ordered in muscle where the RLC is dephosporylated compared with phosphorylated RLC; (ii) relaxed phosphorylated and dephosphorylated cross-bridges rotate equally slowly; and (iii) active phosphorylated cross-bridges rotate considerably faster than dephosphorylated ones during isometric contraction but the duty cycle remained the same, suggesting that both phosphorylated and dephosphorylated muscles develop the same isometric tension at full Ca(2+) saturation.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 533, 539 ] ] }, { "pmid": "23322166", "text": "There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, in fibrotic diseases, but the mechanisms by which LPA-LPA1 signaling promotes pathological fibrosis remain to be fully elucidated.", "type": "CHEMICAL", "entities": [ "LPA", "lysophosphatidic acid", "LPA" ], "offsets": [ [ 163, 166 ], [ 39, 60 ], [ 62, 65 ] ] }, { "pmid": "23322166", "text": "Using a mouse peritoneal fibrosis model, we demonstrate central roles for LPA and LPA1 in fibroblast proliferation.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 74, 77 ] ] }, { "pmid": "23322166", "text": "LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of LPA by driving MRTF-dependent CTGF expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 154, 157 ] ] }, { "pmid": "23327532", "text": "Cooperative effects for CYP2E1 differ between styrene and its metabolites.\n", "type": "CHEMICAL", "entities": [ "styrene" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23327532", "text": "We hypothesized that styrene metabolites have lower affinity than styrene toward CYP2E1 and limited ability to induce cooperative effects during metabolism.", "type": "CHEMICAL", "entities": [ "styrene", "styrene" ], "offsets": [ [ 21, 28 ], [ 66, 73 ] ] }, { "pmid": "23327532", "text": "To test the hypothesis, we determined the potency and mechanism of inhibition for styrene and its metabolites toward oxidation of 4-nitrophenol using CYP2E1 Supersomes® and human liver microsomes.", "type": "CHEMICAL", "entities": [ "styrene", "4-nitrophenol" ], "offsets": [ [ 82, 89 ], [ 130, 143 ] ] }, { "pmid": "23327532", "text": "Styrene oxide and 4-vinylphenol possessed similar affinity for CYP2E1.", "type": "CHEMICAL", "entities": [ "4-vinylphenol" ], "offsets": [ [ 11, 24 ] ] }, { "pmid": "23327532", "text": "Styrene oxide behaved cooperatively like styrene, but 4-vinylphenol decreased turnover at high concentrations.", "type": "CHEMICAL", "entities": [ "styrene", "4-vinylphenol" ], "offsets": [ [ 34, 41 ], [ 47, 60 ] ] }, { "pmid": "23329465", "text": "Its pathogenesis is complex, and involves a state of 'lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a 'lipotoxic liver disease' and its progression to NASH.", "type": "CHEMICAL", "entities": [ "free fatty acid" ], "offsets": [ [ 112, 127 ] ] }, { "pmid": "23329465", "text": "A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other).", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 89, 96 ] ] }, { "pmid": "23329465", "text": "Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials.", "type": "CHEMICAL", "entities": [ "vitamin E", "pioglitazone" ], "offsets": [ [ 80, 89 ], [ 143, 155 ] ] }, { "pmid": "23330546", "text": "Nuclear receptors in bile acid metabolism.\n", "type": "CHEMICAL", "entities": [ "bile acid" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "23330546", "text": "Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism.", "type": "CHEMICAL", "entities": [ "Bile acids", "androstane", "vitamin D", "glucose", "pregnane" ], "offsets": [ [ 0, 10 ], [ 132, 142 ], [ 157, 166 ], [ 230, 237 ], [ 98, 106 ] ] }, { "pmid": "23330546", "text": "These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system.", "type": "CHEMICAL", "entities": [ "bile acid" ], "offsets": [ [ 131, 140 ] ] }, { "pmid": "23330546", "text": "Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity.", "type": "CHEMICAL", "entities": [ "bile acid" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "23330546", "text": "Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease.", "type": "CHEMICAL", "entities": [ "Bile-acid" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23333093", "text": "Green tea catechin leads to global improvement among Alzheimer's disease-related phenotypes in NSE/hAPP-C105 Tg mice.\n", "type": "CHEMICAL", "entities": [ "catechin" ], "offsets": [ [ 10, 18 ] ] }, { "pmid": "23333093", "text": "The aim of this study was to determine whether or not treatment of transgenic (Tg) mice with green tea catechin (GTC), a radical scavenger, improves AD phenotypes.", "type": "CHEMICAL", "entities": [ "catechin" ], "offsets": [ [ 100, 108 ] ] }, { "pmid": "23333093", "text": "Moreover, GTC-treated groups showed lower levels of total cholesterol and low-density lipoprotein cholesterol, whereas the level of high-density lipoprotein cholesterol increased.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "cholesterol" ], "offsets": [ [ 51, 62 ], [ 91, 102 ], [ 150, 161 ] ] }, { "pmid": "23333305", "text": "Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1.", "type": "CHEMICAL", "entities": [ "N", "phospho" ], "offsets": [ [ 51, 52 ], [ 62, 69 ] ] }, { "pmid": "23333834", "text": "Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis.", "type": "CHEMICAL", "entities": [ "Leu", "Arg", "Leu", "Arg", "Tyr", "Asp", "Tyr", "Glu" ], "offsets": [ [ 67, 70 ], [ 74, 77 ], [ 118, 121 ], [ 125, 128 ], [ 37, 40 ], [ 43, 46 ], [ 50, 53 ], [ 56, 59 ] ] }, { "pmid": "23333834", "text": "The efficacy of the candidate peptide was compared with that of the standard drug celecoxib.", "type": "CHEMICAL", "entities": [ "celecoxib" ], "offsets": [ [ 80, 89 ] ] }, { "pmid": "23333834", "text": "The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity.", "type": "CHEMICAL", "entities": [ "YR-11", "cysteine", "serine" ], "offsets": [ [ 10, 15 ], [ 66, 74 ], [ 82, 88 ] ] }, { "pmid": "23333834", "text": "Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats.", "type": "CHEMICAL", "entities": [ "YR-11" ], "offsets": [ [ 16, 21 ] ] }, { "pmid": "23333834", "text": "Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB.", "type": "CHEMICAL", "entities": [ "YR-11" ], "offsets": [ [ 19, 24 ] ] }, { "pmid": "23333897", "text": "Silica nanoparticles were prepared by Stöber synthesis and characterized by dynamic light scattering and scanning electron microscopy.", "type": "CHEMICAL", "entities": [ "Silica" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23333897", "text": "Actin polymerization was measured by phalloidin-TRITC staining, and cell activation was determined by reverse transcription quantitative PCR analysis, L929 cytotoxicity assay (cytokine induction), and pull-down assays (Rho GTPases).", "type": "CHEMICAL", "entities": [ "phalloidin", "TRITC" ], "offsets": [ [ 36, 46 ], [ 47, 52 ] ] }, { "pmid": "23333897", "text": "In contrast to immune stimulatory sequence ISS 1018, BCG DNA spontaneously formed nanoparticulate structures and induced actin polymerization as did synthetic silica nanoparticles.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 158, 164 ] ] }, { "pmid": "23333897", "text": "Co-incubation with silica nanoparticles amplified the responsiveness of macrophages toward the TLR9 ligand ISS 1018.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 18, 24 ] ] }, { "pmid": "23333897", "text": "The activation of Rac1 was induced by silica nanoparticles as well as BCG DNA and is suggested as the critical signaling event inducing both cytoskeleton changes as well as inflammatory cell activation.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 37, 43 ] ] }, { "pmid": "23336337", "text": "Enhancing macrocyclic diterpenes as multidrug-resistance reversers: structure-activity studies on jolkinol D derivatives.\n", "type": "CHEMICAL", "entities": [ "diterpenes", "jolkinol D" ], "offsets": [ [ 22, 32 ], [ 98, 108 ] ] }, { "pmid": "23336337", "text": "The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to 12 ester derivatives (2-13) and hydrolysis to compound 14.", "type": "CHEMICAL", "entities": [ "ester", "jolkinol D" ], "offsets": [ [ 127, 132 ], [ 56, 66 ] ] }, { "pmid": "23336337", "text": "Apart from jolkinol D, all derivatives (2-14) showed potential as MDR reversal agents.", "type": "CHEMICAL", "entities": [ "jolkinol D" ], "offsets": [ [ 11, 21 ] ] }, { "pmid": "23336337", "text": "In this small library of novel bioactive macrocyclic lathyrane diterpene derivatives, designed to evaluate structure-activity relationships essential in overcoming multidrug resistance (MDR), some correlations between MDR reversal and molecular weight, accessible solvent areas, and octanol/water partition coefficient were identified that can contribute to the development of new selective P-gp reversal agents.", "type": "CHEMICAL", "entities": [ "lathyrane diterpene", "octanol" ], "offsets": [ [ 53, 72 ], [ 283, 290 ] ] }, { "pmid": "23337567", "text": "Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway.\n", "type": "CHEMICAL", "entities": [ "arsenic trioxide" ], "offsets": [ [ 24, 40 ] ] }, { "pmid": "23337567", "text": "Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects.", "type": "CHEMICAL", "entities": [ "Arsenic trioxide", "ATO", "arsenic" ], "offsets": [ [ 0, 16 ], [ 18, 21 ], [ 72, 79 ] ] }, { "pmid": "23337567", "text": "We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis.", "type": "CHEMICAL", "entities": [ "ATO" ], "offsets": [ [ 48, 51 ] ] }, { "pmid": "23337567", "text": "We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h.", "type": "CHEMICAL", "entities": [ "ATO" ], "offsets": [ [ 71, 74 ] ] }, { "pmid": "23337567", "text": "Additionally, these effects of ATO on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor.", "type": "CHEMICAL", "entities": [ "ATO" ], "offsets": [ [ 30, 33 ] ] }, { "pmid": "23339076", "text": "Structure prediction of binary pernitride MN2 compounds (M=Ca, Sr, Ba, La, and Ti).\n", "type": "CHEMICAL", "entities": [ "pernitride", "MN2", "Ca", "Sr", "Ba", "La", "Ti" ], "offsets": [ [ 31, 41 ], [ 42, 45 ], [ 59, 61 ], [ 63, 65 ], [ 67, 69 ], [ 71, 73 ], [ 79, 81 ] ] }, { "pmid": "23339076", "text": "Metal-pernitride compounds belong to a class of chemical systems in which both the complex ions and the non-bonding electrons may play roles in the formation of their modified crystalline structures.", "type": "CHEMICAL", "entities": [ "Metal-pernitride" ], "offsets": [ [ 0, 16 ] ] }, { "pmid": "23339076", "text": "To investigate this issue, the energy landscapes of pernitrides of metals with different maximum valence (M=Ca, Sr, Ba, La, and Ti) were globally explored on the ab initio level at standard and high pressures, thereby yielding possible (meta)stable modifications in these systems together with information on how the landscape changed as function of the valence of the metal cation.", "type": "CHEMICAL", "entities": [ "pernitrides", "Ca", "Sr", "Ba", "La", "Ti" ], "offsets": [ [ 52, 63 ], [ 108, 110 ], [ 112, 114 ], [ 116, 118 ], [ 120, 122 ], [ 128, 130 ] ] }, { "pmid": "23339076", "text": "In particular, TiN2 should crystallize in a new structure type, TiN2-I.", "type": "CHEMICAL", "entities": [ "TiN2", "TiN2" ], "offsets": [ [ 15, 19 ], [ 64, 68 ] ] }, { "pmid": "23340897", "text": "25-Hydroxyvitamin D in Obese Youth Across the Spectrum of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes.\n", "type": "CHEMICAL", "entities": [ "25-Hydroxyvitamin D", "Glucose" ], "offsets": [ [ 0, 19 ], [ 58, 65 ] ] }, { "pmid": "23340897", "text": "OBJECTIVETo 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes, and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and β-cell function in this cohort.", "type": "CHEMICAL", "entities": [ "25[OH]D", "glucose", "25(OH)D", "25-hydroxyvitamin D" ], "offsets": [ [ 56, 63 ], [ 117, 124 ], [ 224, 231 ], [ 35, 54 ] ] }, { "pmid": "23340897", "text": "RESEARCH DESIGN AND METHODSPlasma 25(OH)D concentrations were examined in banked specimens in 9- to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity.", "type": "CHEMICAL", "entities": [ "glucose", "25(OH)D" ], "offsets": [ [ 182, 189 ], [ 33, 40 ] ] }, { "pmid": "23340897", "text": "BMI, plasma 25(OH)D, and the proportion of vitamin D-deficient and -insufficient children did not differ across the three groups.", "type": "CHEMICAL", "entities": [ "25(OH)D", "vitamin D" ], "offsets": [ [ 9, 16 ], [ 40, 49 ] ] }, { "pmid": "23340897", "text": "Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or β-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately.", "type": "CHEMICAL", "entities": [ "25(OH)D" ], "offsets": [ [ 43, 50 ] ] }, { "pmid": "23340897", "text": "CONCLUSIONSOur data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups, and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in any of the groups.", "type": "CHEMICAL", "entities": [ "25(OH)D", "glucose", "25(OH)D" ], "offsets": [ [ 64, 71 ], [ 98, 105 ], [ 155, 162 ] ] }, { "pmid": "23340897", "text": "It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth.", "type": "CHEMICAL", "entities": [ "vitamin D" ], "offsets": [ [ 38, 47 ] ] }, { "pmid": "23343565", "text": "[EMIM][N(CN)2], [EMIM][NTf2], and [HMIM][NTf2] with acetone and ethanol by dynamic light scattering (DLS).\n", "type": "CHEMICAL", "entities": [ "acetone", "ethanol", "[EMIM][N(CN)2]", "[EMIM][NTf2]", "[HMIM][NTf2]" ], "offsets": [ [ 52, 59 ], [ 64, 71 ], [ 0, 14 ], [ 16, 28 ], [ 34, 46 ] ] }, { "pmid": "23343565", "text": "[EMIM][N(CN)2] (1-ethyl-3-methylimidazolium dicyanimide), [EMIM][NTf2] (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide), and [HMIM][NTf2] (1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) with acetone and ethanol were studied in dependence on composition in the temperature range from 283.15 to 323.15 K, applying dynamic light scattering (DLS).", "type": "CHEMICAL", "entities": [ "1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide", "acetone", "ethanol", "[EMIM][N(CN)2]", "1-ethyl-3-methylimidazolium dicyanimide", "[EMIM][NTf2]", "1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide", "[HMIM][NTf2]" ], "offsets": [ [ 154, 215 ], [ 222, 229 ], [ 234, 241 ], [ 0, 14 ], [ 16, 55 ], [ 58, 70 ], [ 72, 133 ], [ 140, 152 ] ] }, { "pmid": "23343565", "text": "Mutual diffusivities were found to be lower for the mixtures with ethanol than for those with acetone, which could be related to the formation of hydrogen bonds between ethanol and the ions.", "type": "CHEMICAL", "entities": [ "ethanol", "acetone", "hydrogen", "ethanol" ], "offsets": [ [ 66, 73 ], [ 94, 101 ], [ 146, 154 ], [ 169, 176 ] ] }, { "pmid": "23343565", "text": "For the mixtures of [EMIM][NTf2] with ethanol, however, a minimum of the mutual diffusivities was found in the ethanol mole fraction range from 0.7 to 0.8, which may hint at the vicinity of a critical demixing point.", "type": "CHEMICAL", "entities": [ "[EMIM][NTf2]", "ethanol", "ethanol" ], "offsets": [ [ 20, 32 ], [ 38, 45 ], [ 111, 118 ] ] }, { "pmid": "23347547", "text": "Quercetin-loaded microcapsules ameliorate experimental colitis in mice by anti-inflammatory and antioxidant mechanisms.\n", "type": "CHEMICAL", "entities": [ "Quercetin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23347547", "text": "Quercetin (1) is an anti-inflammatory and antioxidant flavonoid.", "type": "CHEMICAL", "entities": [ "Quercetin", "flavonoid" ], "offsets": [ [ 0, 9 ], [ 54, 63 ] ] }, { "pmid": "23347547", "text": "Thus, the therapeutic effect and mechanisms of 1-loaded microcapsules in acetic acid-induced colitis in mice were evaluated.", "type": "CHEMICAL", "entities": [ "acetic acid" ], "offsets": [ [ 73, 84 ] ] }, { "pmid": "23347547", "text": "Therefore, quercetin seems to be a promising active molecule in inflammatory bowel disease if provided with adequate controlled release.", "type": "CHEMICAL", "entities": [ "quercetin" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23348407", "text": "Single isoflavones have been shown to affect adipocyte differentiation, but knowledge on the effect of dietary relevant mixtures of PEs, including for instance lignans, is lacking.", "type": "CHEMICAL", "entities": [ "isoflavones" ], "offsets": [ [ 7, 18 ] ] }, { "pmid": "23348407", "text": "In the current study dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them, were examined for effects on adipogenesis in 3T3-L1 adipocytes, as well as tested for their PPARγ activating abilities.", "type": "CHEMICAL", "entities": [ "isoflavones", "lignans", "coumestrol" ], "offsets": [ [ 50, 61 ], [ 85, 92 ], [ 116, 126 ] ] }, { "pmid": "23348407", "text": "The results showed that mixtures of isoflavonoid parent compounds and metabolites, respectively, a mixture of lignan metabolites, as well as coumestrol concentration-dependently inhibited adipocyte differentiation.", "type": "CHEMICAL", "entities": [ "isoflavonoid", "lignan", "coumestrol" ], "offsets": [ [ 35, 47 ], [ 109, 115 ], [ 140, 150 ] ] }, { "pmid": "23348407", "text": "Furthermore, a mixture of isoflavonoid parent compounds, and a mixture of isoflavonoid metabolites were found to have PPARγ activating abilities.", "type": "CHEMICAL", "entities": [ "isoflavonoid", "isoflavonoid" ], "offsets": [ [ 25, 37 ], [ 73, 85 ] ] }, { "pmid": "23348408", "text": "Anti-inflammatory activity of patchouli alcohol in RAW264.7 and HT-29 cells.\n", "type": "CHEMICAL", "entities": [ "patchouli alcohol" ], "offsets": [ [ 30, 47 ] ] }, { "pmid": "23348408", "text": "Patchouli alcohol (PA) is a chemical compound extracted from patchouli which belongs to the genus Pogostemon, herb of mint family.", "type": "CHEMICAL", "entities": [ "Patchouli alcohol" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "23349208", "text": "Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells.\n", "type": "CHEMICAL", "entities": [ "EPA", "DHA" ], "offsets": [ [ 55, 58 ], [ 63, 66 ] ] }, { "pmid": "23349208", "text": "Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state.", "type": "CHEMICAL", "entities": [ "eicosapentaenoic acid", "EPA", "docosahexaenoic acid", "DHA" ], "offsets": [ [ 55, 76 ], [ 78, 81 ], [ 87, 107 ], [ 109, 112 ] ] }, { "pmid": "23349208", "text": "To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 88, 98 ] ] }, { "pmid": "23349208", "text": "Both fatty acids, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells.", "type": "CHEMICAL", "entities": [ "fatty acids", "DHA", "EPA" ], "offsets": [ [ 5, 16 ], [ 22, 25 ], [ 59, 62 ] ] }, { "pmid": "23349208", "text": "In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6.", "type": "CHEMICAL", "entities": [ "EPA", "DHA" ], "offsets": [ [ 18, 21 ], [ 26, 29 ] ] }, { "pmid": "23349208", "text": "Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid.", "type": "CHEMICAL", "entities": [ "EPA", "DHA", "arachidonic acid" ], "offsets": [ [ 24, 27 ], [ 32, 35 ], [ 70, 86 ] ] }, { "pmid": "23349208", "text": "Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased.", "type": "CHEMICAL", "entities": [ "(LTB)4", "thromboxane B", "(TXB)2", "leukotriene B", "TXB3", "LTB5" ], "offsets": [ [ 52, 58 ], [ 13, 26 ], [ 27, 33 ], [ 38, 51 ], [ 102, 106 ], [ 111, 115 ] ] }, { "pmid": "23349208", "text": "Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors.", "type": "CHEMICAL", "entities": [ "EPA", "DHA", "mono- and trihydroxy", "resolvins" ], "offsets": [ [ 8, 11 ], [ 16, 19 ], [ 46, 66 ], [ 126, 135 ] ] }, { "pmid": "23349208", "text": "Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses.", "type": "CHEMICAL", "entities": [ "DHA", "EPA" ], "offsets": [ [ 31, 34 ], [ 23, 26 ] ] }, { "pmid": "23352910", "text": "In this work, we investigated the potential of novel bi-ligand (transferrin-poly-l-arginine) liposomal vector for delivery of desired gene to brain, in vivo.", "type": "CHEMICAL", "entities": [ "poly-l-arginine" ], "offsets": [ [ 76, 91 ] ] }, { "pmid": "23352910", "text": "The biodistribution profile of 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide(DiR)-labeled liposomes was evaluated in adult rats after single intravenous injection at dose of 15.2μmoles of phospholipids/kg body weight.", "type": "CHEMICAL", "entities": [ "1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide", "DiR" ], "offsets": [ [ 31, 94 ], [ 95, 98 ] ] }, { "pmid": "23352911", "text": "Encapsulation of Nod1 and Nod2 receptor ligands into poly(lactic acid) nanoparticles potentiates their immune properties.\n", "type": "CHEMICAL", "entities": [ "poly(lactic acid)" ], "offsets": [ [ 53, 70 ] ] }, { "pmid": "23352911", "text": "As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly(Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated.", "type": "CHEMICAL", "entities": [ "Poly(Lactic Acid)", "PLA" ], "offsets": [ [ 156, 173 ], [ 175, 178 ] ] }, { "pmid": "23352911", "text": "Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs.", "type": "CHEMICAL", "entities": [ "PLA" ], "offsets": [ [ 30, 33 ] ] }, { "pmid": "23352911", "text": "Furthermore, co-injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum.", "type": "CHEMICAL", "entities": [ "PLA" ], "offsets": [ [ 59, 62 ] ] }, { "pmid": "23352911", "text": "These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency.", "type": "CHEMICAL", "entities": [ "PLA" ], "offsets": [ [ 61, 64 ] ] }, { "pmid": "23353658", "text": "In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae.\n", "type": "CHEMICAL", "entities": [ "isoimperatorin", "cnidilin", "imperatorin" ], "offsets": [ [ 101, 115 ], [ 120, 128 ], [ 88, 99 ] ] }, { "pmid": "23353658", "text": "Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases.", "type": "CHEMICAL", "entities": [ "Coumarins" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23353658", "text": "By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including imperatorin, isoimperatorin and cnidilin in mice after oral administration of Dahuricae extract at doses of 800mg/kg.", "type": "CHEMICAL", "entities": [ "coumarins", "imperatorin", "isoimperatorin", "cnidilin" ], "offsets": [ [ 113, 122 ], [ 134, 145 ], [ 147, 161 ], [ 166, 174 ] ] }, { "pmid": "23353658", "text": "The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution.", "type": "CHEMICAL", "entities": [ "acetonitrile" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "23353658", "text": "Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of imperatorin, isoimperatorin and cnidilin.", "type": "CHEMICAL", "entities": [ "imperatorin", "isoimperatorin", "cnidilin" ], "offsets": [ [ 166, 177 ], [ 179, 193 ], [ 198, 206 ] ] }, { "pmid": "23353658", "text": "The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for imperatorin, isoimperatorin and cnidilin, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo.", "type": "CHEMICAL", "entities": [ "imperatorin", "isoimperatorin", "cnidilin", "coumarins" ], "offsets": [ [ 296, 307 ], [ 309, 323 ], [ 328, 336 ], [ 378, 387 ] ] }, { "pmid": "23353658", "text": "In the in vitro model we observed high permeability of imperatorin and isoimperatorin with the P-gp-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of cnidilin with 0.82.", "type": "CHEMICAL", "entities": [ "imperatorin", "isoimperatorin", "cnidilin" ], "offsets": [ [ 55, 66 ], [ 71, 85 ], [ 175, 183 ] ] }, { "pmid": "23353658", "text": "All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases.", "type": "CHEMICAL", "entities": [ "coumarins" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "23353701", "text": "Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde.\n", "type": "CHEMICAL", "entities": [ "adenosine dialdehyde" ], "offsets": [ [ 79, 99 ] ] }, { "pmid": "23353701", "text": "Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins.", "type": "CHEMICAL", "entities": [ "methyl", "S-adenosylmethionine", "SAM" ], "offsets": [ [ 59, 65 ], [ 75, 95 ], [ 97, 100 ] ] }, { "pmid": "23353701", "text": "In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor.", "type": "CHEMICAL", "entities": [ "adenosylhomocysteine", "SAH" ], "offsets": [ [ 147, 167 ], [ 169, 172 ] ] }, { "pmid": "23353701", "text": "Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "adenosylhomocysteine", "SAH", "SAH", "adenosine dialdehyde", "AdOx" ], "offsets": [ [ 89, 109 ], [ 111, 114 ], [ 156, 159 ], [ 15, 35 ], [ 37, 41 ] ] }, { "pmid": "23353701", "text": "Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity.", "type": "CHEMICAL", "entities": [ "AdOx" ], "offsets": [ [ 51, 55 ] ] }, { "pmid": "23353701", "text": "Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses.", "type": "CHEMICAL", "entities": [ "AdOx" ], "offsets": [ [ 15, 19 ] ] }, { "pmid": "23353701", "text": "In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src.", "type": "CHEMICAL", "entities": [ "SAH", "3-deazaadenosine", "DAZA" ], "offsets": [ [ 57, 60 ], [ 131, 147 ], [ 149, 153 ] ] }, { "pmid": "23353701", "text": "Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.", "type": "CHEMICAL", "entities": [ "SAH" ], "offsets": [ [ 43, 46 ] ] }, { "pmid": "23353736", "text": "Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1).\n", "type": "CHEMICAL", "entities": [ "methyl rosmarinate" ], "offsets": [ [ 28, 46 ] ] }, { "pmid": "23353736", "text": "A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods.", "type": "CHEMICAL", "entities": [ "methyl rosmarinate" ], "offsets": [ [ 63, 81 ] ] }, { "pmid": "23353741", "text": "Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents.\n", "type": "CHEMICAL", "entities": [ "resveratrol amide" ], "offsets": [ [ 50, 67 ] ] }, { "pmid": "23353741", "text": "Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities.", "type": "CHEMICAL", "entities": [ "resveratrol amide" ], "offsets": [ [ 22, 39 ] ] }, { "pmid": "23353741", "text": "All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis.", "type": "CHEMICAL", "entities": [ "(1)H", "(13)C" ], "offsets": [ [ 36, 40 ], [ 46, 51 ] ] }, { "pmid": "23353741", "text": "All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) inhibitory activity of murine macrophage RAW 264.7 cell line.", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2" ], "offsets": [ [ 156, 172 ], [ 174, 178 ] ] }, { "pmid": "23353821", "text": "We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling.", "type": "CHEMICAL", "entities": [ "oxygen", "tyrosine" ], "offsets": [ [ 52, 58 ], [ 126, 134 ] ] }, { "pmid": "23353821", "text": "Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 93, 99 ] ] }, { "pmid": "23353821", "text": "Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H(2)O(2) resistance and soft agar growth.", "type": "CHEMICAL", "entities": [ "H(2)O(2)" ], "offsets": [ [ 201, 209 ] ] }, { "pmid": "23354728", "text": "The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 40, 47 ] ] }, { "pmid": "23354728", "text": "These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-β-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade.", "type": "CHEMICAL", "entities": [ "fatty acid", "11-β-hydroxysteroid", "sodium", "glucose" ], "offsets": [ [ 170, 180 ], [ 200, 219 ], [ 114, 120 ], [ 129, 136 ] ] }, { "pmid": "23354728", "text": "Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 157, 164 ] ] }, { "pmid": "23355087", "text": "3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients.\n", "type": "CHEMICAL", "entities": [ "3-Methylglutaconic" ], "offsets": [ [ 0, 18 ] ] }, { "pmid": "23355087", "text": "Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic acid" ], "offsets": [ [ 30, 53 ] ] }, { "pmid": "23355087", "text": "In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation.", "type": "CHEMICAL", "entities": [ "3-methylglutaconyl-CoA", "leucine" ], "offsets": [ [ 3, 25 ], [ 83, 90 ] ] }, { "pmid": "23355087", "text": "In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic" ], "offsets": [ [ 28, 46 ] ] }, { "pmid": "23355087", "text": "We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic" ], "offsets": [ [ 145, 163 ] ] }, { "pmid": "23355087", "text": "Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic" ], "offsets": [ [ 124, 142 ] ] }, { "pmid": "23355087", "text": "Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders).", "type": "CHEMICAL", "entities": [ "3-methylglutaconic", "3-methylglutaconic", "urea" ], "offsets": [ [ 67, 85 ], [ 173, 191 ], [ 226, 230 ] ] }, { "pmid": "23355087", "text": "In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic" ], "offsets": [ [ 85, 103 ] ] }, { "pmid": "23355087", "text": "These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.", "type": "CHEMICAL", "entities": [ "3-methylglutaconic" ], "offsets": [ [ 84, 102 ] ] }, { "pmid": "23356880", "text": "An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols).", "type": "CHEMICAL", "entities": [ "tocopherols", "tocotrienols" ], "offsets": [ [ 300, 311 ], [ 316, 328 ] ] }, { "pmid": "23356880", "text": "It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases).", "type": "CHEMICAL", "entities": [ "oleocanthal", "p-HPEA-EDA" ], "offsets": [ [ 24, 35 ], [ 37, 47 ] ] }, { "pmid": "23356880", "text": "Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system).", "type": "CHEMICAL", "entities": [ "polyunsaturated fatty acids", "cis-cis-1,4-pentadiene" ], "offsets": [ [ 171, 198 ], [ 212, 234 ] ] }, { "pmid": "23356880", "text": "Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids).", "type": "CHEMICAL", "entities": [ "trans-β-carotene", "xanthophylls", "lutein", "violaxanthin", "neoxanthin" ], "offsets": [ [ 67, 83 ], [ 88, 100 ], [ 102, 108 ], [ 110, 122 ], [ 124, 134 ] ] }, { "pmid": "23358307", "text": "Synthesis, DNA binding and antitumor evaluation of styelsamine and cystodytin analogues.\n", "type": "CHEMICAL", "entities": [ "styelsamine", "cystodytin" ], "offsets": [ [ 51, 62 ], [ 67, 77 ] ] }, { "pmid": "23358307", "text": "A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2-mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines.", "type": "CHEMICAL", "entities": [ "pyrido[4,3,2-mn]acridin-4-one", "styelsamine", "pyrido[4,3,2-mn]acridine", "cystodytin" ], "offsets": [ [ 107, 136 ], [ 52, 63 ], [ 65, 89 ], [ 95, 105 ] ] }, { "pmid": "23358307", "text": "Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (K(app) 5.33 × 10(6) and 3.64 × 10(6) M(-1), respectively).", "type": "CHEMICAL", "entities": [ "styelsamine", "styelsamines B and D" ], "offsets": [ [ 26, 37 ], [ 101, 121 ] ] }, { "pmid": "23358307", "text": "In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro.", "type": "CHEMICAL", "entities": [ "cystodytin iminoquinone alkaloids", "styelsamine" ], "offsets": [ [ 17, 50 ], [ 119, 130 ] ] }, { "pmid": "23358307", "text": "Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI(50) 0.4", "type": "CHEMICAL", "entities": [ "3-phenylpropanamide" ], "offsets": [ [ 129, 148 ] ] }, { "pmid": "23362838", "text": "Intercalation pathway in many-particle LiFePO4 electrode revealed by nanoscale state-of-charge mapping.\n", "type": "CHEMICAL", "entities": [ "LiFePO4" ], "offsets": [ [ 39, 46 ] ] }, { "pmid": "23362838", "text": "The intercalation pathway of lithium iron phosphate (LFP) in the positive electrode of a lithium-ion battery was probed at the ∼40 nm length scale using oxidation-state-sensitive X-ray microscopy.", "type": "CHEMICAL", "entities": [ "lithium iron phosphate", "LFP", "lithium" ], "offsets": [ [ 29, 51 ], [ 53, 56 ], [ 89, 96 ] ] }, { "pmid": "23362838", "text": "Combined with morphological observations of the same exact locations using transmission electron microscopy, we quantified the local state-of-charge of approximately 450 individual LFP particles over nearly the entire thickness of the porous electrode.", "type": "CHEMICAL", "entities": [ "LFP" ], "offsets": [ [ 179, 182 ] ] }, { "pmid": "23362838", "text": "Therefore, strategies for further enhancing the performance of LFP electrodes should not focus on increasing the phase-boundary velocity but on the rate of phase-transformation initiation.", "type": "CHEMICAL", "entities": [ "LFP" ], "offsets": [ [ 57, 60 ] ] }, { "pmid": "23363425", "text": "Silica precipitation by synthetic minicollagens.\n", "type": "CHEMICAL", "entities": [ "Silica" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23363425", "text": "Oligomeric Pro-Hyp-Gly- (POG-) peptides, wherein the collagenous triple helix is supported by C-terminal capping, exhibit silica precipitation properties (O, Hyp = (2S,4R)hydroxyproline).", "type": "CHEMICAL", "entities": [ "C", "Pro-Hyp-Gly", "silica", "Hyp", "(2S,4R)hydroxyproline" ], "offsets": [ [ 94, 95 ], [ 11, 22 ], [ 122, 128 ], [ 158, 161 ], [ 164, 185 ] ] }, { "pmid": "23363425", "text": "As quantified by a molybdate assay, the length of the covalently tethered triple helix (number of POG units) determines the amount of amorphous silica obtained from silicic acid solution.", "type": "CHEMICAL", "entities": [ "silica", "silicic acid" ], "offsets": [ [ 144, 150 ], [ 165, 177 ] ] }, { "pmid": "23363425", "text": "Although lacking charged side chains, the synthetic collagens precipitate large quantities of silicic acid resulting in micrometer-sized spheres of varying surface morphologies as analyzed by scanning electron microscopy.", "type": "CHEMICAL", "entities": [ "silicic acid" ], "offsets": [ [ 94, 106 ] ] }, { "pmid": "23363425", "text": "The minicollagens described here provide an unexpected alternative to the widely used precipitation conditions, which generally depend on (poly-)amines in phosphate buffer.", "type": "CHEMICAL", "entities": [ "(poly-)amines", "phosphate" ], "offsets": [ [ 138, 151 ], [ 155, 164 ] ] }, { "pmid": "23363425", "text": "Hence, silica-enclosed collagens have promising perspectives as composite materials.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 7, 13 ] ] }, { "pmid": "23368510", "text": "Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin.\n", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 151, 160 ] ] }, { "pmid": "23368510", "text": "AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 135, 144 ] ] }, { "pmid": "23368510", "text": "Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 29, 36 ] ] }, { "pmid": "23368735", "text": "The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway.\n", "type": "CHEMICAL", "entities": [ "iodido", "chlorido ruthenium", "osmium arene azo- and imino-pyridine" ], "offsets": [ [ 28, 34 ], [ 42, 60 ], [ 65, 101 ] ] }, { "pmid": "23368735", "text": "Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells.", "type": "CHEMICAL", "entities": [ "M = Ru(II) or Os(II)", "X ═ Cl or I", "Cl", "I", "[M(p-cymene)(azo/imino-pyridine)X](+)" ], "offsets": [ [ 83, 103 ], [ 108, 119 ], [ 112, 114 ], [ 118, 119 ], [ 39, 76 ] ] }, { "pmid": "23368735", "text": "Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin.", "type": "CHEMICAL", "entities": [ "iodido", "chlorido", "platinum", "cisplatin", "oxaliplatin" ], "offsets": [ [ 15, 21 ], [ 53, 61 ], [ 124, 132 ], [ 139, 148 ], [ 153, 164 ] ] }, { "pmid": "23368735", "text": "They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis.", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 49, 58 ] ] }, { "pmid": "23368735", "text": "The iodido complexes retain potency in p53 mutant colon cells.", "type": "CHEMICAL", "entities": [ "iodido" ], "offsets": [ [ 2, 8 ] ] }, { "pmid": "23368735", "text": "In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime.", "type": "CHEMICAL", "entities": [ "glutathione", "l-buthionine sulfoxime" ], "offsets": [ [ 78, 89 ], [ 109, 131 ] ] }, { "pmid": "23368743", "text": "Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter.\n", "type": "CHEMICAL", "entities": [ "Zinc" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23368743", "text": "Zinc is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities.", "type": "CHEMICAL", "entities": [ "Zinc" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23368743", "text": "Cellular zinc is controlled by zinc-chelating proteins and by zinc transporters.", "type": "CHEMICAL", "entities": [ "zinc", "zinc", "zinc" ], "offsets": [ [ 9, 13 ], [ 31, 35 ], [ 62, 66 ] ] }, { "pmid": "23368743", "text": "The recent identification of zinc permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal zinc levels in cells deficient in TRPML1, suggested a role for TRPML1 in zinc transport.", "type": "CHEMICAL", "entities": [ "zinc", "zinc", "zinc" ], "offsets": [ [ 29, 33 ], [ 156, 160 ], [ 229, 233 ] ] }, { "pmid": "23368743", "text": "In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and zinc staining, when cells are exposed to high concentrations of zinc.", "type": "CHEMICAL", "entities": [ "zinc", "zinc" ], "offsets": [ [ 198, 202 ], [ 262, 266 ] ] }, { "pmid": "23368743", "text": "We now show that lysosomal enlargement and zinc build-up in TRPML1-KD cells exposed to zinc are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the zinc transporter ZnT4.", "type": "CHEMICAL", "entities": [ "zinc", "zinc", "zinc", "zinc" ], "offsets": [ [ 40, 44 ], [ 84, 88 ], [ 118, 122 ], [ 225, 229 ] ] }, { "pmid": "23368743", "text": "TRPML1 KD is associated with a build-up of cytoplasmic zinc and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a).", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 52, 56 ] ] }, { "pmid": "23368743", "text": "TRPML1 KD did not suppress lysosomal secretion, but it did delay zinc leak from the lysosomes into the cytoplasm.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 62, 66 ] ] }, { "pmid": "23368743", "text": "These results underscore a role for TRPML1 in zinc metabolism.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 43, 47 ] ] }, { "pmid": "23368743", "text": "Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "23369343", "text": "Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of α-santalol and sandalwood oil.\n", "type": "CHEMICAL", "entities": [ "α-santalol" ], "offsets": [ [ 71, 81 ] ] }, { "pmid": "23369343", "text": "The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent α-santalol.", "type": "CHEMICAL", "entities": [ "α-santalol" ], "offsets": [ [ 144, 154 ] ] }, { "pmid": "23369343", "text": "The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models.", "type": "CHEMICAL", "entities": [ "alloxan" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "23369343", "text": "The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models.", "type": "CHEMICAL", "entities": [ "d-galactose" ], "offsets": [ [ 50, 61 ] ] }, { "pmid": "23369343", "text": "Intraperitoneal administration of α-santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice.", "type": "CHEMICAL", "entities": [ "α-santalol", "glucose", "bilirubin", "peroxides", "alloxan" ], "offsets": [ [ 32, 42 ], [ 147, 154 ], [ 162, 171 ], [ 199, 208 ], [ 249, 256 ] ] }, { "pmid": "23369343", "text": "Similarly, intraperitoneal administration of α-santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice.", "type": "CHEMICAL", "entities": [ "α-santalol", "bilirubin", "superoxide", "sulfhydryl", "carbonyl", "nitric oxide", "peroxide", "d-galactose" ], "offsets": [ [ 42, 52 ], [ 187, 196 ], [ 198, 208 ], [ 235, 245 ], [ 255, 263 ], [ 265, 277 ], [ 291, 299 ], [ 338, 349 ] ] }, { "pmid": "23369343", "text": "Besides, it was observed that the beneficial effects of α-santalol were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource.", "type": "CHEMICAL", "entities": [ "α-santalol" ], "offsets": [ [ 52, 62 ] ] }, { "pmid": "23370008", "text": "Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice.\n", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 74, 83 ] ] }, { "pmid": "23370008", "text": "The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "23370008", "text": "However, several adverse effects of ritodrine therapy, including liver damage, have been noted.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 35, 44 ] ] }, { "pmid": "23370008", "text": "To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 41, 50 ] ] }, { "pmid": "23370008", "text": "Here, we report the development and analysis of an animal model of ritodrine-induced liver damage.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 66, 75 ] ] }, { "pmid": "23370008", "text": "Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "23370008", "text": "Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself.", "type": "CHEMICAL", "entities": [ "steroid", "ritodrine" ], "offsets": [ [ 66, 73 ], [ 125, 134 ] ] }, { "pmid": "23370008", "text": "Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 103, 112 ] ] }, { "pmid": "23370008", "text": "This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase.", "type": "CHEMICAL", "entities": [ "aspartate", "alanine" ], "offsets": [ [ 117, 126 ], [ 148, 155 ] ] }, { "pmid": "23370008", "text": "The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin.", "type": "CHEMICAL", "entities": [ "ritodrine", "acetaminophen", "valproic acid", "metformin" ], "offsets": [ [ 45, 54 ], [ 151, 164 ], [ 166, 179 ], [ 184, 193 ] ] }, { "pmid": "23370008", "text": "Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase.", "type": "CHEMICAL", "entities": [ "cyclic adenosine 3',5'-monophosphate", "cAMP", "ritodrine" ], "offsets": [ [ 32, 68 ], [ 70, 74 ], [ 120, 129 ] ] }, { "pmid": "23370008", "text": "Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor.", "type": "CHEMICAL", "entities": [ "ritodrine" ], "offsets": [ [ 146, 155 ] ] }, { "pmid": "23371303", "text": "Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination.\n", "type": "CHEMICAL", "entities": [ "Ceftazidime", "avibactam", "cephalosporin" ], "offsets": [ [ 0, 11 ], [ 12, 21 ], [ 31, 44 ] ] }, { "pmid": "23371303", "text": "Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes.", "type": "CHEMICAL", "entities": [ "NXL104", "AVE1330A", "β-lactam" ], "offsets": [ [ 19, 25 ], [ 27, 35 ], [ 56, 64 ] ] }, { "pmid": "23371303", "text": "This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 51, 62 ], [ 63, 72 ] ] }, { "pmid": "23371303", "text": "Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases.", "type": "CHEMICAL", "entities": [ "β-lactam", "avibactam", "cephem", "avibactam" ], "offsets": [ [ 11, 19 ], [ 47, 56 ], [ 91, 97 ], [ 124, 133 ] ] }, { "pmid": "23371303", "text": "Very little is known about the potential for avibactam to select for resistance.", "type": "CHEMICAL", "entities": [ "avibactam" ], "offsets": [ [ 39, 48 ] ] }, { "pmid": "23371303", "text": "The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s).", "type": "CHEMICAL", "entities": [ "avibactam", "ceftazidime" ], "offsets": [ [ 10, 19 ], [ 116, 127 ] ] }, { "pmid": "23371303", "text": "Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction).", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 81, 92 ], [ 41, 50 ] ] }, { "pmid": "23371303", "text": "Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp.", "type": "CHEMICAL", "entities": [ "avibactam", "ceftazidime" ], "offsets": [ [ 35, 44 ], [ 78, 89 ] ] }, { "pmid": "23371303", "text": "The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime.", "type": "CHEMICAL", "entities": [ "avibactam", "ceftazidime" ], "offsets": [ [ 17, 26 ], [ 118, 129 ] ] }, { "pmid": "23371303", "text": "The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg.", "type": "CHEMICAL", "entities": [ "avibactam" ], "offsets": [ [ 100, 109 ] ] }, { "pmid": "23371303", "text": "The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime.", "type": "CHEMICAL", "entities": [ "ceftazidime" ], "offsets": [ [ 100, 111 ] ] }, { "pmid": "23371303", "text": "Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance.", "type": "CHEMICAL", "entities": [ "avibactam", "creatinine" ], "offsets": [ [ 9, 18 ], [ 80, 90 ] ] }, { "pmid": "23371303", "text": "Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam", "ceftazidime" ], "offsets": [ [ 25, 36 ], [ 37, 46 ], [ 148, 159 ] ] }, { "pmid": "23371303", "text": "Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam", "carbapenem", "cephalosporin" ], "offsets": [ [ 33, 44 ], [ 45, 54 ], [ 83, 93 ], [ 214, 227 ] ] }, { "pmid": "23371303", "text": "The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 21, 32 ], [ 33, 42 ] ] }, { "pmid": "23371303", "text": "Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.", "type": "CHEMICAL", "entities": [ "avibactam" ], "offsets": [ [ 2, 11 ] ] }, { "pmid": "23371303", "text": "In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli.", "type": "CHEMICAL", "entities": [ "avibactam", "ceftazidime" ], "offsets": [ [ 5, 14 ], [ 49, 60 ] ] }, { "pmid": "23371303", "text": "The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 9, 20 ], [ 21, 30 ] ] }, { "pmid": "23371303", "text": "Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 16, 27 ], [ 28, 37 ] ] }, { "pmid": "23371303", "text": "In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam", "metronidazole" ], "offsets": [ [ 0, 11 ], [ 12, 21 ], [ 55, 68 ] ] }, { "pmid": "23371303", "text": "Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections.", "type": "CHEMICAL", "entities": [ "ceftazidime", "avibactam" ], "offsets": [ [ 22, 33 ], [ 34, 43 ] ] }, { "pmid": "23371451", "text": "Increased human dermal microvascular endothelial cell survival induced by cysteamine.\n", "type": "CHEMICAL", "entities": [ "cysteamine" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "23371451", "text": "Cystinosis is an autosomal recessive disease caused by intralysosomal cystine accumulation, treated with cysteamine.", "type": "CHEMICAL", "entities": [ "cysteamine" ], "offsets": [ [ 105, 115 ] ] }, { "pmid": "23371451", "text": "Recently, new adverse effects of cysteamine were reported.", "type": "CHEMICAL", "entities": [ "cysteamine" ], "offsets": [ [ 33, 43 ] ] }, { "pmid": "23371451", "text": "To examine the mechanism of angioendotheliomatosis associated with cysteamine toxicity, we examined the effect of cysteamine on human dermal microvascular endothelial cells (HDMVEC).", "type": "CHEMICAL", "entities": [ "cysteamine", "cysteamine" ], "offsets": [ [ 67, 77 ], [ 114, 124 ] ] }, { "pmid": "23371451", "text": "After cysteamine exposure (range 0-3.0 mM) during 24 h, cell viability was measured using water soluble tetrazolium salt-1 (WST-1) in both control HDMVEC and fibroblasts.", "type": "CHEMICAL", "entities": [ "cysteamine", "tetrazolium salt-1" ], "offsets": [ [ 6, 16 ], [ 104, 122 ] ] }, { "pmid": "23371451", "text": "Cell proliferation and apoptosis rate were measured in HDMVEC by bromodeoxyuridine (BrdU) incorporation and caspase 3 and caspase 7 activity, respectively.", "type": "CHEMICAL", "entities": [ "bromodeoxyuridine", "BrdU" ], "offsets": [ [ 63, 80 ], [ 82, 86 ] ] }, { "pmid": "23371451", "text": "Intracellular glutathione (GSH) was measured in HDMVEC after cysteamine exposure of 0, 0.1 or 1.0 mM. Medium and cysteamine were refreshed every 6 h to mimic the in vivo situation.", "type": "CHEMICAL", "entities": [ "glutathione", "GSH", "cysteamine", "cysteamine" ], "offsets": [ [ 12, 23 ], [ 25, 28 ], [ 59, 69 ], [ 111, 121 ] ] }, { "pmid": "23371451", "text": "Next, cell viability in HDMVEC was measured after 24 h of GSH exposure (range 0-10.0 mM).", "type": "CHEMICAL", "entities": [ "GSH" ], "offsets": [ [ 54, 57 ] ] }, { "pmid": "23371451", "text": "HDMVEC viability and proliferation increased after cysteamine exposure 0.03-3.0 mM (p < 0.01) and 0.03-1.0 mM (p = 0.01) respectively; cell viability in fibroblasts was not affected by incubation with cysteamine.", "type": "CHEMICAL", "entities": [ "cysteamine", "cysteamine" ], "offsets": [ [ 45, 55 ], [ 195, 205 ] ] }, { "pmid": "23371451", "text": "Apoptosis remained unaffected by incubation with 0-1.0 mM cysteamine, 3.0 mM caused increased apoptosis.", "type": "CHEMICAL", "entities": [ "cysteamine", "GSH" ], "offsets": [ [ 42, 52 ], [ 103, 106 ] ] }, { "pmid": "23371451", "text": "Intracellular GSH was significantly increased after incubation with cysteamine 0.1 mM (p = 0.02) and 1.0 mM", "type": "CHEMICAL", "entities": [ "cysteamine" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "23371451", "text": "HDMVEC viability increased after exposure to GSH 1.0-5.0 mM (p < 0.01).", "type": "CHEMICAL", "entities": [ "GSH", "Cysteamine" ], "offsets": [ [ 17, 20 ], [ 56, 66 ] ] }, { "pmid": "23371451", "text": "Cysteamine concentrations, similar to those described in plasma of cystinosis patients, stimulate HDMVEC viability and proliferation and increase intracellular GSH content.", "type": "CHEMICAL", "entities": [ "GSH" ], "offsets": [ [ 127, 130 ] ] }, { "pmid": "23371451", "text": "We postulate that this mechanism might underlie angioendotheliomatosis induced by cysteamine.", "type": "CHEMICAL", "entities": [ "cysteamine" ], "offsets": [ [ 49, 59 ] ] }, { "pmid": "23372041", "text": "Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 34, 46 ] ] }, { "pmid": "23372041", "text": "In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10(-5)) for percentage of total caloric intake from protein and carbohydrate.", "type": "CHEMICAL", "entities": [ "carbohydrate" ], "offsets": [ [ 329, 341 ] ] }, { "pmid": "23373677", "text": "Investigation of astatine(III) hydrolyzed species: experiments and relativistic calculations.\n", "type": "CHEMICAL", "entities": [ "astatine(III)" ], "offsets": [ [ 17, 30 ] ] }, { "pmid": "23373677", "text": "This work aims to resolve some controversies about astatine(III) hydroxide species present in oxidant aqueous solution.", "type": "CHEMICAL", "entities": [ "astatine(III) hydroxide" ], "offsets": [ [ 51, 74 ] ] }, { "pmid": "23373677", "text": "AtO(+) is the dominant species existing under oxidizing and acidic pH conditions.", "type": "CHEMICAL", "entities": [ "AtO(+)" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23373677", "text": "Batch-experiments using a competition method show the exchange of one proton indicating the formation of the AtO(OH) species.", "type": "CHEMICAL", "entities": [ "AtO(OH)" ], "offsets": [ [ 109, 116 ] ] }, { "pmid": "23377542", "text": "Here we show that Trim24 and Trim33 cooperatively repress retinoic acid receptor-dependent activity of VL30-class endogenous retroviruses (ERVs) in liver.", "type": "CHEMICAL", "entities": [ "retinoic acid" ], "offsets": [ [ 56, 69 ] ] }, { "pmid": "23378608", "text": "Fatty acids present in the high-fat diet induced hyperpermeability of endothelial cells, causing adipocyte differentiation, whereas apelin promoted vascular stabilization.", "type": "CHEMICAL", "entities": [ "Fatty acids" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23378608", "text": "Moreover, treatment of high-fat-diet-fed apelin-knockout mice with a selective cyclooxygenase-2 inhibitor, celecoxib, improved vascular function, and also attenuated obesity.", "type": "CHEMICAL", "entities": [ "celecoxib" ], "offsets": [ [ 107, 116 ] ] }, { "pmid": "23379481", "text": "Activation of the anti-cancer agent upamostat by the mARC enzyme system.\n", "type": "CHEMICAL", "entities": [ "upamostat" ], "offsets": [ [ 36, 45 ] ] }, { "pmid": "23379481", "text": "Upamostat (Mesupron®) is a new small molecule serine protease inhibitor.", "type": "CHEMICAL", "entities": [ "serine", "Upamostat", "Mesupron" ], "offsets": [ [ 46, 52 ], [ 0, 9 ], [ 11, 19 ] ] }, { "pmid": "23379481", "text": "2. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1.", "type": "CHEMICAL", "entities": [ "Upamostat", "amidoxime", "hydroxyamidine", "WX-UK1" ], "offsets": [ [ 2, 11 ], [ 36, 45 ], [ 53, 67 ], [ 116, 122 ] ] }, { "pmid": "23379481", "text": "In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed.", "type": "CHEMICAL", "entities": [ "WX-UK1", "upamostat" ], "offsets": [ [ 91, 97 ], [ 52, 61 ] ] }, { "pmid": "23379481", "text": "The recently discovered molybdenum enzyme \"mitochondrial Amidoxime Reducing Component\" (mARC) catalyses together with its electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase the reduction of N-hydroxylated prodrugs.", "type": "CHEMICAL", "entities": [ "molybdenum", "Amidoxime", "NADH", "N" ], "offsets": [ [ 23, 33 ], [ 56, 65 ], [ 169, 173 ], [ 217, 218 ] ] }, { "pmid": "23379481", "text": "In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat.", "type": "CHEMICAL", "entities": [ "N", "upamostat" ], "offsets": [ [ 134, 135 ], [ 149, 158 ] ] }, { "pmid": "23381641", "text": "Protein phosphatase 2A is one of four major classes of serine/threonine phosphatases.", "type": "CHEMICAL", "entities": [ "serine", "threonine" ], "offsets": [ [ 55, 61 ], [ 62, 71 ] ] }, { "pmid": "23381641", "text": "We have reported that Bβ2 clones are sensitive to reactive oxygen species (ROS) treatment by inducing autophagic cell death.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 55, 61 ] ] }, { "pmid": "23381641", "text": "The pharmacological inhibitor, Bafilomycin A1, rescued the cell death while suppressing autophagy.", "type": "CHEMICAL", "entities": [ "Bafilomycin A1" ], "offsets": [ [ 23, 37 ] ] }, { "pmid": "23381641", "text": "On the other hand, to assess how cells respond to ER stress, the cells were treated with 0.1 μM of N-glycosylation inhibitor, tunicamycin (TM).", "type": "CHEMICAL", "entities": [ "N", "tunicamycin" ], "offsets": [ [ 91, 92 ], [ 118, 129 ] ] }, { "pmid": "23381641", "text": "The autophagy inhibitor, 3-methyladenine, salvaged the final apoptosis.", "type": "CHEMICAL", "entities": [ "3-methyladenine" ], "offsets": [ [ 10, 25 ] ] }, { "pmid": "23381936", "text": "Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults.\n", "type": "CHEMICAL", "entities": [ "atorvastatin" ], "offsets": [ [ 31, 43 ] ] }, { "pmid": "23381936", "text": "The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite.", "type": "CHEMICAL", "entities": [ "atorvastatin", "o-hydroxyatorvastatin" ], "offsets": [ [ 41, 53 ], [ 91, 112 ] ] }, { "pmid": "23381936", "text": "Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation.", "type": "CHEMICAL", "entities": [ "Atorvastatin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23381936", "text": "Variability in atorvastatin PK was primarily affected by weight.", "type": "CHEMICAL", "entities": [ "atorvastatin" ], "offsets": [ [ 7, 19 ] ] }, { "pmid": "23382074", "text": "We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1.", "type": "CHEMICAL", "entities": [ "ZnF" ], "offsets": [ [ 64, 67 ] ] }, { "pmid": "23382074", "text": "Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex.", "type": "CHEMICAL", "entities": [ "lysine", "lysine", "ZnF" ], "offsets": [ [ 55, 61 ], [ 103, 109 ], [ 128, 131 ] ] }, { "pmid": "23384997", "text": "Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro selenium exposure.\n", "type": "CHEMICAL", "entities": [ "selenium", "glutathione", "hydroperoxide", "glutathione" ], "offsets": [ [ 185, 193 ], [ 30, 41 ], [ 70, 83 ], [ 84, 95 ] ] }, { "pmid": "23384997", "text": "Selenium (Se) is an oligonutrient with both essential biological functions and recognized harmful effects.", "type": "CHEMICAL", "entities": [ "Selenium", "Se" ], "offsets": [ [ 0, 8 ], [ 10, 12 ] ] }, { "pmid": "23384997", "text": "As the selenocysteine (SeCys) amino acid, selenium is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis.", "type": "CHEMICAL", "entities": [ "amino acid", "selenium", "Se", "selenocysteine", "SeCys" ], "offsets": [ [ 30, 40 ], [ 42, 50 ], [ 76, 78 ], [ 7, 21 ], [ 23, 28 ] ] }, { "pmid": "23384997", "text": "Nevertheless, selenium may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS).", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 132, 138 ] ] }, { "pmid": "23384997", "text": "The selenium chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism.", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 4, 12 ] ] }, { "pmid": "23384997", "text": "Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family.", "type": "CHEMICAL", "entities": [ "Glutathione" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23384997", "text": "Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell.", "type": "CHEMICAL", "entities": [ "glutathione", "hydroperoxide", "glutathione" ], "offsets": [ [ 10, 21 ], [ 63, 76 ], [ 77, 88 ] ] }, { "pmid": "23384997", "text": "An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources.", "type": "CHEMICAL", "entities": [ "sodium selenite", "Na2SeO3", "selenocysteine", "Cys-Se-Se-Cys", "Se" ], "offsets": [ [ 14, 29 ], [ 31, 38 ], [ 53, 67 ], [ 69, 82 ], [ 117, 119 ] ] }, { "pmid": "23384997", "text": "To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity.", "type": "CHEMICAL", "entities": [ "Se", "Se" ], "offsets": [ [ 90, 92 ], [ 211, 213 ] ] }, { "pmid": "23384997", "text": "Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments.", "type": "CHEMICAL", "entities": [ "Se", "Se", "Se" ], "offsets": [ [ 8, 10 ], [ 92, 94 ], [ 126, 128 ] ] }, { "pmid": "23384997", "text": "Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to selenium exposure in vitro, especially to the organic form.", "type": "CHEMICAL", "entities": [ "selenium" ], "offsets": [ [ 182, 190 ] ] }, { "pmid": "23384997", "text": "Interestingly, GPx1a was the most sensitive to selenium availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to selenium levels that had some toxic effects on the cells.", "type": "CHEMICAL", "entities": [ "selenium", "selenium" ], "offsets": [ [ 47, 55 ], [ 159, 167 ] ] }, { "pmid": "23384997", "text": "Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for selenium intake, helping to evaluate if selenium concentration and chemical speciation impact on cell homeostasis.", "type": "CHEMICAL", "entities": [ "selenium", "selenium" ], "offsets": [ [ 117, 125 ], [ 157, 165 ] ] }, { "pmid": "23385959", "text": "Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.\n", "type": "CHEMICAL", "entities": [ "Manganese", "Trolox" ], "offsets": [ [ 0, 9 ], [ 108, 114 ] ] }, { "pmid": "23385959", "text": "While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity.", "type": "CHEMICAL", "entities": [ "Mn", "manganese", "Mn" ], "offsets": [ [ 17, 19 ], [ 6, 15 ], [ 97, 99 ] ] }, { "pmid": "23385959", "text": "Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 0, 2 ] ] }, { "pmid": "23385959", "text": "Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 59, 61 ] ] }, { "pmid": "23385959", "text": "Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 49, 51 ] ] }, { "pmid": "23385959", "text": "The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 75, 77 ] ] }, { "pmid": "23385959", "text": "Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 113, 115 ] ] }, { "pmid": "23385959", "text": "Mn (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation).", "type": "CHEMICAL", "entities": [ "F(2)-isoprostane" ], "offsets": [ [ 49, 65 ] ] }, { "pmid": "23385959", "text": "Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 56, 58 ] ] }, { "pmid": "23385959", "text": "Notably, the antioxidant Trolox™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F(2)-isoprostane production.", "type": "CHEMICAL", "entities": [ "Trolox", "Mn", "Mn", "F(2)-isoprostane", "Trolox" ], "offsets": [ [ 20, 26 ], [ 41, 43 ], [ 123, 125 ], [ 166, 182 ], [ 195, 201 ] ] }, { "pmid": "23385959", "text": "Trolox™ also reversed the Mn-induced motor coordination deficits.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 17, 19 ] ] }, { "pmid": "23385959", "text": "These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 53, 55 ] ] }, { "pmid": "23385959", "text": "Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects.", "type": "CHEMICAL", "entities": [ "Trolox", "Mn" ], "offsets": [ [ 12, 18 ], [ 93, 95 ] ] }, { "pmid": "23386029", "text": "Nocapyrones H-J, 3,6-Disubstituted α-Pyrones from the Marine Actinomycete Nocardiopsis sp. KMF-001.\n", "type": "CHEMICAL", "entities": [ "Nocapyrones H-J", "3,6-Disubstituted α-Pyrones" ], "offsets": [ [ 0, 15 ], [ 17, 44 ] ] }, { "pmid": "23386029", "text": "Three new 3,6-disubstituted α-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp. KMF-001.", "type": "CHEMICAL", "entities": [ "3,6-disubstituted α-pyrones", "nocapyrones H-J" ], "offsets": [ [ 9, 36 ], [ 38, 53 ] ] }, { "pmid": "23386029", "text": "Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and high resolution (HR)-FAB-MS analyses.", "type": "CHEMICAL", "entities": [ "3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones" ], "offsets": [ [ 35, 86 ] ] }, { "pmid": "23386029", "text": "Nocapyrone H (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1β (IL-1β).", "type": "CHEMICAL", "entities": [ "nitric oxide", "NO", "prostaglandin E2", "PGE2" ], "offsets": [ [ 59, 71 ], [ 73, 75 ], [ 78, 94 ], [ 96, 100 ] ] }, { "pmid": "23386029", "text": "Moreover, nocapyrone H showed 5.82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 µm in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells.", "type": "CHEMICAL", "entities": [ "NO", "nocapyrone H" ], "offsets": [ [ 62, 64 ], [ 6, 18 ] ] }, { "pmid": "23386703", "text": "Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.\n", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "23386703", "text": "The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 219, 227 ] ] }, { "pmid": "23386703", "text": "The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC).", "type": "CHEMICAL", "entities": [ "apixaban", "charcoal" ], "offsets": [ [ 48, 56 ], [ 231, 239 ] ] }, { "pmid": "23386703", "text": "Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "23386703", "text": "Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC).", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 27, 35 ] ] }, { "pmid": "23386703", "text": "The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor).", "type": "CHEMICAL", "entities": [ "apixaban", "GF-120918" ], "offsets": [ [ 53, 61 ], [ 168, 177 ] ] }, { "pmid": "23386703", "text": "BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 99, 107 ] ] }, { "pmid": "23386703", "text": "These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 28, 36 ] ] }, { "pmid": "23386703", "text": "Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect).", "type": "CHEMICAL", "entities": [ "apixaban", "charcoal" ], "offsets": [ [ 27, 35 ], [ 108, 116 ] ] }, { "pmid": "23386703", "text": "This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 98, 106 ] ] }, { "pmid": "23386703", "text": "The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 71, 79 ] ] }, { "pmid": "23386703", "text": "IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.", "type": "CHEMICAL", "entities": [ "apixaban" ], "offsets": [ [ 193, 201 ] ] }, { "pmid": "23391336", "text": "Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease.\n", "type": "CHEMICAL", "entities": [ "Sulfonamide", "Thiol" ], "offsets": [ [ 31, 42 ], [ 47, 52 ] ] }, { "pmid": "23391336", "text": "The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle.", "type": "CHEMICAL", "entities": [ "CO(2)", "His" ], "offsets": [ [ 59, 64 ], [ 173, 176 ] ] }, { "pmid": "23391336", "text": "A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors.", "type": "CHEMICAL", "entities": [ "aromatic/heterocyclic sulfonamides", "5-mercapto-1,3,4-thiadiazoles" ], "offsets": [ [ 16, 50 ], [ 60, 89 ] ] }, { "pmid": "23391336", "text": "The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.", "type": "CHEMICAL", "entities": [ "aromatic sulfonamides", "thiols" ], "offsets": [ [ 2, 23 ], [ 184, 190 ] ] }, { "pmid": "23391632", "text": "The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis.\n", "type": "CHEMICAL", "entities": [ "di(2-ethylhexyl) phthalate" ], "offsets": [ [ 40, 66 ] ] }, { "pmid": "23391632", "text": "The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism.", "type": "CHEMICAL", "entities": [ "di(2-ethylhexyl) phthalate", "DEHP" ], "offsets": [ [ 59, 85 ], [ 87, 91 ] ] }, { "pmid": "23391632", "text": "90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg DEHP daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells.", "type": "CHEMICAL", "entities": [ "EDS", "DEHP", "ethane dimethanesulfonate" ], "offsets": [ [ 235, 238 ], [ 127, 131 ], [ 208, 233 ] ] }, { "pmid": "23391632", "text": "Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 6, 18 ] ] }, { "pmid": "23391632", "text": "EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium.", "type": "CHEMICAL", "entities": [ "EDS", "EDS", "testosterone", "3β-hydroxysteroid" ], "offsets": [ [ 0, 3 ], [ 68, 71 ], [ 105, 117 ], [ 131, 148 ] ] }, { "pmid": "23391632", "text": "However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium.", "type": "CHEMICAL", "entities": [ "DEHP", "testosterone" ], "offsets": [ [ 10, 14 ], [ 59, 71 ] ] }, { "pmid": "23391632", "text": "These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage.", "type": "CHEMICAL", "entities": [ "11β-hydroxysteroid" ], "offsets": [ [ 62, 80 ] ] }, { "pmid": "23391632", "text": "The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS.", "type": "CHEMICAL", "entities": [ "EDS" ], "offsets": [ [ 149, 152 ] ] }, { "pmid": "23391632", "text": "but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells.", "type": "CHEMICAL", "entities": [ "DEHP" ], "offsets": [ [ 63, 67 ] ] }, { "pmid": "23391632", "text": "The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the DEHP treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes.", "type": "CHEMICAL", "entities": [ "EDS", "DEHP", "DEHP" ], "offsets": [ [ 122, 125 ], [ 142, 146 ], [ 268, 272 ] ] }, { "pmid": "23391632", "text": "The present study suggests that DEHP increases the differentiation of stem cells into progenitor Leydig cells.", "type": "CHEMICAL", "entities": [ "DEHP" ], "offsets": [ [ 25, 29 ] ] }, { "pmid": "23393127", "text": "GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB.\n", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23393127", "text": "Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 66, 70 ] ] }, { "pmid": "23393127", "text": "cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 155, 159 ] ] }, { "pmid": "23393127", "text": "We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 94, 98 ] ] }, { "pmid": "23393127", "text": "GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89.", "type": "CHEMICAL", "entities": [ "H89" ], "offsets": [ [ 142, 145 ] ] }, { "pmid": "23393127", "text": "A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway.", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH" ], "offsets": [ [ 36, 40 ], [ 81, 85 ] ] }, { "pmid": "23393127", "text": "In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 84, 88 ] ] }, { "pmid": "23393127", "text": "DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 20, 24 ] ] }, { "pmid": "23393127", "text": "Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies.", "type": "CHEMICAL", "entities": [ "GnRH" ], "offsets": [ [ 123, 127 ] ] }, { "pmid": "23393127", "text": "Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation.", "type": "CHEMICAL", "entities": [ "GnRH", "GnRH" ], "offsets": [ [ 72, 76 ], [ 185, 189 ] ] }, { "pmid": "23395669", "text": "Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway.\n", "type": "CHEMICAL", "entities": [ "Sophocarpine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23395669", "text": "Sophocarpine, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis.", "type": "CHEMICAL", "entities": [ "Sophocarpine" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23395669", "text": "In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with sophocarpine for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis.", "type": "CHEMICAL", "entities": [ "oleic acid", "sophocarpine" ], "offsets": [ [ 133, 143 ], [ 197, 209 ] ] }, { "pmid": "23395669", "text": "While sophocarpine treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold).", "type": "CHEMICAL", "entities": [ "sophocarpine" ], "offsets": [ [ 5, 17 ] ] }, { "pmid": "23395669", "text": "Moreover, compared with the model group, sophocarpine could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression.", "type": "CHEMICAL", "entities": [ "sophocarpine" ], "offsets": [ [ 40, 52 ] ] }, { "pmid": "23395669", "text": "We concluded that sophocarpine could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK.", "type": "CHEMICAL", "entities": [ "sophocarpine" ], "offsets": [ [ 14, 26 ] ] }, { "pmid": "23395825", "text": "Elevation of 4-hydroxynonenal and malondialdehyde modified protein levels in cerebral cortex with cognitive dysfunction in rats exposed to 1-bromopropane.\n", "type": "CHEMICAL", "entities": [ "4-hydroxynonenal", "1-bromopropane", "malondialdehyde" ], "offsets": [ [ 13, 29 ], [ 139, 153 ], [ 34, 49 ] ] }, { "pmid": "23395825", "text": "1-Bromopropane (1-BP), an alternative to ozone-depleting solvents (ODS), exhibits central nervous system (CNS) toxicity in animals and humans.", "type": "CHEMICAL", "entities": [ "1-BP", "ozone", "1-Bromopropane" ], "offsets": [ [ 16, 20 ], [ 41, 46 ], [ 0, 14 ] ] }, { "pmid": "23395825", "text": "This study was designed to relate CNS damage by Morris water maze (MWM) test and oxidative stress to 1-BP exposure in the rat.", "type": "CHEMICAL", "entities": [ "1-BP" ], "offsets": [ [ 101, 105 ] ] }, { "pmid": "23395825", "text": "Male Wistar rats were randomly divided into 4 groups (n=10), and treated with 0, 200, 400 and 800mg/kgbw 1-BP for consecutive 12 days, respectively.", "type": "CHEMICAL", "entities": [ "1-BP" ], "offsets": [ [ 105, 109 ] ] }, { "pmid": "23395825", "text": "Glutathione (GSH), oxidized glutathione (GSSG) and total thiol (total-SH) content, GSH reductase (GR) and GSH peroxidase (GSH-Px) activities, malondialdehyde (MDA) level, as well as 4-hydroxynonenal (4-HNE) and MDA modified proteins in homogenates of cerebral cortex were measured.", "type": "CHEMICAL", "entities": [ "Glutathione", "GSH", "oxidized glutathione", "GSSG", "thiol", "SH", "GSH", "GSH", "GSH", "malondialdehyde", "MDA", "4-hydroxynonenal", "4-HNE", "MDA" ], "offsets": [ [ 0, 11 ], [ 13, 16 ], [ 19, 39 ], [ 41, 45 ], [ 57, 62 ], [ 70, 72 ], [ 83, 86 ], [ 106, 109 ], [ 122, 125 ], [ 142, 157 ], [ 159, 162 ], [ 182, 198 ], [ 200, 205 ], [ 211, 214 ] ] }, { "pmid": "23395825", "text": "The obtained results showed that 1-BP led to cognitive dysfunction of rats, which was evidenced by delayed escape latency time and swimming distances in MWM performance.", "type": "CHEMICAL", "entities": [ "1-BP" ], "offsets": [ [ 33, 37 ] ] }, { "pmid": "23395825", "text": "GSH and total-SH content, GSH/GSSG ratio, GR activity significantly decreased in cerebral cortex of rats, coupling with the increase of MDA level.", "type": "CHEMICAL", "entities": [ "GSH", "SH", "GSH", "GSSG", "MDA" ], "offsets": [ [ 0, 3 ], [ 14, 16 ], [ 26, 29 ], [ 30, 34 ], [ 136, 139 ] ] }, { "pmid": "23395825", "text": "4-HNE and MDA modified protein levels obviously elevated after 1-BP exposure.", "type": "CHEMICAL", "entities": [ "4-HNE", "MDA", "1-BP" ], "offsets": [ [ 0, 5 ], [ 10, 13 ], [ 63, 67 ] ] }, { "pmid": "23395825", "text": "GSH-Px activities in cerebral cortex of rats also increased.", "type": "CHEMICAL", "entities": [ "GSH" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23395825", "text": "These data suggested that 1-BP resulted in enhanced lipid peroxidation of brain, which might play an important role in CNS damage induced by 1-BP.", "type": "CHEMICAL", "entities": [ "1-BP", "1-BP" ], "offsets": [ [ 26, 30 ], [ 141, 145 ] ] }, { "pmid": "23395914", "text": "Site dependent intestinal absorption of darunavir and its interaction with ketoconazole.\n", "type": "CHEMICAL", "entities": [ "darunavir", "ketoconazole" ], "offsets": [ [ 40, 49 ], [ 75, 87 ] ] }, { "pmid": "23395914", "text": "To evaluate to what extent the regional differences in expression of P-gp and P450 enzymes affect the absorption of a dual substrate, we investigated the transport of darunavir across different small intestinal segments (duodenum, proximal jejunum and ileum).", "type": "CHEMICAL", "entities": [ "darunavir" ], "offsets": [ [ 167, 176 ] ] }, { "pmid": "23395914", "text": "Moreover, the effect of ketoconazole on the intestinal absorption of darunavir was explored, since these drugs are commonly co-administered.", "type": "CHEMICAL", "entities": [ "ketoconazole", "darunavir" ], "offsets": [ [ 24, 36 ], [ 69, 78 ] ] }, { "pmid": "23395914", "text": "Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of darunavir at the different intestinal segments.", "type": "CHEMICAL", "entities": [ "darunavir" ], "offsets": [ [ 146, 155 ] ] }, { "pmid": "23395914", "text": "The involvement of P-gp in the absorption of darunavir was clearly shown by coperfusion of darunavir with the P-gp inhibitor zosuquidar.", "type": "CHEMICAL", "entities": [ "darunavir", "darunavir", "zosuquidar" ], "offsets": [ [ 45, 54 ], [ 91, 100 ], [ 125, 135 ] ] }, { "pmid": "23395914", "text": "In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively.", "type": "CHEMICAL", "entities": [ "zosuquidar" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "23395914", "text": "Involvement of P450 mediated metabolism in the absorption of darunavir could not be demonstrated in this rat model.", "type": "CHEMICAL", "entities": [ "darunavir" ], "offsets": [ [ 61, 70 ] ] }, { "pmid": "23395914", "text": "Upon studying the drug-drug interaction of darunavir with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on P-gp as the main mechanism for the increased transport of darunavir across the small intestine.", "type": "CHEMICAL", "entities": [ "darunavir", "ketoconazole", "ketoconazole", "darunavir" ], "offsets": [ [ 43, 52 ], [ 58, 70 ], [ 121, 133 ], [ 195, 204 ] ] }, { "pmid": "23396144", "text": "In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α).", "type": "CHEMICAL", "entities": [ "buthanol", "ethylacetate", "methanol", "clerosterol", "CLS", "nitric oxide" ], "offsets": [ [ 16, 24 ], [ 29, 41 ], [ 59, 67 ], [ 123, 134 ], [ 136, 139 ], [ 306, 318 ] ] }, { "pmid": "23396144", "text": "Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO).", "type": "CHEMICAL", "entities": [ "prostaglandin E2", "PGE2", "nitric oxide", "NO", "CLS" ], "offsets": [ [ 109, 125 ], [ 127, 131 ], [ 137, 149 ], [ 151, 153 ], [ 21, 24 ] ] }, { "pmid": "23396144", "text": "In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α.", "type": "CHEMICAL", "entities": [ "CLS" ], "offsets": [ [ 56, 59 ] ] }, { "pmid": "23396144", "text": "Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes.", "type": "CHEMICAL", "entities": [ "CLS" ], "offsets": [ [ 23, 26 ] ] }, { "pmid": "23398572", "text": "Strong effects of cluster size and air exposure on oxygen reduction and carbon oxidation electrocatalysis by size-selected Pt(n) (n ≤ 11) on glassy carbon electrodes.\n", "type": "CHEMICAL", "entities": [ "Pt(n)", "glassy carbon", "oxygen", "carbon" ], "offsets": [ [ 123, 128 ], [ 141, 154 ], [ 51, 57 ], [ 72, 78 ] ] }, { "pmid": "23398572", "text": "Model Pt(n)/glassy carbon electrodes (Pt(n)/GCE) were prepared by deposition of mass-selected Pt(n)(+) (n ≤ 11) on GCE substrates in ultrahigh vacuum.", "type": "CHEMICAL", "entities": [ "Pt(n)(+)", "glassy carbon", "Pt(n)", "Pt(n)" ], "offsets": [ [ 92, 100 ], [ 10, 23 ], [ 36, 41 ], [ 4, 9 ] ] }, { "pmid": "23398572", "text": "Electrocatalysis under conditions appropriate for the oxygen reduction reaction (ORR) was studied, for samples both in situ with no exposure to laboratory air and with air exposure prior to electrochemical measurements.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 50, 56 ] ] }, { "pmid": "23398572", "text": "Of the small clusters, only a few cluster sizes show the expected ORR activity, and in those cases, the activity per Pt atom is similar to that seen under identical conditions with a conventionally prepared electrode with Pt nanoparticles grown on a GCE.", "type": "CHEMICAL", "entities": [ "Pt", "Pt" ], "offsets": [ [ 113, 115 ], [ 218, 220 ] ] }, { "pmid": "23398572", "text": "For other small Pt(n) on GCE, any ORR signal is overwhelmed by large oxidative currents attributed to catalysis of carbon oxidation by water.", "type": "CHEMICAL", "entities": [ "Pt(n)", "carbon" ], "offsets": [ [ 12, 17 ], [ 111, 117 ] ] }, { "pmid": "23398572", "text": "If the samples are exposed to air prior to electrochemistry, both ORR and carbon oxidation signals are absent, and instead only small capacitive currents or currents attributed to redox chemistry of adventitious organic adsorbates are observed, indicating that air exposure results in passivation of the small Pt clusters.", "type": "CHEMICAL", "entities": [ "carbon", "Pt" ], "offsets": [ [ 70, 76 ], [ 306, 308 ] ] }, { "pmid": "23399323", "text": "Inhibition of ghrelin O-acyltransferase attenuates food deprivation-induced increases in ingestive behavior.\n", "type": "CHEMICAL", "entities": [ "O" ], "offsets": [ [ 22, 23 ] ] }, { "pmid": "23399323", "text": "The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation.", "type": "CHEMICAL", "entities": [ "O" ], "offsets": [ [ 100, 101 ] ] }, { "pmid": "23400796", "text": "The accumulation of metal (Co, Cr, Cu, Mn and Zn) in freshwater Ulva (Chlorophyta) and its habitat.\n", "type": "CHEMICAL", "entities": [ "Co", "Cr", "Cu", "Mn", "Zn" ], "offsets": [ [ 27, 29 ], [ 31, 33 ], [ 35, 37 ], [ 39, 41 ], [ 46, 48 ] ] }, { "pmid": "23400796", "text": "The possibility of using freshwater Ulva (Chlorophyta) as a bioaccumulator of metals (Co, Cr, Cu, Mn and Zn) in lake and river water was examined weekly in the summer of 2010 in three types of samples: the water, the sediment and the thalli of Ulva.", "type": "CHEMICAL", "entities": [ "Co", "Cr", "Cu", "Mn", "Zn" ], "offsets": [ [ 86, 88 ], [ 90, 92 ], [ 94, 96 ], [ 98, 100 ], [ 105, 107 ] ] }, { "pmid": "23400796", "text": "The mean metal concentrations in the Ulva tissue from the river and the lake decreased in the following order: Mn >", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 111, 113 ] ] }, { "pmid": "23400796", "text": "Zn >", "type": "CHEMICAL", "entities": [ "Zn", "Zn" ], "offsets": [ [ 0, 2 ], [ 0, 2 ] ] }, { "pmid": "23400796", "text": "Cr >", "type": "CHEMICAL", "entities": [ "Cr", "Cr" ], "offsets": [ [ 0, 2 ], [ 0, 2 ] ] }, { "pmid": "23400796", "text": "Cu > Co and Mn >", "type": "CHEMICAL", "entities": [ "Cu", "Co", "Mn" ], "offsets": [ [ 0, 2 ], [ 5, 7 ], [ 12, 14 ] ] }, { "pmid": "23400796", "text": "Cu > Co, respectively.", "type": "CHEMICAL", "entities": [ "Cu", "Co" ], "offsets": [ [ 0, 2 ], [ 5, 7 ] ] }, { "pmid": "23400796", "text": "Moreover, a negative and statistically significant correlation between Mn concentrations in the Ulva thalli and the river water was observed.", "type": "CHEMICAL", "entities": [ "Mn" ], "offsets": [ [ 71, 73 ] ] }, { "pmid": "23400796", "text": "The great concentrations of Mn and Zn and the smallest of Co were found in thalli of Ulva, irrespective of the type of the ecosystem from which samples of algal thalli originated.", "type": "CHEMICAL", "entities": [ "Mn", "Zn", "Co" ], "offsets": [ [ 28, 30 ], [ 35, 37 ], [ 58, 60 ] ] }, { "pmid": "23400796", "text": "Freshwater Ulva populations examined in this study were clearly characterized a dozen or so times by the higher Mn and Cr accumulation than taxa from that genera coming from sea ecosystems.", "type": "CHEMICAL", "entities": [ "Mn", "Cr" ], "offsets": [ [ 112, 114 ], [ 119, 121 ] ] }, { "pmid": "23401298", "text": "Exploring the Interplay Between Ligand Derivatisation and Cation Type in the Assembly of Hybrid Polyoxometalate Mn-Andersons.\n", "type": "CHEMICAL", "entities": [ "Mn", "Polyoxometalate" ], "offsets": [ [ 112, 114 ], [ 96, 111 ] ] }, { "pmid": "23401298", "text": "Herein a library of hybrid Mn-Anderson polyoxometalates anions are presented: 1, [(MnMo(6) O(18) )((OCH(2) )", "type": "CHEMICAL", "entities": [ "Mn", "polyoxometalates" ], "offsets": [ [ 27, 29 ], [ 39, 55 ] ] }, { "pmid": "23401298", "text": "(2) ](3-) ; compound 2, [(MnMo(6) O(18) )((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(2) ](3-) ; compound 3, [(MnMo(6) O(18) )((OCH(2) )(3) C-(CH(2) )(7) CHCH(2) )", "type": "CHEMICAL", "entities": [ "[(MnMo(6) O(18) )((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(2) ](3-)" ], "offsets": [ [ 24, 86 ] ] }, { "pmid": "23401298", "text": "(2) ](3-) and compounds 5-9, [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ]), where x = 4, 10, 12, 14, and 18 respectively.", "type": "CHEMICAL", "entities": [ "[(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ]" ], "offsets": [ [ 29, 92 ] ] }, { "pmid": "23401298", "text": "The compounds resulting from the cation exchange of the anions 1-9 to give TBA (a) and DMDOA (b) salts, and additionally for compounds 1, 2 and 3, tetraphenylphosphonium (PPh(4) )", "type": "CHEMICAL", "entities": [ "PPh(4)", "TBA", "DMDOA", "tetraphenylphosphonium" ], "offsets": [ [ 171, 177 ], [ 75, 78 ], [ 87, 92 ], [ 147, 169 ] ] }, { "pmid": "23401473", "text": "Interaction of silymarin flavonolignans with organic anion-transporting polypeptides.\n", "type": "CHEMICAL", "entities": [ "flavonolignans" ], "offsets": [ [ 25, 39 ] ] }, { "pmid": "23401473", "text": "The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes.", "type": "CHEMICAL", "entities": [ "flavonolignans" ], "offsets": [ [ 51, 65 ] ] }, { "pmid": "23401473", "text": "In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated.", "type": "CHEMICAL", "entities": [ "estradiol-17β-glucuronide", "estrone-3-sulfate", "flavonolignans" ], "offsets": [ [ 60, 85 ], [ 114, 131 ], [ 179, 193 ] ] }, { "pmid": "23401473", "text": "silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively).", "type": "CHEMICAL", "entities": [ "silybin B", "silychristin" ], "offsets": [ [ 60, 69 ], [ 126, 138 ] ] }, { "pmid": "23401473", "text": "Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes.", "type": "CHEMICAL", "entities": [ "silybin A", "silybin B", "estradiol-17β-glucuronide", "rosuvastatin" ], "offsets": [ [ 19, 28 ], [ 34, 43 ], [ 91, 116 ], [ 121, 133 ] ] }, { "pmid": "23401473", "text": "The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport.", "type": "CHEMICAL", "entities": [ "flavonolignans" ], "offsets": [ [ 93, 107 ] ] }, { "pmid": "23401473", "text": "Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.", "type": "CHEMICAL", "entities": [ "flavonolignan" ], "offsets": [ [ 107, 120 ] ] }, { "pmid": "23402628", "text": "Oxidation of tertiary amine-derivatized surfaces to control protein adhesion.\n", "type": "CHEMICAL", "entities": [ "tertiary amine" ], "offsets": [ [ 13, 27 ] ] }, { "pmid": "23402628", "text": "Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them.", "type": "CHEMICAL", "entities": [ "tertiary amine N-oxides", "ω-tertiary amine", "thiol" ], "offsets": [ [ 75, 98 ], [ 23, 39 ], [ 55, 60 ] ] }, { "pmid": "23402628", "text": "Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU).", "type": "CHEMICAL", "entities": [ "secondary and tertiary linker amides", "amide", "quartz", "2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium", "HATU" ], "offsets": [ [ 29, 65 ], [ 180, 185 ], [ 209, 215 ], [ 257, 348 ], [ 350, 354 ] ] }, { "pmid": "23402628", "text": "Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM.", "type": "CHEMICAL", "entities": [ "phosphate", "hydrogen peroxide" ], "offsets": [ [ 101, 110 ], [ 14, 31 ] ] }, { "pmid": "23402628", "text": "Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates.", "type": "CHEMICAL", "entities": [ "tertiary amine N-oxides", "triethylene glycol" ], "offsets": [ [ 90, 113 ], [ 118, 136 ] ] }, { "pmid": "23402628", "text": "The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins.", "type": "CHEMICAL", "entities": [ "dimethylamine N-oxide", "ethyl secondary amide" ], "offsets": [ [ 24, 45 ], [ 60, 81 ] ] }, { "pmid": "23402628", "text": "Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques.", "type": "CHEMICAL", "entities": [ "tertiary amine" ], "offsets": [ [ 12, 26 ] ] }, { "pmid": "23403014", "text": "In this study, the stabilization effects of three polymers on four model drugs (felodipine, fenofibrate, carbamazepine, and celecoxib) under saturated humidity were investigated.", "type": "CHEMICAL", "entities": [ "carbamazepine", "celecoxib", "felodipine", "fenofibrate" ], "offsets": [ [ 105, 118 ], [ 124, 133 ], [ 80, 90 ], [ 92, 103 ] ] }, { "pmid": "23403014", "text": "Amongst the polymers tested in this study, EUDRAGIT E PO was found to have the greatest inhibitory effect on crystallization, whilst PVP K30 was found to have the least protective effect; presumably because of its hygroscopic nature.", "type": "CHEMICAL", "entities": [ "EUDRAGIT E PO", "PVP K30" ], "offsets": [ [ 43, 56 ], [ 133, 140 ] ] }, { "pmid": "23403085", "text": "Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells.\n", "type": "CHEMICAL", "entities": [ "mercaptoethylleonurine", "mercaptoethylguanidine", "hydrogen peroxide" ], "offsets": [ [ 27, 49 ], [ 54, 76 ], [ 88, 105 ] ] }, { "pmid": "23403085", "text": "A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized.", "type": "CHEMICAL", "entities": [ "mercaptoethylleonurine", "mercaptoethylguanidine" ], "offsets": [ [ 12, 34 ], [ 39, 61 ] ] }, { "pmid": "23403085", "text": "Their neuroprotective effects toward H2O2-induced apoptosis were investigated in human SH-SY5Y cells.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 37, 41 ] ] }, { "pmid": "23403085", "text": "Further investigation demonstrated that 8k reduced H2O2-induced activation of mitochondrial apoptosis by inhibiting the expression of Bax and elevating the expression of Bcl-2.", "type": "CHEMICAL", "entities": [ "H2O2" ], "offsets": [ [ 51, 55 ] ] }, { "pmid": "23404443", "text": "[HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine).", "type": "CHEMICAL", "entities": [ "glucose", "glucose", "glucose", "glucose", "arginine" ], "offsets": [ [ 166, 173 ], [ 175, 182 ], [ 189, 196 ], [ 212, 219 ], [ 244, 252 ] ] }, { "pmid": "23404443", "text": "Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine).", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 262, 270 ] ] }, { "pmid": "23404443", "text": "Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "23404505", "text": "VEGF-D is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 187, 188 ], [ 194, 195 ] ] }, { "pmid": "23404505", "text": "We report for the first time that VEGF-D binds heparin, and that the C-terminal propeptide significantly enhances this interaction (removal of this propeptide from full-length VEGF-D completely prevents heparin binding).", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 69, 70 ] ] }, { "pmid": "23404505", "text": "We also show that removal of either the N- or C-terminal propeptide is required for VEGF-D to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting.", "type": "CHEMICAL", "entities": [ "N", "C" ], "offsets": [ [ 40, 41 ], [ 46, 47 ] ] }, { "pmid": "23404505", "text": "In a mouse tumor model, removal of only the C-terminal propeptide from full-length VEGF-D was sufficient to enhance angiogenesis and tumor growth.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 44, 45 ] ] }, { "pmid": "23406497", "text": "To test this hypothesis, constructs were evaluated consisting of an immunophilin: human FK-506 binding protein 12 (FKBP) attached to an ELP.", "type": "CHEMICAL", "entities": [ "FK-506" ], "offsets": [ [ 88, 94 ] ] }, { "pmid": "23406956", "text": "Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats.\n", "type": "CHEMICAL", "entities": [ "L-carnitine", "vitamin E" ], "offsets": [ [ 19, 30 ], [ 35, 44 ] ] }, { "pmid": "23406956", "text": "Vitamin E and l-carnitine have well-known lipid-lowering and antioxidative activities.", "type": "CHEMICAL", "entities": [ "Vitamin E", "l-carnitine" ], "offsets": [ [ 0, 9 ], [ 14, 34 ] ] }, { "pmid": "23406956", "text": "Triton WR 1339 is a non-ionic detergent, which induces severe hyperlipidemia by inhibition of lipoprotein lipase.", "type": "CHEMICAL", "entities": [ "Triton WR 1339" ], "offsets": [ [ 0, 14 ] ] }, { "pmid": "23406956", "text": "The present study evaluates the protective role of vitamin E and l-carnitine on the testis in atherosclerosis and detects the most effective choice for protection against atherosclerosis; vitamin E, l-carnitine or a combination of both.", "type": "CHEMICAL", "entities": [ "vitamin E", "l-carnitine", "vitamin E", "l-carnitine" ], "offsets": [ [ 51, 60 ], [ 65, 85 ], [ 197, 206 ], [ 208, 228 ] ] }, { "pmid": "23406956", "text": "A total of 80 albino male rats were divided into eight groups (10 rats for each group): control (G(1)), triton (G(2)), l-carnitine (G(3)), triton + l-carnitine (G(4)), vitamin E (G(5)), triton + vitamin E (G(6)), l-carnitine + vitamin E (G(7)) and triton + l-carnitine + vitamin E (G(8)).", "type": "CHEMICAL", "entities": [ "vitamin E", "triton", "l-carnitine", "triton", "l-carnitine", "vitamin E", "triton", "vitamin E", "l-carnitine", "vitamin E", "triton", "l-carnitine" ], "offsets": [ [ 307, 316 ], [ 104, 110 ], [ 119, 139 ], [ 148, 154 ], [ 157, 177 ], [ 186, 195 ], [ 204, 210 ], [ 213, 222 ], [ 231, 251 ], [ 254, 263 ], [ 275, 281 ], [ 284, 304 ] ] }, { "pmid": "23406956", "text": "Data showed a significant increase in the levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), 17 beta hydroxysteroid dehydrogenase (17 β HSD), testicular catalase and malondialdehyde (MDA) in G(2) when compared with G(1), whereas high-density lipoprotein cholesterol (HDL-C), serum testosterone, testicular 17 ketosteroid reductase (17 KSR), total thiol and glutathione-S-transferase (GST) data showed a significant decrease in G(2) when compared with G(1).", "type": "CHEMICAL", "entities": [ "ketosteroid", "thiol", "glutathione", "S", "cholesterol", "triglycerides", "cholesterol", "17 beta hydroxysteroid", "malondialdehyde", "MDA", "cholesterol", "testosterone" ], "offsets": [ [ 358, 369 ], [ 396, 401 ], [ 406, 417 ], [ 418, 419 ], [ 58, 69 ], [ 76, 89 ], [ 121, 132 ], [ 142, 164 ], [ 215, 230 ], [ 232, 235 ], [ 303, 314 ], [ 330, 342 ] ] }, { "pmid": "23406956", "text": "Treatment with l-carnitine or/and vitamin E helps in improving the adverse effect of triton; also the histological changes confirm this finding.", "type": "CHEMICAL", "entities": [ "l-carnitine", "vitamin E", "triton" ], "offsets": [ [ 14, 34 ], [ 42, 51 ], [ 93, 99 ] ] }, { "pmid": "23406956", "text": "So the present study recommends all people to include l-carnitine and vitamin E in their diet to be protected against atherosclerosis.", "type": "CHEMICAL", "entities": [ "l-carnitine", "vitamin E" ], "offsets": [ [ 53, 73 ], [ 78, 87 ] ] }, { "pmid": "23407783", "text": "The CRF(1) receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and D-cycloserine.\n", "type": "CHEMICAL", "entities": [ "paroxetine", "D-cycloserine", "SSR125543" ], "offsets": [ [ 140, 150 ], [ 155, 168 ], [ 31, 40 ] ] }, { "pmid": "23407783", "text": "The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure.", "type": "CHEMICAL", "entities": [ "SSR125543" ], "offsets": [ [ 81, 90 ] ] }, { "pmid": "23407783", "text": "The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability.", "type": "CHEMICAL", "entities": [ "SSR125543" ], "offsets": [ [ 63, 72 ] ] }, { "pmid": "23407783", "text": "Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD.", "type": "CHEMICAL", "entities": [ "NMDA", "D-cycloserine", "SSR125543", "5-HT", "paroxetine", "N-methyl-D-aspartate" ], "offsets": [ [ 139, 143 ], [ 163, 176 ], [ 9, 18 ], [ 49, 53 ], [ 74, 84 ], [ 117, 137 ] ] }, { "pmid": "23407783", "text": "Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine.", "type": "CHEMICAL", "entities": [ "SSR125543", "paroxetine", "D-cycloserine" ], "offsets": [ [ 67, 76 ], [ 78, 88 ], [ 93, 106 ] ] }, { "pmid": "23407783", "text": "These findings confirm that the CRF(1) receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.", "type": "CHEMICAL", "entities": [ "SSR125543" ], "offsets": [ [ 53, 62 ] ] }, { "pmid": "23409871", "text": "Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.\n", "type": "CHEMICAL", "entities": [ "indazole arylsulfonamides" ], "offsets": [ [ 50, 75 ] ] }, { "pmid": "23409871", "text": "A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists.", "type": "CHEMICAL", "entities": [ "indazole arylsulfonamides" ], "offsets": [ [ 12, 37 ] ] }, { "pmid": "23409871", "text": "Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents.", "type": "CHEMICAL", "entities": [ "Methoxy", "hydroxyl", "indazole" ], "offsets": [ [ 0, 7 ], [ 12, 20 ], [ 60, 68 ] ] }, { "pmid": "23409871", "text": "The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide.", "type": "CHEMICAL", "entities": [ "5-chlorothiophene-2-sulfonamide" ], "offsets": [ [ 35, 66 ] ] }, { "pmid": "23409871", "text": "N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents.", "type": "CHEMICAL", "entities": [ "benzyl", "3-[(methylamino)acyl]" ], "offsets": [ [ 20, 26 ], [ 56, 77 ] ] }, { "pmid": "23409871", "text": "Strongly basic amino groups had low oral absorption in vivo.", "type": "CHEMICAL", "entities": [ "amino" ], "offsets": [ [ 14, 19 ] ] }, { "pmid": "23409871", "text": "Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance.", "type": "CHEMICAL", "entities": [ "morpholines" ], "offsets": [ [ 29, 40 ] ] }, { "pmid": "23409871", "text": "The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development.", "type": "CHEMICAL", "entities": [ "GSK2239633A" ], "offsets": [ [ 76, 87 ] ] }, { "pmid": "23409871", "text": "X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.", "type": "CHEMICAL", "entities": [ "indazole sulfonamide" ], "offsets": [ [ 32, 52 ] ] }, { "pmid": "23411185", "text": "Comparative analysis of nutritional compositions of transgenic high iron rice with its non-transgenic counterpart.\n", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 68, 72 ] ] }, { "pmid": "23411185", "text": "Iron is an essential micronutrient for human nutrition and polished rice contains very low amount of iron.", "type": "CHEMICAL", "entities": [ "Iron", "iron" ], "offsets": [ [ 0, 4 ], [ 101, 105 ] ] }, { "pmid": "23411185", "text": "Rice with high iron content in seed endosperm has been developed by insertion of soybean ferritin gene under the control of the endosperm specific glutelin promoter into the genome of indica rice line IR68144.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 15, 19 ] ] }, { "pmid": "23411185", "text": "Our studies established that apart from the increased level of iron and zinc in transgenic seeds, the nutritional quality of both the brown and milled rice grains from the transgenic line was substantially equivalent to that of the non-transgenic rice plants.", "type": "CHEMICAL", "entities": [ "iron", "zinc" ], "offsets": [ [ 63, 67 ], [ 72, 76 ] ] }, { "pmid": "23412396", "text": "Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects.\n", "type": "CHEMICAL", "entities": [ "Monoacylglycerol", "JZL184" ], "offsets": [ [ 40, 56 ], [ 74, 80 ] ] }, { "pmid": "23412396", "text": "The monoacylglycerol lipase (MAGL) inhibitor JZL184 produces antinociceptive and anti-inflammatory effects.", "type": "CHEMICAL", "entities": [ "monoacylglycerol", "JZL184" ], "offsets": [ [ 4, 20 ], [ 45, 51 ] ] }, { "pmid": "23412396", "text": "However, repeated administration of high dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and CB(1) receptor downregulation and desensitization.", "type": "CHEMICAL", "entities": [ "JZL184" ], "offsets": [ [ 46, 52 ] ] }, { "pmid": "23412396", "text": "Consequently, the present study tested whether repeated administration of low dose JZL184 maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages.", "type": "CHEMICAL", "entities": [ "JZL184" ], "offsets": [ [ 83, 89 ] ] }, { "pmid": "23412396", "text": "Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively.", "type": "CHEMICAL", "entities": [ "JZL184", "[(3)H]SR141716A", "CP55,940", "(35)S" ], "offsets": [ [ 41, 47 ], [ 154, 169 ], [ 182, 190 ], [ 203, 208 ] ] }, { "pmid": "23412396", "text": "In contrast, normal CB(1) receptor expression and function were maintained following repeated administration of low dose JZL184 (≤8 mg/kg).", "type": "CHEMICAL", "entities": [ "JZL184" ], "offsets": [ [ 118, 124 ] ] }, { "pmid": "23412396", "text": "Likewise, the antinociceptive and gastroprotective effects of high dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low dose JZL184 treatment.", "type": "CHEMICAL", "entities": [ "JZL184", "JZL184" ], "offsets": [ [ 67, 73 ], [ 191, 197 ] ] }, { "pmid": "23412396", "text": "Consistent with these observations, repeated high dose JZL184, but not repeated low dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC).", "type": "CHEMICAL", "entities": [ "JZL184", "JZL184", "Δ(9)-tetrahydrocannabinol", "THC" ], "offsets": [ [ 50, 56 ], [ 84, 90 ], [ 158, 183 ], [ 185, 188 ] ] }, { "pmid": "23412396", "text": "This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence.", "type": "CHEMICAL", "entities": [ "rimonabant" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "23412922", "text": "In our previous study, we identified the estrogen receptor alpha (ERα) as a relevant enhancer of leptin-induced signal transduction leading to transactivation of signal transducer and activator of transcription 3 (Stat3).", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 38, 46 ] ] }, { "pmid": "23416003", "text": "Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.\n", "type": "CHEMICAL", "entities": [ "bicyclic pyrazinone and pyrimidinone amides" ], "offsets": [ [ 24, 67 ] ] }, { "pmid": "23416003", "text": "Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors.", "type": "CHEMICAL", "entities": [ "Bicyclic pyrazinone and pyrimidinone amides" ], "offsets": [ [ 0, 43 ] ] }, { "pmid": "23416003", "text": "An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets.", "type": "CHEMICAL", "entities": [ "hydrogen" ], "offsets": [ [ 131, 139 ] ] }, { "pmid": "23416007", "text": "While HIF-1α in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, HIF-1α is degraded under normoxia, which involves its proline hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex.", "type": "CHEMICAL", "entities": [ "proline" ], "offsets": [ [ 199, 206 ] ] }, { "pmid": "23416070", "text": "Circulating levels of insulin and glucagon reflect the nutritional state of animals and elicit regulatory responses in the liver that maintain glucose and lipid homeostasis.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 143, 150 ] ] }, { "pmid": "23416070", "text": "Introduction of the acetylation-mimicking (K259Q) or -deficient (K259R) mutations promotes or inhibits Foxa2 activity, respectively, and adenoviral expression of Foxa2-K259Q augments expression of genes involved in fatty acid oxidation and ketogenesis.", "type": "CHEMICAL", "entities": [ "fatty acid" ], "offsets": [ [ 215, 225 ] ] }, { "pmid": "23416131", "text": "In addition, SCPP11 (at 50mg/kg) could also increased in thymus indexes as well as IL-2 and TNF-α levels in serum in vivo and significantly enhance the phagocytosis activity and the productions of NO of RAW264.7 in vitro.", "type": "CHEMICAL", "entities": [ "NO" ], "offsets": [ [ 196, 198 ] ] }, { "pmid": "23416191", "text": "Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy.\n", "type": "CHEMICAL", "entities": [ "HJC0123" ], "offsets": [ [ 49, 56 ] ] }, { "pmid": "23416191", "text": "The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values.", "type": "CHEMICAL", "entities": [ "HJC0123" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "23416191", "text": "Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "23416946", "text": "To map supercoiling, we used biotinylated trimethylpsoralen as a DNA structure probe to show that the human genome is organized into supercoiling domains.", "type": "CHEMICAL", "entities": [ "biotinylated trimethylpsoralen" ], "offsets": [ [ 29, 59 ] ] }, { "pmid": "23421877", "text": "Four new eudesmane-type sesquiterpenoid lactones from atractylenolide II by biotransformation of rat hepatic microsomes.\n", "type": "CHEMICAL", "entities": [ "eudesmane", "sesquiterpenoid lactones", "atractylenolide II" ], "offsets": [ [ 9, 18 ], [ 24, 48 ], [ 54, 72 ] ] }, { "pmid": "23421877", "text": "The biotransformation of atractylenolide II, a major bioactive principle of the rhizomes of Atractylodes macrocephala Koidz., was investigated in vitro by incubation with rat hepatic microsomes pretreated with sodium phenobarbital.", "type": "CHEMICAL", "entities": [ "sodium phenobarbital", "atractylenolide II" ], "offsets": [ [ 210, 230 ], [ 25, 43 ] ] }, { "pmid": "23421877", "text": "Seven biotransformation products (BP1-BP7) were obtained and their structures were elucidated by NMR and MS data analyses and by comparison with the previously reported values, including four new compounds, namely 4(R),15-epoxy-atractylenolide II (BP1), 4(R),15-epoxy-13-hydroxyatractylenolide II (BP5), 4(R),15-epoxy-1β-hydroxyatractylenolide II (BP6), and 4(R),15-dihydroxyatractylenolide II (BP7).", "type": "CHEMICAL", "entities": [ "4(R),15-epoxy-atractylenolide II", "4(R),15-epoxy-13-hydroxyatractylenolide II", "4(R),15-epoxy-1β-hydroxyatractylenolide II", "4(R),15-dihydroxyatractylenolide II" ], "offsets": [ [ 214, 246 ], [ 254, 296 ], [ 304, 346 ], [ 358, 393 ] ] }, { "pmid": "23421877", "text": "The biotransformation pathway of atractylenolide II by hepatic microsomes was deducted based on the structure resolution of the products.", "type": "CHEMICAL", "entities": [ "atractylenolide II" ], "offsets": [ [ 32, 50 ] ] }, { "pmid": "23427190", "text": "The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral- electroencephalography study.\n", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 54, 64 ] ] }, { "pmid": "23427190", "text": "Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 42, 52 ] ] }, { "pmid": "23427190", "text": "Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo).", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 140, 150 ] ] }, { "pmid": "23427190", "text": "No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil.", "type": "CHEMICAL", "entities": [ "vardenafil", "vardenafil" ], "offsets": [ [ 24, 34 ], [ 133, 143 ] ] }, { "pmid": "23427190", "text": "During encoding of words, the P300 was generally smaller after vardenafil treatment.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 63, 73 ] ] }, { "pmid": "23427190", "text": "Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "23427190", "text": "Finally, headache and feeling weak were reported more after vardenafil treatment.", "type": "CHEMICAL", "entities": [ "vardenafil" ], "offsets": [ [ 60, 70 ] ] }, { "pmid": "23427190", "text": "Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs.", "type": "CHEMICAL", "entities": [ "Vardenafil" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23428346", "text": "Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex.\n", "type": "CHEMICAL", "entities": [ "Atorvastatin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23428346", "text": "Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis.", "type": "CHEMICAL", "entities": [ "3-hydroxy-3-methylglutaryl coenzyme A", "cholesterol" ], "offsets": [ [ 37, 74 ], [ 112, 123 ] ] }, { "pmid": "23428346", "text": "Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol" ], "offsets": [ [ 98, 109 ], [ 213, 224 ] ] }, { "pmid": "23428346", "text": "In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration.", "type": "CHEMICAL", "entities": [ "atorvastatin", "atorvastatin", "atorvastatin", "atorvastatin" ], "offsets": [ [ 174, 186 ], [ 62, 74 ], [ 206, 218 ], [ 246, 258 ] ] }, { "pmid": "23428346", "text": "We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex.", "type": "CHEMICAL", "entities": [ "atorvastatin", "nitric oxide", "superoxide", "NADPH", "3-nitrotyrosine" ], "offsets": [ [ 14, 26 ], [ 58, 70 ], [ 89, 99 ], [ 138, 143 ], [ 215, 230 ] ] }, { "pmid": "23428346", "text": "Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity.", "type": "CHEMICAL", "entities": [ "glutathione", "S", "xanthine", "atorvastatin", "carbonyl", "4-hydroxy-2-nonenal" ], "offsets": [ [ 10, 21 ], [ 22, 23 ], [ 40, 48 ], [ 88, 100 ], [ 145, 153 ], [ 158, 177 ] ] }, { "pmid": "23428346", "text": "Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity.", "type": "CHEMICAL", "entities": [ "3-nitrotyrosine", "atorvastatin" ], "offsets": [ [ 65, 80 ], [ 178, 190 ] ] }, { "pmid": "23428346", "text": "Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects.", "type": "CHEMICAL", "entities": [ "atorvastatin", "NADPH", "superoxide" ], "offsets": [ [ 37, 49 ], [ 146, 151 ], [ 187, 197 ] ] }, { "pmid": "23428368", "text": "Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 μg/100 g BW, oral) and were found to improve in the Bzf co-treated condition.", "type": "CHEMICAL", "entities": [ "fatty acid", "triiodothyronine", "bezafibrate", "Bzf", "Bzf" ], "offsets": [ [ 88, 98 ], [ 145, 161 ], [ 294, 305 ], [ 307, 310 ], [ 367, 370 ] ] }, { "pmid": "23428368", "text": "Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration.", "type": "CHEMICAL", "entities": [ "Bzf" ], "offsets": [ [ 81, 84 ] ] }, { "pmid": "23428368", "text": "Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf.", "type": "CHEMICAL", "entities": [ "ATP", "Bzf" ], "offsets": [ [ 91, 94 ], [ 144, 147 ] ] }, { "pmid": "23428368", "text": "Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment.", "type": "CHEMICAL", "entities": [ "Bzf" ], "offsets": [ [ 177, 180 ] ] }, { "pmid": "23429231", "text": "For exploring the effect of polymer hydrophilicity on nanoparticle interactions with human umbilical vein endothelial cells (HUVECs) in vitro, a series of monomodal poly[acrylonitrile-co-(N-vinylpyrrolidone)] model nanoparticles with increasing hydrophilicity as related to their increasing content (0-30mol.%) of N-vinylpyrrolidone (NVP) were synthesized by miniemulsion polymerization.", "type": "CHEMICAL", "entities": [ "poly[acrylonitrile-co-(N-vinylpyrrolidone)]", "N-vinylpyrrolidone", "NVP" ], "offsets": [ [ 165, 208 ], [ 314, 332 ], [ 334, 337 ] ] }, { "pmid": "23429231", "text": "Nanoparticles with a low NVP content were rapidly endocytized into all cells independent from the particle dose with toxic effects only observed at high particle concentrations, while only 10-30% of the cells incorporated particles with ⩾20mol.% NVP.", "type": "CHEMICAL", "entities": [ "NVP", "NVP" ], "offsets": [ [ 25, 28 ], [ 246, 249 ] ] }, { "pmid": "23429231", "text": "Since pathologies are often related to inflammation, an inflammatory HUVEC culture condition with IL-1β stimulation has been introduced and suggested to be widely applied for studying nanocarriers, since cellular uptake in this assay was clearly increased for NVP contents ⩾20mol.%.", "type": "CHEMICAL", "entities": [ "NVP" ], "offsets": [ [ 258, 261 ] ] }, { "pmid": "23429231", "text": "Additionally, rapidly endocytized RhodaminB loaded particles with low NVP content may be explored for cell labeling and tracking.", "type": "CHEMICAL", "entities": [ "RhodaminB", "NVP" ], "offsets": [ [ 29, 38 ], [ 65, 68 ] ] }, { "pmid": "23429911", "text": "Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum.\n", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 49, 57 ] ] }, { "pmid": "23429911", "text": "The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 4, 12 ] ] }, { "pmid": "23429911", "text": "The transcription of DRD3 was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα functions as a regulator of DRD3 oscillations in the cellular autonomous clock.", "type": "CHEMICAL", "entities": [ "retinoic acid", "dexamethasone" ], "offsets": [ [ 46, 59 ], [ 207, 220 ] ] }, { "pmid": "23429911", "text": "Moreover, the effects of the DRD3 agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant.", "type": "CHEMICAL", "entities": [ "7-hydroxy-N,N-dipropyl-2-aminotetralin", "7-OH-DPAT" ], "offsets": [ [ 35, 73 ], [ 75, 84 ] ] }, { "pmid": "23432124", "text": "Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.\n", "type": "CHEMICAL", "entities": [ "IKM-159", "(S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid", "AMPA" ], "offsets": [ [ 103, 110 ], [ 14, 75 ], [ 77, 81 ] ] }, { "pmid": "23432124", "text": "IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists.", "type": "CHEMICAL", "entities": [ "IKM-159", "AMPA", "glutamate" ], "offsets": [ [ 0, 7 ], [ 115, 119 ], [ 83, 92 ] ] }, { "pmid": "23432124", "text": "However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities.", "type": "CHEMICAL", "entities": [ "IKM-159" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23432124", "text": "Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis.", "type": "CHEMICAL", "entities": [ "IKM-159" ], "offsets": [ [ 80, 87 ] ] }, { "pmid": "23432124", "text": "By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps.", "type": "CHEMICAL", "entities": [ "(R)-2-amino-2-(4-methoxyphenyl)ethanol", "(2R)-IKM-159" ], "offsets": [ [ 17, 55 ], [ 79, 91 ] ] }, { "pmid": "23432124", "text": "Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays.", "type": "CHEMICAL", "entities": [ "(2R)-IKM-159" ], "offsets": [ [ 142, 154 ] ] }, { "pmid": "23432124", "text": "Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site.", "type": "CHEMICAL", "entities": [ "(2R)-IKM-159", "Racemic IKM-159" ], "offsets": [ [ 122, 134 ], [ 0, 15 ] ] }, { "pmid": "23432124", "text": "(2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.", "type": "CHEMICAL", "entities": [ "(2R)-IKM-159" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23432429", "text": "A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6.", "type": "CHEMICAL", "entities": [ "phenanthrene", "fluoranthene", "pyrene", "biphenyl", "flavone", "naphthalene" ], "offsets": [ [ 62, 74 ], [ 76, 88 ], [ 90, 96 ], [ 98, 106 ], [ 112, 119 ], [ 49, 60 ] ] }, { "pmid": "23432429", "text": "Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with P450 2A13 than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for P450 2A13.", "type": "CHEMICAL", "entities": [ "iron" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "23432429", "text": "In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with P450 2A13.", "type": "CHEMICAL", "entities": [ "fluoranthene", "2,3-dihydroxy-2,3-dihydrofluoranthene", "pyrene", "1-hydroxypyrene", "1-nitropyrene", "1-acetylpyrene", "2-acetylpyrene", "2,5,2',5'-tetrachlorobiphenyl", "7-hydroxyflavone", "chrysin", "galangin", "benzo[c]phenanthrene" ], "offsets": [ [ 34, 46 ], [ 48, 85 ], [ 87, 93 ], [ 95, 110 ], [ 112, 125 ], [ 127, 141 ], [ 143, 157 ], [ 159, 188 ], [ 190, 206 ], [ 208, 215 ], [ 221, 229 ], [ 12, 32 ] ] }, { "pmid": "23432429", "text": "Coumarin 7-hydroxylation, catalyzed by P450 2A13, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values.", "type": "CHEMICAL", "entities": [ "flavanone", "2'-methoxy-5,7-dihydroxyflavone", "2-ethynylnaphthalene", "2'-methoxyflavone", "2-naphththalene propargyl ether", "acenaphthene", "chrysin", "acenaphthylene", "naphthalene", "1-acetylpyrene", "3-ethynylphenanthrene", "flavone", "7-hydroxyflavone" ], "offsets": [ [ 241, 250 ], [ 75, 106 ], [ 108, 128 ], [ 130, 147 ], [ 149, 180 ], [ 182, 194 ], [ 252, 259 ], [ 196, 210 ], [ 212, 223 ], [ 225, 239 ], [ 261, 282 ], [ 284, 291 ], [ 297, 313 ] ] }, { "pmid": "23432662", "text": "Full agonists to the peroxisome proliferator-activated receptor (PPAR)γ, such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity.", "type": "CHEMICAL", "entities": [ "Rosiglitazone" ], "offsets": [ [ 80, 93 ] ] }, { "pmid": "23432662", "text": "Nevertheless, PPARγ is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 70, 77 ] ] }, { "pmid": "23432662", "text": "A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions.", "type": "CHEMICAL", "entities": [ "carbonitrile" ], "offsets": [ [ 25, 37 ] ] }, { "pmid": "23434648", "text": "The EL of the LPA(1) receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 13, 16 ] ] }, { "pmid": "23434648", "text": "This study involved development of a peptide to characterize the intrinsic structure of the LPA(1) GPCR second EL.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 91, 94 ] ] }, { "pmid": "23434648", "text": "The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA(1)-CC-EL2 peptide).", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 130, 133 ] ] }, { "pmid": "23434648", "text": "In contrast, the EL2 sequence showed well-defined structure only near its C-terminal residues.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 73, 74 ] ] }, { "pmid": "23434648", "text": "The NMR ensemble was combined with a computational model of the LPA(1) receptor that had previously been validated.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 63, 66 ] ] }, { "pmid": "23434648", "text": "Nine different hybrid models interacted with LPA 18:1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends.", "type": "CHEMICAL", "entities": [ "LPA" ], "offsets": [ [ 44, 47 ] ] }, { "pmid": "23435615", "text": "The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers.\n", "type": "CHEMICAL", "entities": [ "(R)-omeprazole" ], "offsets": [ [ 4, 18 ] ] }, { "pmid": "23435615", "text": "Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups.", "type": "CHEMICAL", "entities": [ "Omeprazole" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23435615", "text": "The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals.", "type": "CHEMICAL", "entities": [ "(R)-omeprazole", "racemic omeprazole" ], "offsets": [ [ 75, 89 ], [ 118, 136 ] ] }, { "pmid": "23435615", "text": "Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column.", "type": "CHEMICAL", "entities": [ "omeprazole", "omeprazole" ], "offsets": [ [ 53, 63 ], [ 92, 102 ] ] }, { "pmid": "23435615", "text": "Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone.", "type": "CHEMICAL", "entities": [ "(R)- and (S)-omeprazole", "omeprazole sulfone" ], "offsets": [ [ 16, 39 ], [ 153, 171 ] ] }, { "pmid": "23435615", "text": "Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole.", "type": "CHEMICAL", "entities": [ "(R)-5-hydroxyomeprazole", "(S)-5-hydroxyomeprazole" ], "offsets": [ [ 63, 86 ], [ 178, 201 ] ] }, { "pmid": "23435615", "text": "Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI.", "type": "CHEMICAL", "entities": [ "(S)-omeprazole" ], "offsets": [ [ 163, 177 ] ] }, { "pmid": "23435615", "text": "Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.", "type": "CHEMICAL", "entities": [ "(R)-omeprazole", "racemic-omeprazole" ], "offsets": [ [ 16, 30 ], [ 86, 104 ] ] }, { "pmid": "23439660", "text": "Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone.\n", "type": "CHEMICAL", "entities": [ "oxycodone" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "23439660", "text": "[XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs.", "type": "CHEMICAL", "entities": [ "androstane", "Aryl hydrocarbon" ], "offsets": [ [ 52, 62 ], [ 83, 99 ] ] }, { "pmid": "23439660", "text": "The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats.", "type": "CHEMICAL", "entities": [ "oxycodone" ], "offsets": [ [ 62, 71 ] ] }, { "pmid": "23439660", "text": "Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone).", "type": "CHEMICAL", "entities": [ "oxycodone", "noroxycodone", "oxymorphone" ], "offsets": [ [ 195, 204 ], [ 231, 243 ], [ 248, 259 ] ] }, { "pmid": "23439660", "text": "Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone.", "type": "CHEMICAL", "entities": [ "oxycodone", "oxycodone", "oxycodone", "oxycodone" ], "offsets": [ [ 8, 17 ], [ 164, 173 ], [ 218, 227 ], [ 436, 445 ] ] }, { "pmid": "23439872", "text": "Strain-dependent dysregulation of one-carbon metabolism in male mice is associated with choline- and folate-deficient diet-induced liver injury.\n", "type": "CHEMICAL", "entities": [ "folate", "carbon", "choline" ], "offsets": [ [ 101, 107 ], [ 38, 44 ], [ 88, 95 ] ] }, { "pmid": "23439872", "text": "Dysregulation of one-carbon metabolism-related metabolic processes is a major contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD).", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 21, 27 ] ] }, { "pmid": "23439872", "text": "It is well established that genetic and gender-specific variations in one-carbon metabolism contribute to the vulnerability to NAFLD in humans.", "type": "CHEMICAL", "entities": [ "carbon" ], "offsets": [ [ 74, 80 ] ] }, { "pmid": "23439872", "text": "To examine the role of one-carbon metabolism dysregulation in the pathogenesis and individual susceptibility to NAFLD, we used a \"population-based\" mouse model where male mice from 7 inbred were fed a choline- and folate-deficient (CFD) diet for 12 wk.", "type": "CHEMICAL", "entities": [ "folate", "carbon", "choline" ], "offsets": [ [ 214, 220 ], [ 27, 33 ], [ 201, 208 ] ] }, { "pmid": "23439872", "text": "Strain-dependent down-regulation of several key one-carbon metabolism genes, including methionine adenosyltransferase 1α (Mat1a), cystathionine-β-synthase (Cbs), methylenetetrahydrofolate reductase (Mthfr), adenosyl-homocysteinase (Ahcy), and methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), was observed.", "type": "CHEMICAL", "entities": [ "carbon", "methionine", "cystathionine", "methylenetetrahydrofolate", "adenosyl", "methylenetetrahydrofolate" ], "offsets": [ [ 52, 58 ], [ 87, 97 ], [ 130, 143 ], [ 162, 187 ], [ 207, 215 ], [ 243, 268 ] ] }, { "pmid": "23439872", "text": "The strain specificity of diet-induced dysregulation of one-carbon metabolism suggests that interstrain variation in the regulation of one-carbon metabolism may contribute to the differential vulnerability to NFLD and that correcting the imbalance may be considered as preventive and treatment strategies for NAFLD.-Pogribny, I. P., Kutanzi, K., Melnyk, S., de Conti, A., Tryndyak, V., Montgomery, B., Pogribna, M., Muskhelishvili, L., Latendresse, J. R., James, S. J., Beland, F. A., Rusyn, I. Strain-dependent dysregulation of one-carbon metabolism in male mice is associated with choline- and folate-deficient diet-induced liver injury.", "type": "CHEMICAL", "entities": [ "carbon", "carbon", "carbon", "choline", "folate" ], "offsets": [ [ 56, 62 ], [ 135, 141 ], [ 529, 535 ], [ 579, 586 ], [ 592, 598 ] ] }, { "pmid": "23440512", "text": "Vitamin A and retinoid signaling: genomic and non-genomic effects.\n", "type": "CHEMICAL", "entities": [ "Vitamin A", "retinoid" ], "offsets": [ [ 0, 9 ], [ 14, 22 ] ] }, { "pmid": "23440512", "text": "Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood.", "type": "CHEMICAL", "entities": [ "Vitamin A", "retinol", "vitamin" ], "offsets": [ [ 0, 9 ], [ 13, 20 ], [ 58, 65 ] ] }, { "pmid": "23440512", "text": "The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators.", "type": "CHEMICAL", "entities": [ "vitamin A", "all-trans retinoic acid", "atRA", "retinoic acid" ], "offsets": [ [ 27, 36 ], [ 82, 105 ], [ 107, 111 ], [ 258, 271 ] ] }, { "pmid": "23440512", "text": "However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 7, 16 ] ] }, { "pmid": "23440512", "text": "All these new concepts expand the scope of the biologic functions of vitamin A and RA.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "23441017", "text": "Phase stability and elastic properties of chromium borides with various stoichiometries.\n", "type": "CHEMICAL", "entities": [ "chromium borides" ], "offsets": [ [ 42, 58 ] ] }, { "pmid": "23441017", "text": "By first-principles calculations, we establish the phase stability of chromium borides with various stoichiometries.", "type": "CHEMICAL", "entities": [ "chromium borides" ], "offsets": [ [ 70, 86 ] ] }, { "pmid": "23441017", "text": "Moreover, the phases of CrB3 and CrB4 have been predicted by using a newly developed particle swarm optimization (PSO) algorithm.", "type": "CHEMICAL", "entities": [ "CrB3", "CrB4" ], "offsets": [ [ 24, 28 ], [ 33, 37 ] ] }, { "pmid": "23441017", "text": "Formation enthalpy-pressure diagrams reveal that the MoB-type structure is more energetically favorable than the TiI-type structure for CrB. For CrB2 , the WB2 -type structure is preferred at zero pressure.", "type": "CHEMICAL", "entities": [ "TiI", "CrB", "CrB2", "WB2", "MoB" ], "offsets": [ [ 113, 116 ], [ 136, 139 ], [ 145, 149 ], [ 156, 159 ], [ 53, 56 ] ] }, { "pmid": "23441017", "text": "The predicted new phase of CrB3 belongs to the hexagonal P-6m2 space group and it transforms into an orthorhombic phase as the pressure exceeds 93 GPa.", "type": "CHEMICAL", "entities": [ "CrB3" ], "offsets": [ [ 27, 31 ] ] }, { "pmid": "23441017", "text": "The predicted CrB4 (space group: Pnnm) phase is more energetically favorable than the previously proposed Immm structure.", "type": "CHEMICAL", "entities": [ "CrB4" ], "offsets": [ [ 14, 18 ] ] }, { "pmid": "23441017", "text": "The mechanical and thermodynamic stabilities of predicted CrB3 and CrB4 are verified by the calculated elastic constants and formation enthalpies.", "type": "CHEMICAL", "entities": [ "CrB3", "CrB4" ], "offsets": [ [ 58, 62 ], [ 67, 71 ] ] }, { "pmid": "23441017", "text": "The full phonon dispersion calculations confirm the dynamic stability of WB2 -type CrB2 and predicted CrB3 .", "type": "CHEMICAL", "entities": [ "WB2", "CrB2", "CrB3" ], "offsets": [ [ 73, 76 ], [ 83, 87 ], [ 102, 106 ] ] }, { "pmid": "23441017", "text": "The large shear moduli, large Young's moduli, low Poisson ratios, and low bulk and shear modulus ratios of CrB4 PSC and CrB4 PSD indicate that they are potential hard materials.", "type": "CHEMICAL", "entities": [ "CrB4", "CrB4" ], "offsets": [ [ 107, 111 ], [ 121, 125 ] ] }, { "pmid": "23443810", "text": "Interestingly, miR-21 expression positively correlated with urine albumin creatine ratio (ACR), TIMP1, collagen IV (ColIV), and fibronectin (FN); while negatively correlated with creatine clearance ratio (Ccr) and MMP-9 protein.", "type": "CHEMICAL", "entities": [ "creatine", "creatine" ], "offsets": [ [ 74, 82 ], [ 179, 187 ] ] }, { "pmid": "23444386", "text": "Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds.\n", "type": "CHEMICAL", "entities": [ "Disulfide", "Hydroxysteroid" ], "offsets": [ [ 105, 114 ], [ 48, 62 ] ] }, { "pmid": "23444386", "text": "The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids.", "type": "CHEMICAL", "entities": [ "hydroxysteroids", "bile acids" ], "offsets": [ [ 125, 140 ], [ 145, 155 ] ] }, { "pmid": "23444386", "text": "We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "23444386", "text": "Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide).", "type": "CHEMICAL", "entities": [ "thiol", "glutathione disulfide", "5,5'-dithiobis(2-nitrobenzoic acid)", "1,1'-azobis(N,N-dimethylformamide", "diamide" ], "offsets": [ [ 6, 11 ], [ 120, 141 ], [ 143, 178 ], [ 184, 217 ], [ 220, 227 ] ] }, { "pmid": "23444386", "text": "Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "23444386", "text": "Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme.", "type": "CHEMICAL", "entities": [ "dehydroepiandrosterone", "DHEA", "disulfide" ], "offsets": [ [ 63, 85 ], [ 87, 91 ], [ 115, 124 ] ] }, { "pmid": "23444386", "text": "The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined.", "type": "CHEMICAL", "entities": [ "disulfides" ], "offsets": [ [ 133, 143 ] ] }, { "pmid": "23444386", "text": "Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide.", "type": "CHEMICAL", "entities": [ "DHEA", "disulfide", "cysteines", "nucleotide", "nucleotide" ], "offsets": [ [ 141, 145 ], [ 231, 240 ], [ 52, 61 ], [ 71, 81 ], [ 126, 136 ] ] }, { "pmid": "23444386", "text": "Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 23, 32 ] ] }, { "pmid": "23448346", "text": "Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity.\n", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 19, 27 ] ] }, { "pmid": "23448346", "text": "Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer.", "type": "CHEMICAL", "entities": [ "Estrogen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23448346", "text": "In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays.", "type": "CHEMICAL", "entities": [ "17β-estradiol" ], "offsets": [ [ 67, 80 ] ] }, { "pmid": "23448346", "text": "Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of ICI-182,780, a pure ER antagonist.", "type": "CHEMICAL", "entities": [ "ICI-182,780" ], "offsets": [ [ 187, 198 ] ] }, { "pmid": "23448346", "text": "These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780.", "type": "CHEMICAL", "entities": [ "ICI-182,780" ], "offsets": [ [ 157, 168 ] ] }, { "pmid": "23449197", "text": "Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia.\n", "type": "CHEMICAL", "entities": [ "7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole", "TASP0382088" ], "offsets": [ [ 13, 91 ], [ 93, 104 ] ] }, { "pmid": "23449197", "text": "7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor", "type": "CHEMICAL", "entities": [ "TASP0382088" ], "offsets": [ [ 82, 93 ] ] }, { "pmid": "23449197", "text": "The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11.", "type": "CHEMICAL", "entities": [ "methoxy", "benzothiazole", "imidazole", "thiazole" ], "offsets": [ [ 14, 21 ], [ 35, 48 ], [ 105, 114 ], [ 128, 136 ] ] }, { "pmid": "23449888", "text": "ARF represses androgen receptor transactivation in prostate cancer.\n", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "23449888", "text": "Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans.", "type": "CHEMICAL", "entities": [ "Androgen" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23449888", "text": "Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner.", "type": "CHEMICAL", "entities": [ "androgen", "androgen" ], "offsets": [ [ 114, 122 ], [ 137, 145 ] ] }, { "pmid": "23449888", "text": "Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters.", "type": "CHEMICAL", "entities": [ "androgen" ], "offsets": [ [ 81, 89 ] ] }, { "pmid": "23449888", "text": "Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of AR, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and AR proteins.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 59, 60 ] ] }, { "pmid": "23449888", "text": "p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of AR.", "type": "CHEMICAL", "entities": [ "androgen", "N", "C" ], "offsets": [ [ 20, 28 ], [ 61, 62 ], [ 76, 77 ] ] }, { "pmid": "23454144", "text": "Reactive oxygen species (ROS) can serve as essential second messengers mediating cellular responses resulting in immune cells activation.", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 9, 15 ] ] }, { "pmid": "23454145", "text": "Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells.\n", "type": "CHEMICAL", "entities": [ "7-ketosterol", "cholesterol" ], "offsets": [ [ 112, 124 ], [ 23, 34 ] ] }, { "pmid": "23454145", "text": "Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides.", "type": "CHEMICAL", "entities": [ "sterol", "cholesterol oxides" ], "offsets": [ [ 20, 26 ], [ 98, 116 ] ] }, { "pmid": "23454145", "text": "However, phytosterol oxides effects have been less extensively investigated.", "type": "CHEMICAL", "entities": [ "phytosterol oxides" ], "offsets": [ [ 9, 27 ] ] }, { "pmid": "23454145", "text": "This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells.", "type": "CHEMICAL", "entities": [ "cholesterol", "HMGCoA", "7-ketosterols", "stigmasterol", "cholesterol" ], "offsets": [ [ 163, 174 ], [ 219, 225 ], [ 245, 258 ], [ 260, 272 ], [ 273, 284 ] ] }, { "pmid": "23454145", "text": "Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol.", "type": "CHEMICAL", "entities": [ "7-ketostigmasterol", "7-ketocholesterol" ], "offsets": [ [ 13, 31 ], [ 81, 98 ] ] }, { "pmid": "23454145", "text": "In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression.", "type": "CHEMICAL", "entities": [ "7-ketosterols" ], "offsets": [ [ 72, 85 ] ] }, { "pmid": "23454145", "text": "Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells.", "type": "CHEMICAL", "entities": [ "bradykinin", "7-ketocholesterol", "7-ketostigmasterol" ], "offsets": [ [ 23, 33 ], [ 192, 209 ], [ 82, 100 ] ] }, { "pmid": "23454145", "text": "In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols.", "type": "CHEMICAL", "entities": [ "HMG-CoA", "7-ketosterols" ], "offsets": [ [ 24, 31 ], [ 57, 70 ] ] }, { "pmid": "23454145", "text": "However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells.", "type": "CHEMICAL", "entities": [ "7-ketocholesterol" ], "offsets": [ [ 78, 95 ] ] }, { "pmid": "23454145", "text": "These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism.", "type": "CHEMICAL", "entities": [ "7-ketostigmasterol", "Ca", "HMGCoA" ], "offsets": [ [ 58, 76 ], [ 104, 106 ], [ 135, 141 ] ] }, { "pmid": "23454145", "text": "However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization.", "type": "CHEMICAL", "entities": [ "7-ketosterol" ], "offsets": [ [ 89, 101 ] ] }, { "pmid": "23454297", "text": "Caffeic acid treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats.\n", "type": "CHEMICAL", "entities": [ "Caffeic acid", "adenine nucleotide" ], "offsets": [ [ 0, 12 ], [ 48, 66 ] ] }, { "pmid": "23454297", "text": "This study evaluated the effects of caffeic acid on ectonucleotidase activities such as NTPDase (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5'-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation.", "type": "CHEMICAL", "entities": [ "nucleoside triphosphate", "nucleotide", "adenosine", "caffeic acid" ], "offsets": [ [ 97, 120 ], [ 152, 162 ], [ 219, 228 ], [ 36, 48 ] ] }, { "pmid": "23454297", "text": "Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10mg/kg); IV (caffeic acid 50mg/kg); and V (caffeic acid 100mg/kg).", "type": "CHEMICAL", "entities": [ "caffeic acid", "caffeic acid", "caffeic acid" ], "offsets": [ [ 67, 79 ], [ 94, 106 ], [ 124, 136 ] ] }, { "pmid": "23454297", "text": "Animals were treated with caffeic acid diluted in oil for 30days.", "type": "CHEMICAL", "entities": [ "caffeic acid" ], "offsets": [ [ 26, 38 ] ] }, { "pmid": "23454297", "text": "In platelets, caffeic acid decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P<0.05).", "type": "CHEMICAL", "entities": [ "caffeic acid", "ATP", "ADP" ], "offsets": [ [ 14, 26 ], [ 41, 44 ], [ 70, 73 ] ] }, { "pmid": "23454297", "text": "Caffeic acid reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P<0.05).", "type": "CHEMICAL", "entities": [ "Caffeic acid" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23454297", "text": "In lymphocytes, the NTPDase and ADA activities were increased in all groups treated with caffeic acid when compared to control (P<0.05).", "type": "CHEMICAL", "entities": [ "caffeic acid" ], "offsets": [ [ 89, 101 ] ] }, { "pmid": "23454297", "text": "These findings demonstrated that the enzymes were altered in tissues by caffeic acid and this compound decreased the platelet aggregation suggesting that caffeic acid should be considered a potentially therapeutic agent in disorders related to the purinergic system.", "type": "CHEMICAL", "entities": [ "caffeic acid", "caffeic acid" ], "offsets": [ [ 72, 84 ], [ 154, 166 ] ] }, { "pmid": "23455323", "text": "We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation.", "type": "CHEMICAL", "entities": [ "serine", "tyrosine" ], "offsets": [ [ 40, 46 ], [ 55, 63 ] ] }, { "pmid": "23462233", "text": "Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice.\n", "type": "CHEMICAL", "entities": [ "Aldehyde", "imidacloprid" ], "offsets": [ [ 0, 8 ], [ 62, 74 ] ] }, { "pmid": "23462233", "text": "Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems.", "type": "CHEMICAL", "entities": [ "Aldehyde" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23462233", "text": "Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions.", "type": "CHEMICAL", "entities": [ "neonicotinoids", "nitroimino" ], "offsets": [ [ 47, 61 ], [ 121, 131 ] ] }, { "pmid": "23462233", "text": "The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain.", "type": "CHEMICAL", "entities": [ "tungsten", "hydralazine" ], "offsets": [ [ 60, 68 ], [ 72, 83 ] ] }, { "pmid": "23462233", "text": "Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls.", "type": "CHEMICAL", "entities": [ "tungsten", "hydralazine" ], "offsets": [ [ 43, 51 ], [ 65, 76 ] ] }, { "pmid": "23462233", "text": "When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice.", "type": "CHEMICAL", "entities": [ "imidacloprid", "IMI", "nitrosoguanidine", "tungsten", "hydralazine" ], "offsets": [ [ 55, 67 ], [ 69, 72 ], [ 169, 185 ], [ 223, 231 ], [ 245, 256 ] ] }, { "pmid": "23462233", "text": "The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively.", "type": "CHEMICAL", "entities": [ "IMI", "IMI", "tungsten", "hydralazine" ], "offsets": [ [ 10, 13 ], [ 50, 53 ], [ 95, 103 ], [ 105, 116 ] ] }, { "pmid": "23462233", "text": "Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice.", "type": "CHEMICAL", "entities": [ "IMI" ], "offsets": [ [ 152, 155 ] ] }, { "pmid": "23462233", "text": "Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains.", "type": "CHEMICAL", "entities": [ "IMI", "IMI" ], "offsets": [ [ 28, 31 ], [ 152, 155 ] ] }, { "pmid": "23462233", "text": "This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general.", "type": "CHEMICAL", "entities": [ "neonicotinoid" ], "offsets": [ [ 69, 82 ] ] }, { "pmid": "23462380", "text": "Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis.", "type": "CHEMICAL", "entities": [ "neostigmine" ], "offsets": [ [ 80, 91 ] ] }, { "pmid": "23462526", "text": "Cell cycle arrest, extracellular matrix changes and intrinsic apoptosis in human melanoma cells are induced by Boron Neutron Capture Therapy.\n", "type": "CHEMICAL", "entities": [ "Boron" ], "offsets": [ [ 111, 116 ] ] }, { "pmid": "23462526", "text": "Boron Neutron Capture Therapy (BNCT) involves the selective accumulation of boron carriers in tumor tissue followed by irradiation with a thermal or epithermal neutron beam.", "type": "CHEMICAL", "entities": [ "Boron" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23462526", "text": "Human normal melanocytes and melanoma cells were treated with BNCT at different boronophenylalanine concentrations for signaling pathways analysis.", "type": "CHEMICAL", "entities": [ "boronophenylalanine" ], "offsets": [ [ 80, 99 ] ] }, { "pmid": "23465614", "text": "Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells.\n", "type": "CHEMICAL", "entities": [ "diarylheptanoids" ], "offsets": [ [ 16, 32 ] ] }, { "pmid": "23465614", "text": "A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation.", "type": "CHEMICAL", "entities": [ "diarylheptanoids", "methanol", "(5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one", "diarylheptanoid" ], "offsets": [ [ 143, 159 ], [ 176, 184 ], [ 23, 97 ], [ 6, 21 ] ] }, { "pmid": "23465614", "text": "Of the compounds active in the present assay system, the most potent compound 7, platyphyllonol-5-O-β-d-xylopyranoside, significantly suppressed the induction of peroxisome proliferator activated receptor γ (PPARγ and CCAAT/enhancer binding protein α (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist.", "type": "CHEMICAL", "entities": [ "platyphyllonol-5-O-β-d-xylopyranoside", "troglitazone" ], "offsets": [ [ 81, 118 ], [ 331, 343 ] ] }, { "pmid": "23468189", "text": "Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors.\n", "type": "CHEMICAL", "entities": [ "Benzenesulfonamides" ], "offsets": [ [ 0, 19 ] ] }, { "pmid": "23468189", "text": "Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction.", "type": "CHEMICAL", "entities": [ "aryl sulfonamides" ], "offsets": [ [ 93, 110 ] ] }, { "pmid": "23468189", "text": "These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.", "type": "CHEMICAL", "entities": [ "benzenesulfonamides" ], "offsets": [ [ 28, 47 ] ] }, { "pmid": "2347042", "text": "Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride.\n", "type": "CHEMICAL", "entities": [ "L-cysteine", "L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride" ], "offsets": [ [ 54, 64 ], [ 77, 141 ] ] }, { "pmid": "2347042", "text": "A study on the oncolytic activity of the L-cysteine derivative L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride (NSC 303861), revealed that the drug caused complete regression of the MX-1 human mammary tumor xenograft.", "type": "CHEMICAL", "entities": [ "L-cysteine", "L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride", "NSC 303861" ], "offsets": [ [ 41, 51 ], [ 63, 127 ], [ 129, 139 ] ] }, { "pmid": "2347042", "text": "Studies on the mechanism of action revealed that the cytotoxicity of the drug could be partially abrogated by protecting hepatoma 3924A cells in culture with L-glutamine.", "type": "CHEMICAL", "entities": [ "L-glutamine" ], "offsets": [ [ 158, 169 ] ] }, { "pmid": "2347042", "text": "At 6 h after injection of the compound (400 mg/kg) into rats bearing hepatoma 3924A, the pools of L-glutamine and L-glutamate in the tumor decreased to 33% and 71%, respectively, of control levels; the drug selectively inhibited the activities of L-glutamine-requiring enzymes of purine nucleotide biosynthesis, amidophosphoribosyltransferase, FGAM synthase, and GMP synthase, to 21%, 1%, and 69%, respectively, without significantly altering the activities of pyrimidine biosynthetic enzymes, carbamoylphosphate synthase II and CTP synthase.", "type": "CHEMICAL", "entities": [ "L-glutamine", "L-glutamine", "L-glutamate", "purine nucleotide", "FGAM", "GMP", "pyrimidine", "carbamoylphosphate", "CTP" ], "offsets": [ [ 247, 258 ], [ 98, 109 ], [ 114, 125 ], [ 280, 297 ], [ 344, 348 ], [ 363, 366 ], [ 461, 471 ], [ 494, 512 ], [ 529, 532 ] ] }, { "pmid": "2347042", "text": "Measurement of the nucleotide concentrations further corroborated the actions of the drug on the purine nucleotide biosynthetic enzyme activities.", "type": "CHEMICAL", "entities": [ "purine nucleotide", "nucleotide" ], "offsets": [ [ 97, 114 ], [ 19, 29 ] ] }, { "pmid": "2347042", "text": "Drug injection (400 mg/kg) in the hepatoma 3924A-bearing rats reduced the concentrations of IMP in the tumor to 52%, those of total adenylates to 52%, those of total guanylates to 57%, and those of NAD to 73%, without significantly perturbing the pyrimidine nucleotide pools.", "type": "CHEMICAL", "entities": [ "IMP", "adenylates", "guanylates", "NAD", "pyrimidine nucleotide" ], "offsets": [ [ 92, 95 ], [ 132, 142 ], [ 166, 176 ], [ 198, 201 ], [ 247, 268 ] ] }, { "pmid": "2347042", "text": "Studies on the mechanism of action of the L-cysteine derivative suggested that the compound behaved as an L-glutamine antagonist, selectively acting on the enzymes of purine nucleotide biosynthesis.", "type": "CHEMICAL", "entities": [ "L-cysteine", "L-glutamine", "purine nucleotide" ], "offsets": [ [ 42, 52 ], [ 106, 117 ], [ 167, 184 ] ] }, { "pmid": "23470629", "text": "Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS.\n", "type": "CHEMICAL", "entities": [ "3β-Hydroxy-Δ(5)-bile Acids", "Bile Salt" ], "offsets": [ [ 39, 65 ], [ 69, 78 ] ] }, { "pmid": "23470629", "text": "A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry.", "type": "CHEMICAL", "entities": [ "3β-hydroxy-Δ(5)-bile acids" ], "offsets": [ [ 119, 145 ] ] }, { "pmid": "23470629", "text": "Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis.", "type": "CHEMICAL", "entities": [ "bile acids", "3β-hydroxy-Δ(5)-bile acids" ], "offsets": [ [ 23, 33 ], [ 136, 162 ] ] }, { "pmid": "23470629", "text": "The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids.", "type": "CHEMICAL", "entities": [ "bile salt", "3β-hydroxy-Δ(5)-bile acids" ], "offsets": [ [ 163, 172 ], [ 221, 247 ] ] }, { "pmid": "23470629", "text": "The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate.", "type": "CHEMICAL", "entities": [ "3β-hydroxy-Δ(5)-bile acids", "bile acids", "glycocholic acid", "taurolithocholic acid 3-sulfate" ], "offsets": [ [ 101, 127 ], [ 146, 156 ], [ 165, 181 ], [ 186, 217 ] ] }, { "pmid": "23471969", "text": "Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of p75(NTR) interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 35, 45 ] ] }, { "pmid": "23471969", "text": "An endogenous intracellular domain fragment of p75(NTR) (p75(ICD)) containing these 29 amino acids is produced by regulated proteolysis of the full-length receptor.", "type": "CHEMICAL", "entities": [ "amino acids" ], "offsets": [ [ 87, 98 ] ] }, { "pmid": "23474389", "text": "Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents.\n", "type": "CHEMICAL", "entities": [ "3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines" ], "offsets": [ [ 28, 83 ] ] }, { "pmid": "23474389", "text": "A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents.", "type": "CHEMICAL", "entities": [ "3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines" ], "offsets": [ [ 24, 82 ] ] }, { "pmid": "23474389", "text": "Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation.", "type": "CHEMICAL", "entities": [ "indole-3-carboxylic acid hydrazide", "carbon disulfide", "S" ], "offsets": [ [ 113, 147 ], [ 152, 168 ], [ 205, 206 ] ] }, { "pmid": "23474389", "text": "Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in Bcl-2 expressing human cancer cell lines.", "type": "CHEMICAL", "entities": [ "nitrobenzyl" ], "offsets": [ [ 30, 41 ] ] }, { "pmid": "23475432", "text": "Effect of nicotine pretreatment on arsenic-induced oxidative stress in male Wistar rats.\n", "type": "CHEMICAL", "entities": [ "nicotine", "arsenic" ], "offsets": [ [ 10, 18 ], [ 35, 42 ] ] }, { "pmid": "23475432", "text": "Humans are commonly exposed to nicotine, one of the most important lifestyle chemicals.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 31, 39 ] ] }, { "pmid": "23475432", "text": "The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 33, 40 ] ] }, { "pmid": "23475432", "text": "Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of nicotine, a major tobacco alkaloid, on arsenic toxicity.", "type": "CHEMICAL", "entities": [ "nicotine", "arsenic" ], "offsets": [ [ 116, 124 ], [ 155, 162 ] ] }, { "pmid": "23475432", "text": "Adult male rats were pre-exposed to two different doses of nicotine (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water).", "type": "CHEMICAL", "entities": [ "nicotine", "arsenic", "sodium arsenite" ], "offsets": [ [ 59, 67 ], [ 140, 147 ], [ 165, 180 ] ] }, { "pmid": "23475432", "text": "Nicotine pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration.", "type": "CHEMICAL", "entities": [ "arsenic", "arsenic" ], "offsets": [ [ 49, 56 ], [ 92, 99 ] ] }, { "pmid": "23475432", "text": "Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and nicotine but no such inhibition was noted in arsenic-treated animals pre-exposed to nicotine.", "type": "CHEMICAL", "entities": [ "nicotine", "S", "arsenic", "nicotine", "arsenic" ], "offsets": [ [ 160, 168 ], [ 8, 9 ], [ 64, 71 ], [ 76, 84 ], [ 121, 128 ] ] }, { "pmid": "23475432", "text": "Upon nicotine pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (MAO) decreased.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 1, 9 ] ] }, { "pmid": "23475432", "text": "The toxic effects of MAO significantly attenuated with nicotine pre-exposure.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23475432", "text": "The present study suggests that nicotine may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic.", "type": "CHEMICAL", "entities": [ "nicotine", "arsenic" ], "offsets": [ [ 28, 36 ], [ 156, 163 ] ] }, { "pmid": "23475432", "text": "Nicotine pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration.", "type": "CHEMICAL", "entities": [ "arsenic" ], "offsets": [ [ 21, 28 ] ] }, { "pmid": "23475784", "text": "We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD).", "type": "CHEMICAL", "entities": [ "fadrozole", "FAD" ], "offsets": [ [ 218, 227 ], [ 229, 232 ] ] }, { "pmid": "23475784", "text": "For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study.", "type": "CHEMICAL", "entities": [ "17β-estradiol" ], "offsets": [ [ 38, 51 ] ] }, { "pmid": "23475784", "text": "Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l FAD exposure concentrations, and good fits to these data were obtained.", "type": "CHEMICAL", "entities": [ "FAD" ], "offsets": [ [ 78, 81 ] ] }, { "pmid": "23475784", "text": "The model accurately predicted CYP19A mRNA fold changes for controls and three FAD doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study.", "type": "CHEMICAL", "entities": [ "FAD" ], "offsets": [ [ 77, 80 ] ] }, { "pmid": "23478802", "text": "Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1.\n", "type": "CHEMICAL", "entities": [ "Benzoquinone", "Cysteine" ], "offsets": [ [ 0, 12 ], [ 23, 31 ] ] }, { "pmid": "23478802", "text": "Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region.", "type": "CHEMICAL", "entities": [ "cysteine", "amino" ], "offsets": [ [ 95, 103 ], [ 120, 125 ] ] }, { "pmid": "23478802", "text": "Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1.", "type": "CHEMICAL", "entities": [ "cinnamaldehyde" ], "offsets": [ [ 84, 98 ] ] }, { "pmid": "23478802", "text": "We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel.", "type": "CHEMICAL", "entities": [ "para-benzoquinone", "pBQN" ], "offsets": [ [ 79, 96 ], [ 98, 102 ] ] }, { "pmid": "23478802", "text": "We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S).", "type": "CHEMICAL", "entities": [ "serine", "cysteines" ], "offsets": [ [ 131, 137 ], [ 150, 159 ] ] }, { "pmid": "23478802", "text": "We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline.", "type": "CHEMICAL", "entities": [ "pBQN" ], "offsets": [ [ 14, 18 ] ] }, { "pmid": "23478802", "text": "Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles.", "type": "CHEMICAL", "entities": [ "pBQN", "cysteine" ], "offsets": [ [ 14, 18 ], [ 44, 52 ] ] }, { "pmid": "23478802", "text": "The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation.", "type": "CHEMICAL", "entities": [ "pBQN" ], "offsets": [ [ 41, 45 ] ] }, { "pmid": "23478802", "text": "The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation).", "type": "CHEMICAL", "entities": [ "cysteines", "iodoacetamide", "2-(trimethylammonium)ethyl methanesulfonate" ], "offsets": [ [ 4, 13 ], [ 86, 99 ], [ 123, 166 ] ] }, { "pmid": "23478802", "text": "Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response.", "type": "CHEMICAL", "entities": [ "pBQN", "carvacrol", "cysteine" ], "offsets": [ [ 25, 29 ], [ 128, 137 ], [ 158, 166 ] ] }, { "pmid": "23478802", "text": "Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel.", "type": "CHEMICAL", "entities": [ "cysteine" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23479059", "text": "A study of parabens and bisphenol A in surface water and fish brain tissue from the Greater Pittsburgh Area.\n", "type": "CHEMICAL", "entities": [ "parabens", "bisphenol A" ], "offsets": [ [ 11, 19 ], [ 24, 35 ] ] }, { "pmid": "23479059", "text": "Pollution from xenoestrogens has been discovered in the aquatic environment of the Greater Pittsburgh Area and is suspected to be caused by the failing sewer system.", "type": "CHEMICAL", "entities": [ "xenoestrogens" ], "offsets": [ [ 15, 28 ] ] }, { "pmid": "23479059", "text": "Many of these compounds are suspected xenoestrogens.", "type": "CHEMICAL", "entities": [ "xenoestrogens" ], "offsets": [ [ 38, 51 ] ] }, { "pmid": "23479059", "text": "Paraben detection in surface waters was as follows: methyl paraben ranged between 2.2 to 17.3 ppt; ethyl paraben was not detectable; propyl paraben was detected at 9.2 and 12.0 ppt; butyl paraben was detected at 0.2 ppt.", "type": "CHEMICAL", "entities": [ "Paraben", "methyl paraben", "ethyl paraben", "propyl paraben", "butyl paraben" ], "offsets": [ [ 0, 7 ], [ 52, 66 ], [ 99, 112 ], [ 133, 147 ], [ 182, 195 ] ] }, { "pmid": "23479059", "text": "Estrogenic potential of extracts from fish brain tissue was tested via Bromodeoxyuridine MCF-7 analysis and paired with HPLC-MS to investigate the presence of xenoestrogens.", "type": "CHEMICAL", "entities": [ "Bromodeoxyuridine", "xenoestrogens" ], "offsets": [ [ 67, 84 ], [ 155, 168 ] ] }, { "pmid": "23479059", "text": "All samples were non-detectable for parabens.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 42, 45 ] ] }, { "pmid": "23479059", "text": "Results were statistically significant for location of capture (p < 0.05) and correlation existed between estrogenicity and BPA.", "type": "CHEMICAL", "entities": [ "BPA" ], "offsets": [ [ 119, 122 ] ] }, { "pmid": "23479193", "text": "Synthesis and in-silico studies of some diaryltriazole derivatives as potential cyclooxygenase inhibitors.\n", "type": "CHEMICAL", "entities": [ "diaryltriazole" ], "offsets": [ [ 40, 54 ] ] }, { "pmid": "23479193", "text": "The synthesis of several 4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones possessing N-2 Mannich bases or S-alkyl substituents, is reported.", "type": "CHEMICAL", "entities": [ "Mannich bases", "S-alkyl", "4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones" ], "offsets": [ [ 104, 117 ], [ 121, 128 ], [ 25, 88 ] ] }, { "pmid": "23479193", "text": "Most of the compounds showed inhibition of edema was similar to that evoked by celocoxib in animal model.", "type": "CHEMICAL", "entities": [ "celocoxib" ], "offsets": [ [ 79, 88 ] ] }, { "pmid": "23479738", "text": "Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation.\nS-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes.", "type": "CHEMICAL", "entities": [ "SNOs", "nitric oxide", "NO", "S-Nitrosothiols", "S", "hydrogen peroxide", "H2O2", "cys", "oxygen" ], "offsets": [ [ 97, 101 ], [ 114, 126 ], [ 128, 130 ], [ 80, 95 ], [ 141, 142 ], [ 162, 179 ], [ 181, 185 ], [ 27, 30 ], [ 209, 215 ] ] }, { "pmid": "23479738", "text": "Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood.", "type": "CHEMICAL", "entities": [ "SNOs", "H2O2", "thiol" ], "offsets": [ [ 69, 73 ], [ 78, 82 ], [ 104, 109 ] ] }, { "pmid": "23479738", "text": "In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases.", "type": "CHEMICAL", "entities": [ "NO", "SNO", "Cys" ], "offsets": [ [ 34, 36 ], [ 37, 40 ], [ 131, 134 ] ] }, { "pmid": "23479738", "text": "We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations.", "type": "CHEMICAL", "entities": [ "NO", "SNO", "S-nitrosocysteine", "S-nitrosoglutathione", "S" ], "offsets": [ [ 56, 58 ], [ 59, 62 ], [ 78, 95 ], [ 100, 120 ], [ 141, 142 ] ] }, { "pmid": "23479738", "text": "In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity.", "type": "CHEMICAL", "entities": [ "disulfide", "cysteines", "Cys", "Cys" ], "offsets": [ [ 38, 47 ], [ 90, 99 ], [ 101, 104 ], [ 112, 115 ] ] }, { "pmid": "23479738", "text": "A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system.", "type": "CHEMICAL", "entities": [ "NO", "SNO" ], "offsets": [ [ 67, 69 ], [ 70, 73 ] ] }, { "pmid": "23479738", "text": "In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1.", "type": "CHEMICAL", "entities": [ "S-nitrosocysteine" ], "offsets": [ [ 17, 34 ] ] }, { "pmid": "23479738", "text": "This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity.", "type": "CHEMICAL", "entities": [ "S-nitrosocysteine", "S-nitrosocysteine" ], "offsets": [ [ 58, 75 ], [ 129, 146 ] ] }, { "pmid": "23479738", "text": "Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis.", "type": "CHEMICAL", "entities": [ "SNO", "NO" ], "offsets": [ [ 20, 23 ], [ 17, 19 ] ] }, { "pmid": "23480597", "text": "A polyamine-derivative side chain was conjugated to this core to make it aqueous-soluble and cell-penetrable.", "type": "CHEMICAL", "entities": [ "polyamine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23483103", "text": "The induction of mitochondria-mediated apoptosis in cancer cells by ruthenium(ii) asymmetric complexes.\n", "type": "CHEMICAL", "entities": [ "ruthenium(ii)" ], "offsets": [ [ 68, 81 ] ] }, { "pmid": "23483103", "text": "Four ruthenium(ii) asymmetric complexes, [Ru(bpy)2(PAIDH)](2+) (bpy = 2,2'-bipyridine, PAIDH = 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione, ), [Ru(phen)2(PAIDH)](2+) (phen = 1,10-phenanthroline, ), [Ru(dmp)2(PAIDH)](2+) (dmp = 4,7-dimethyl-1,10-phenanthroline, ) and [Ru(dip)2(PAIDH)](2+) (dip = 4,7-diphenyl-1,10-phenanthroline, ), have been synthesized and characterized.", "type": "CHEMICAL", "entities": [ "[Ru(bpy)2(PAIDH)](2+)", "ruthenium(ii)", "bpy", "2,2'-bipyridine", "PAIDH", "2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione", "[Ru(phen)2(PAIDH)](2+)", "phen", "1,10-phenanthroline", "[Ru(dmp)2(PAIDH)](2+)", "dmp", "4,7-dimethyl-1,10-phenanthroline", "[Ru(dip)2(PAIDH)](2+)", "dip", "4,7-diphenyl-1,10-phenanthroline" ], "offsets": [ [ 41, 62 ], [ 5, 18 ], [ 64, 67 ], [ 70, 85 ], [ 87, 92 ], [ 95, 141 ], [ 146, 168 ], [ 170, 174 ], [ 177, 196 ], [ 201, 222 ], [ 224, 227 ], [ 230, 262 ], [ 270, 291 ], [ 293, 296 ], [ 299, 331 ] ] }, { "pmid": "23485615", "text": "Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes.\n", "type": "CHEMICAL", "entities": [ "dimethylnitrosamine" ], "offsets": [ [ 27, 46 ] ] }, { "pmid": "23485615", "text": "The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats.", "type": "CHEMICAL", "entities": [ "dimethylnitrosamine", "DMN" ], "offsets": [ [ 140, 159 ], [ 161, 164 ] ] }, { "pmid": "23485615", "text": "DMN treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content.", "type": "CHEMICAL", "entities": [ "DMN" ], "offsets": [ [ 0, 3 ] ] }, { "pmid": "23485615", "text": "CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content.", "type": "CHEMICAL", "entities": [ "DMN", "alanine", "aspartate", "malondialdehyde" ], "offsets": [ [ 27, 30 ], [ 58, 65 ], [ 93, 102 ], [ 166, 181 ] ] }, { "pmid": "23485615", "text": "CK also inhibited DMN-induced reductions in rat body and liver weights.", "type": "CHEMICAL", "entities": [ "DMN" ], "offsets": [ [ 18, 21 ] ] }, { "pmid": "23485615", "text": "Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein.", "type": "CHEMICAL", "entities": [ "DMN" ], "offsets": [ [ 110, 113 ] ] }, { "pmid": "23485615", "text": "Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells.", "type": "CHEMICAL", "entities": [ "γ-glutamylcysteine", "heme", "NAD(P)H", "quinone", "glutathione", "S" ], "offsets": [ [ 115, 133 ], [ 154, 158 ], [ 179, 186 ], [ 187, 194 ], [ 224, 235 ], [ 236, 237 ] ] }, { "pmid": "23485615", "text": "These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes.", "type": "CHEMICAL", "entities": [ "DMN" ], "offsets": [ [ 40, 43 ] ] }, { "pmid": "23485651", "text": "Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells.\n", "type": "CHEMICAL", "entities": [ "Cadmium telluride" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "23485651", "text": "The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated.", "type": "CHEMICAL", "entities": [ "CdTe", "cadmium telluride" ], "offsets": [ [ 125, 129 ], [ 93, 110 ] ] }, { "pmid": "23485651", "text": "CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner.", "type": "CHEMICAL", "entities": [ "CdTe" ], "offsets": [ [ 0, 4 ] ] }, { "pmid": "23485651", "text": "Treated cells showed an increase in reactive oxygen species (ROS).", "type": "CHEMICAL", "entities": [ "oxygen" ], "offsets": [ [ 45, 51 ] ] }, { "pmid": "23485651", "text": "Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation.", "type": "CHEMICAL", "entities": [ "reduced glutathione", "GSH", "glutathione", "oxidized glutathione", "GSH", "GSSG" ], "offsets": [ [ 61, 80 ], [ 82, 85 ], [ 117, 128 ], [ 132, 152 ], [ 154, 157 ], [ 158, 162 ] ] }, { "pmid": "23485651", "text": "Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed.", "type": "CHEMICAL", "entities": [ "superoxide", "glutathione", "S" ], "offsets": [ [ 26, 36 ], [ 102, 113 ], [ 114, 115 ] ] }, { "pmid": "23485651", "text": "Further analyses revealed that CdTe-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization.", "type": "CHEMICAL", "entities": [ "CdTe", "poly ADP-ribose", "phosphatidylserine" ], "offsets": [ [ 31, 35 ], [ 125, 140 ], [ 172, 190 ] ] }, { "pmid": "23485651", "text": "Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure.", "type": "CHEMICAL", "entities": [ "CdTe" ], "offsets": [ [ 103, 107 ] ] }, { "pmid": "23485651", "text": "Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 330, 331 ] ] }, { "pmid": "23485651", "text": "Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways.", "type": "CHEMICAL", "entities": [ "CdTe" ], "offsets": [ [ 25, 29 ] ] }, { "pmid": "23485651", "text": "Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs.", "type": "CHEMICAL", "entities": [ "CdTe", "CdCl2", "cadmium", "CdTe" ], "offsets": [ [ 21, 25 ], [ 98, 103 ], [ 136, 143 ], [ 185, 189 ] ] }, { "pmid": "23494236", "text": "Reinforcement enhancing effects of nicotine via smoking.\n", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 35, 43 ] ] }, { "pmid": "23494236", "text": "In animals, nicotine enhances reinforcement from stimuli unrelated to nicotine intake.", "type": "CHEMICAL", "entities": [ "nicotine", "nicotine" ], "offsets": [ [ 70, 78 ], [ 12, 20 ] ] }, { "pmid": "23494236", "text": "Human research is suggestive but has not clearly shown a similar influence of nicotine.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "23494236", "text": "We assessed acute effects of nicotine via smoking on enhancement of positive (money, music) or negative (termination of noise) reinforcers, or no \"reward\" (control).", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 29, 37 ] ] }, { "pmid": "23494236", "text": "These different rewards determined the generalizability of nicotine effects.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 59, 67 ] ] }, { "pmid": "23494236", "text": "Using a within-subjects design, sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) Quest(R) brand cigarettes.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 91, 99 ] ] }, { "pmid": "23494236", "text": "For comparison, a fourth session involved no abstinence prior to smoking one's own brand to gauge responses under typical nicotine satiation.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 112, 120 ] ] }, { "pmid": "23494236", "text": "The reinforcing effect of music, but not other rewards, was greater due to the nicotine cigarette, compared to the denicotinized cigarette or no smoking.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 69, 77 ] ] }, { "pmid": "23494236", "text": "Reinforcement enhancing effects of nicotine did not differ between dependent and nondependent groups, indicating no influence of withdrawal relief.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "23494236", "text": "Responding due to acute nicotine after abstinence was very similar to responding to one's own brand after no abstinence.", "type": "CHEMICAL", "entities": [ "nicotine" ], "offsets": [ [ 14, 22 ] ] }, { "pmid": "23494236", "text": "CONCLUSIONS: Acute nicotine intake per se from smoking after abstinence enhances the reinforcing value of rewards unassociated with smoking, perhaps in a manner comparable to ad lib smoking after no abstinence.", "type": "CHEMICAL", "entities": [ "nicotine", "Nicotine" ], "offsets": [ [ 9, 17 ], [ 201, 209 ] ] }, { "pmid": "23500061", "text": "Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: Use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier.\n", "type": "CHEMICAL", "entities": [ "deoxycholic acid", "polyethyleneimine" ], "offsets": [ [ 108, 124 ], [ 155, 172 ] ] }, { "pmid": "23500061", "text": "Herein, we report ischemic-reperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 131, 139 ] ] }, { "pmid": "23500061", "text": "A low molecular weight polyethyleneimine modified with deoxycholic acid (PEI1.8-DA)-based delivery strategy was suggested for the cardiac application of SHP-1 siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles.", "type": "CHEMICAL", "entities": [ "polyethyleneimine", "deoxycholic acid" ], "offsets": [ [ 23, 40 ], [ 55, 71 ] ] }, { "pmid": "23500411", "text": "Synthesis of C17-OH-north unit of ritterazine G via \"Red-Ox\" modifications of hecogenin acetate.\n", "type": "CHEMICAL", "entities": [ "OH", "ritterazine G", "hecogenin acetate" ], "offsets": [ [ 17, 19 ], [ 34, 47 ], [ 78, 95 ] ] }, { "pmid": "23500411", "text": "The C17-OH-north unit of ritterazine G was prepared in 13 steps from hecogenin acetate.", "type": "CHEMICAL", "entities": [ "ritterazine G", "hecogenin acetate", "OH" ], "offsets": [ [ 25, 38 ], [ 69, 86 ], [ 8, 10 ] ] }, { "pmid": "23500411", "text": "This synthesis features a highly efficient and stereoselective introduction of the C17-OH via E-ring cleavage/F-ring formation, D-ring oxidation, and F-ring cleavage/E-ring formation.", "type": "CHEMICAL", "entities": [ "OH" ], "offsets": [ [ 87, 89 ] ] }, { "pmid": "23507868", "text": "Compared to control HDLs, ABLP HDLs showed a 40% decrease of α-tocopherol and an 11-fold increased malondialdehyde concentration.", "type": "CHEMICAL", "entities": [ "α-tocopherol", "malondialdehyde" ], "offsets": [ [ 61, 73 ], [ 99, 114 ] ] }, { "pmid": "23511088", "text": "Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities.", "type": "CHEMICAL", "entities": [ "alkylphenones" ], "offsets": [ [ 68, 81 ] ] }, { "pmid": "23511088", "text": "Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells.", "type": "CHEMICAL", "entities": [ "butoxy" ], "offsets": [ [ 35, 41 ] ] }, { "pmid": "23512787", "text": "Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice.\nPuerarin, an active component of Pueraria montana var.", "type": "CHEMICAL", "entities": [ "Puerarin", "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine", "Puerarin" ], "offsets": [ [ 27, 35 ], [ 39, 83 ], [ 127, 135 ] ] }, { "pmid": "23512787", "text": "Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 46, 54 ] ] }, { "pmid": "23512787", "text": "In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion.", "type": "CHEMICAL", "entities": [ "puerarin", "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine", "MPTP", "dopamine" ], "offsets": [ [ 33, 41 ], [ 53, 97 ], [ 99, 103 ], [ 173, 181 ] ] }, { "pmid": "23512787", "text": "Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/", "type": "CHEMICAL", "entities": [ "glutathione", "GSH", "Puerarin" ], "offsets": [ [ 33, 44 ], [ 46, 49 ], [ 0, 8 ] ] }, { "pmid": "23512787", "text": "Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice.", "type": "CHEMICAL", "entities": [ "MPTP", "oxygen" ], "offsets": [ [ 47, 51 ], [ 104, 110 ] ] }, { "pmid": "23512787", "text": "In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression.", "type": "CHEMICAL", "entities": [ "puerarin", "MPTP" ], "offsets": [ [ 34, 42 ], [ 55, 59 ] ] }, { "pmid": "23512787", "text": "Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression.", "type": "CHEMICAL", "entities": [ "puerarin", "MPTP", "GSH", "MPTP" ], "offsets": [ [ 42, 50 ], [ 62, 66 ], [ 163, 166 ], [ 209, 213 ] ] }, { "pmid": "23517729", "text": "Efficient induction of apoptosis in HeLa cells by a novel cationic porphycene photosensitizer.\n", "type": "CHEMICAL", "entities": [ "porphycene" ], "offsets": [ [ 67, 77 ] ] }, { "pmid": "23517729", "text": "porphycene (Py3MeO-TBPo) in Hela cells, in order to assess its potential as a new photosensitizer for photodynamic therapy of cultured tumor cells.", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo" ], "offsets": [ [ 11, 22 ] ] }, { "pmid": "23517729", "text": "Using 0.5 μM Py3MeO-TBPo, flow cytometry studies demonstrated an increase of intracellular drug levels related to the incubation time, reaching a maximum at 18 h. LysoTracker(®)", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo" ], "offsets": [ [ 12, 23 ] ] }, { "pmid": "23517729", "text": "Upon exposure to ultraviolet excitation, red porphycene fluorescence was detected as red granules in the cytoplasm that colocalized with LTG.", "type": "CHEMICAL", "entities": [ "porphycene" ], "offsets": [ [ 39, 49 ] ] }, { "pmid": "23517729", "text": "No significant toxic effects were detected for Py3MeO-TBPo in the dark at concentrations below 1 μM.", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "23517729", "text": "In contrast, Py3MeO-TBPo combined with red-light irradiation induced concentration- and fluence-dependent HeLa cells inactivation.", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo" ], "offsets": [ [ 5, 16 ] ] }, { "pmid": "23517729", "text": "After 18 h incubation with 0.5 μM Py3MeO-TBPo and subsequent red light irradiation (3.6 J/cm(2)), a high number of cells die by apoptosis, as evaluated by morphological alterations, immunofluorescent relocalization of Bax from cytosol to mitochondria, and TUNEL assay.", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo" ], "offsets": [ [ 26, 37 ] ] }, { "pmid": "23517729", "text": "In contrast, with 0.75 μM Py3MeO-TBPo and 3.6 J/cm(2) irradiation, morphological changes showed a preferential necrotic cell death.", "type": "CHEMICAL", "entities": [ "Py3MeO-TBPo", "oxygen" ], "offsets": [ [ 13, 24 ], [ 127, 133 ] ] }, { "pmid": "23517729", "text": "Moreover, cell cultures pre-exposed to the singlet oxygen scavenger sodium azide showed pronounced protection against the loss of viability induced by Py3MeO-TBPo and light.", "type": "CHEMICAL", "entities": [ "oxygen", "sodium azide", "Py3MeO-TBPo" ], "offsets": [ [ 35, 41 ], [ 52, 64 ], [ 135, 146 ] ] }, { "pmid": "23522564", "text": "The gp41 subunit contains several functional domains: the N-terminal heptad repeat (NHR) domains fold a triple stranded coiled-coil forming a meta-stable prefusion intermediate.", "type": "CHEMICAL", "entities": [ "N" ], "offsets": [ [ 58, 59 ] ] }, { "pmid": "23522564", "text": "C-terminal heptad repeat (CHR) subsequently folds onto the hydrophobic grooves of the NHR coiled-coil to form a stable 6-helix bundle, which juxtaposes the viral and cellular membranes for fusion.", "type": "CHEMICAL", "entities": [ "C" ], "offsets": [ [ 0, 1 ] ] }, { "pmid": "23522564", "text": "The C34 which has 34 amino acid residues is known as the core structure in CHR.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 21, 31 ] ] }, { "pmid": "23522564", "text": "An artificial salt bridge was added in the 6-helical bundle by substitution of lysine for Ile646.", "type": "CHEMICAL", "entities": [ "lysine", "Ile" ], "offsets": [ [ 79, 85 ], [ 90, 93 ] ] }, { "pmid": "23522564", "text": "With a cholesterol modification at C-terminal, the inhibitor containing I646K mutation represented higher anti-viral activity than C34-cholesterol combination without mutation.", "type": "CHEMICAL", "entities": [ "cholesterol", "C", "cholesterol" ], "offsets": [ [ 7, 18 ], [ 35, 36 ], [ 135, 146 ] ] }, { "pmid": "23523831", "text": "Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound nerolidol.\n", "type": "CHEMICAL", "entities": [ "nerolidol" ], "offsets": [ [ 88, 97 ] ] }, { "pmid": "23523831", "text": "One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound.", "type": "CHEMICAL", "entities": [ "(E)-nerolidol" ], "offsets": [ [ 106, 119 ] ] }, { "pmid": "23523831", "text": "The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and nerolidol using Saccharomyces cerevisiae as model study.", "type": "CHEMICAL", "entities": [ "nerolidol" ], "offsets": [ [ 111, 120 ] ] }, { "pmid": "23523831", "text": "Treatment of the XV185-14c and N123 strains with essential oil and nerolidol led to cytotoxicity but did not induce mutagenicity.", "type": "CHEMICAL", "entities": [ "nerolidol" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "23523831", "text": "Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and nerolidol.", "type": "CHEMICAL", "entities": [ "nerolidol" ], "offsets": [ [ 161, 170 ] ] }, { "pmid": "23523831", "text": "In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and nerolidol increased indicating that this oil and nerolidol are generating reactive oxygen species (ROS).", "type": "CHEMICAL", "entities": [ "nerolidol", "oxygen", "superoxide", "nerolidol" ], "offsets": [ [ 150, 159 ], [ 184, 190 ], [ 18, 28 ], [ 101, 110 ] ] }, { "pmid": "23523831", "text": "The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains.", "type": "CHEMICAL", "entities": [ "DCF-DA" ], "offsets": [ [ 35, 41 ] ] }, { "pmid": "23523831", "text": "From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and nerolidol is mainly related to ROS and DNA", "type": "CHEMICAL", "entities": [ "nerolidol" ], "offsets": [ [ 93, 102 ] ] }, { "pmid": "23524160", "text": "Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents.", "type": "CHEMICAL", "entities": [ "pyrrolidine-2,5-dione" ], "offsets": [ [ 45, 66 ] ] }, { "pmid": "23524160", "text": "A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated.", "type": "CHEMICAL", "entities": [ "3-(1H-indol-3-yl)pyrrolidine-2,5-dione" ], "offsets": [ [ 11, 49 ] ] }, { "pmid": "23524160", "text": "The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data.", "type": "CHEMICAL", "entities": [ "(1)H", "(13)C" ], "offsets": [ [ 73, 77 ], [ 83, 88 ] ] }, { "pmid": "23524160", "text": "All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands.", "type": "CHEMICAL", "entities": [ "serotonin" ], "offsets": [ [ 60, 69 ] ] }, { "pmid": "23524663", "text": "Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice.\n", "type": "CHEMICAL", "entities": [ "3H" ], "offsets": [ [ 47, 49 ] ] }, { "pmid": "23524663", "text": "Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3)H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3)H-exchange.", "type": "CHEMICAL", "entities": [ "(3)H", "Br", "(3)H" ], "offsets": [ [ 137, 141 ], [ 228, 230 ], [ 231, 235 ] ] }, { "pmid": "23524663", "text": "Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3)H]-siRNAs, at a target dose level of 5 mg/kg.", "type": "CHEMICAL", "entities": [ "(3)H" ], "offsets": [ [ 157, 161 ] ] }, { "pmid": "23524663", "text": "In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3)H]-siRNAs.", "type": "CHEMICAL", "entities": [ "(3)H" ], "offsets": [ [ 139, 143 ] ] }, { "pmid": "23524663", "text": "The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [(3)H]-MRP4 and [(3)H]-SSB siRNA, respectively).", "type": "CHEMICAL", "entities": [ "(3)H", "(3)H" ], "offsets": [ [ 169, 173 ], [ 185, 189 ] ] }, { "pmid": "23524663", "text": "A nearly complete mass balance was obtained for the [(3)H]-SSB siRNA and renal excretion was the main route of elimination (38%).", "type": "CHEMICAL", "entities": [ "(3)H" ], "offsets": [ [ 53, 57 ] ] }, { "pmid": "23524663", "text": "Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed.", "type": "CHEMICAL", "entities": [ "nucleosides" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "23524663", "text": "In the metabolism profiles obtained from various tissues only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites.", "type": "CHEMICAL", "entities": [ "nucleosides" ], "offsets": [ [ 75, 86 ] ] }, { "pmid": "23525902", "text": "The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation.", "type": "CHEMICAL", "entities": [ "phosphates" ], "offsets": [ [ 195, 205 ] ] }, { "pmid": "23525902", "text": "We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306).", "type": "CHEMICAL", "entities": [ "ATP", "1NMPP1", "RO3306" ], "offsets": [ [ 107, 110 ], [ 131, 137 ], [ 166, 172 ] ] }, { "pmid": "23525902", "text": "At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds.", "type": "CHEMICAL", "entities": [ "1NMPP1" ], "offsets": [ [ 6, 12 ] ] }, { "pmid": "23525902", "text": "We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation.", "type": "CHEMICAL", "entities": [ "RO3306" ], "offsets": [ [ 16, 22 ] ] }, { "pmid": "23526644", "text": "A high throughput screen identified adamantane dipeptide 1 as an inhibitor of Ebola virus (EboV) infection.", "type": "CHEMICAL", "entities": [ "adamantane" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "23527317", "text": "Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse.\n", "type": "CHEMICAL", "entities": [ "nor-lobelane", "methamphetamine", "N" ], "offsets": [ [ 42, 54 ], [ 147, 162 ], [ 24, 25 ] ] }, { "pmid": "23527317", "text": "A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [(3)H]dopamine uptake.", "type": "CHEMICAL", "entities": [ "N", "monoamine", "[(3)H]dopamine", "lobelane", "[(3)H]dihydrotetrabenazine" ], "offsets": [ [ 12, 13 ], [ 146, 155 ], [ 206, 220 ], [ 26, 34 ], [ 85, 111 ] ] }, { "pmid": "23527317", "text": "Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse.", "type": "CHEMICAL", "entities": [ "N-1,2(R)-dihydroxypropyl", "methamphetamine" ], "offsets": [ [ 32, 56 ], [ 139, 154 ] ] }, { "pmid": "23527529", "text": "The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway.\n", "type": "CHEMICAL", "entities": [ "IPI-926" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "23527529", "text": "Abstract 1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway.", "type": "CHEMICAL", "entities": [ "IPI-926", "cyclopamine" ], "offsets": [ [ 12, 19 ], [ 45, 56 ] ] }, { "pmid": "23527529", "text": "The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey.", "type": "CHEMICAL", "entities": [ "IPI-926" ], "offsets": [ [ 25, 32 ] ] }, { "pmid": "23527529", "text": "5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone).", "type": "CHEMICAL", "entities": [ "IPI-926", "testosterone" ], "offsets": [ [ 82, 89 ], [ 67, 79 ] ] }, { "pmid": "23527529", "text": "IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926", "type": "CHEMICAL", "entities": [ "midazolam", "IPI-926" ], "offsets": [ [ 48, 57 ], [ 110, 117 ] ] }, { "pmid": "23528363", "text": "Protection of glycyrrhizic acid against AGEs-induced endothelial dysfunction through inhibiting RAGE/NF-κB pathway activation in human umbilical vein endothelial cells.\n", "type": "CHEMICAL", "entities": [ "glycyrrhizic acid" ], "offsets": [ [ 14, 31 ] ] }, { "pmid": "23528363", "text": "Glycyrrhizic acid (GA, also known as Glycyrrhizin), a triterpenoid saponin glycoside, is considered to be a bioactive component in Licorice and is beneficial to diabetic vascular complications.", "type": "CHEMICAL", "entities": [ "Glycyrrhizin", "triterpenoid saponin glycoside" ], "offsets": [ [ 36, 48 ], [ 53, 83 ] ] }, { "pmid": "23528363", "text": "The superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in cell supernatant were detected by kits while the intracellular reactive oxygen species (ROS) generation was determined by 2,7-dichlorodihydrofluorescin diacetate (DCFH-DA) kit.", "type": "CHEMICAL", "entities": [ "MDA", "oxygen", "2,7-dichlorodihydrofluorescin diacetate", "DCFH-DA", "superoxide", "malondialdehyde" ], "offsets": [ [ 58, 61 ], [ 144, 150 ], [ 194, 233 ], [ 235, 242 ], [ 1, 11 ], [ 41, 56 ] ] }, { "pmid": "23528363", "text": "GA significantly increased antioxidant enzyme SOD activity and decreased peroxide degradation product MDA level in a dose-dependent manner.", "type": "CHEMICAL", "entities": [ "MDA" ], "offsets": [ [ 97, 100 ] ] }, { "pmid": "23529671", "text": "Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 247, 254 ] ] }, { "pmid": "23529671", "text": "There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 76, 83 ] ] }, { "pmid": "23529825", "text": "Lorcaserin: a review of its use in chronic weight management.\n", "type": "CHEMICAL", "entities": [ "Lorcaserin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23529825", "text": "Oral lorcaserin (BELVIQ(®)), a selective serotonin 5-HT2C receptor agonist, is indicated in the US as an adjunct to diet and exercise in the chronic weight management of obese adults, or overweight adults with at least one weight-related comorbidity (e.g. dyslipidaemia, hypertension, type 2 diabetes).", "type": "CHEMICAL", "entities": [ "lorcaserin", "BELVIQ", "serotonin" ], "offsets": [ [ 5, 15 ], [ 17, 23 ], [ 41, 50 ] ] }, { "pmid": "23529825", "text": "This article reviews the pharmacological properties, therapeutic efficacy and tolerability of oral lorcaserin in this patient population.", "type": "CHEMICAL", "entities": [ "lorcaserin" ], "offsets": [ [ 98, 108 ] ] }, { "pmid": "23529825", "text": "In three large randomized, double-blind, multicentre studies, oral lorcaserin was more effective than placebo in the management of obese and overweight adults with or without type 2 diabetes mellitus.", "type": "CHEMICAL", "entities": [ "lorcaserin" ], "offsets": [ [ 66, 76 ] ] }, { "pmid": "23529825", "text": "Following 12 months' therapy, significantly higher proportions of lorcaserin than placebo recipients achieved a ≥5 and ≥10 % reduction from baseline in their bodyweight and a significant between-group difference favouring lorcaserin over placebo was observed for the change from baseline in bodyweight.", "type": "CHEMICAL", "entities": [ "lorcaserin", "lorcaserin" ], "offsets": [ [ 65, 75 ], [ 221, 231 ] ] }, { "pmid": "23529825", "text": "Moreover, among patients who had achieved a ≥5 % reduction in their bodyweight after 12 months' therapy with lorcaserin, a significantly higher proportion who received lorcaserin for a further 12 months than those who switched to placebo maintained ≥5 % weight loss at 24 months.", "type": "CHEMICAL", "entities": [ "lorcaserin", "lorcaserin" ], "offsets": [ [ 102, 112 ], [ 161, 171 ] ] }, { "pmid": "23529825", "text": "In general, oral lorcaserin was well tolerated in clinical studies, with hypoglycaemia and headache the most frequently reported adverse events in those with or without type 2 diabetes, respectively.", "type": "CHEMICAL", "entities": [ "lorcaserin" ], "offsets": [ [ 1, 11 ] ] }, { "pmid": "23529825", "text": "According to a pooled analysis, the risk of US-FDA-defined valvulopathy with lorcaserin is generally low and not statistically significantly different from placebo.", "type": "CHEMICAL", "entities": [ "lorcaserin" ], "offsets": [ [ 61, 71 ] ] }, { "pmid": "23529825", "text": "From these and other data, the FDA has concluded that lorcaserin is unlikely to elevate the risk of valvulopathy.", "type": "CHEMICAL", "entities": [ "lorcaserin" ], "offsets": [ [ 38, 48 ] ] }, { "pmid": "23530834", "text": "Design, Synthesis, Biological Evaluation, and Docking Studies of (S)-Phenylalanine Derivatives with a 2-Cyanopyrrolidine Moiety as Potent Dipeptidyl Peptidase 4 Inhibitors.\n", "type": "CHEMICAL", "entities": [ "2-Cyanopyrrolidine", "(S)-Phenylalanine" ], "offsets": [ [ 102, 120 ], [ 65, 82 ] ] }, { "pmid": "23530834", "text": "A novel series of (S)-phenylalanine derivatives with a 2-cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy.", "type": "CHEMICAL", "entities": [ "(S)-phenylalanine", "2-cyanopyrrolidine" ], "offsets": [ [ 18, 35 ], [ 55, 73 ] ] }, { "pmid": "23530834", "text": "Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors, among them, the cyclopropyl-substituted phenylalanine derivative 11h displayed the most potent DPP-4 inhibitory activity with an IC50 value of 0.247 μM.", "type": "CHEMICAL", "entities": [ "cyclopropyl-substituted phenylalanine" ], "offsets": [ [ 129, 166 ] ] }, { "pmid": "23532932", "text": "genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel.", "type": "CHEMICAL", "entities": [ "paclitaxel", "docetaxel", "pregnenolone-16α-carbonitrile", "PCN", "taxanes" ], "offsets": [ [ 142, 152 ], [ 157, 166 ], [ 42, 71 ], [ 73, 76 ], [ 133, 140 ] ] }, { "pmid": "23532932", "text": "All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and docetaxel appeared to act primarily via PXR.", "type": "CHEMICAL", "entities": [ "PCN", "docetaxel" ], "offsets": [ [ 74, 77 ], [ 82, 91 ] ] }, { "pmid": "23534440", "text": "The available X-ray structures contain only UCCG tetraloops which in addition differ in orientation (anti vs syn) of the guanine.", "type": "CHEMICAL", "entities": [ "guanine" ], "offsets": [ [ 120, 127 ] ] }, { "pmid": "23534440", "text": "Alternatively, the anti conformation may be a real substate whose population could be pH-dependent, since the guanine syn orientation requires protonation of cytosine in the tertiary contact.", "type": "CHEMICAL", "entities": [ "guanine", "cytosine" ], "offsets": [ [ 109, 116 ], [ 157, 165 ] ] }, { "pmid": "23534440", "text": "Kink-turn Kt-77 is unusual due to its 11-nucleotide bulge.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 40, 50 ] ] }, { "pmid": "23534440", "text": "The simulations indicate that the long bulge is a stalk-specific eight-nucleotide insertion into consensual kink-turn only subtly modifying its structural dynamics.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "23534440", "text": "Still, even bsc0χOL3 is unable to fully stabilize an essential sugar-edge H-bond between the bulge and non-canonical stem of the kink-turn.", "type": "CHEMICAL", "entities": [ "sugar", "H" ], "offsets": [ [ 61, 66 ], [ 72, 73 ] ] }, { "pmid": "23534440", "text": "Inclusion of Mg(2+) ions may deteriorate the simulations.", "type": "CHEMICAL", "entities": [ "Mg(2+)" ], "offsets": [ [ 10, 16 ] ] }, { "pmid": "23534440", "text": "On the other hand, monovalent ions can in simulations readily occupy experimental Mg(2+) binding sites.", "type": "CHEMICAL", "entities": [ "Mg(2+)" ], "offsets": [ [ 79, 85 ] ] }, { "pmid": "23535185", "text": "Galangin attenuates mast cell-mediated allergic inflammation.\n", "type": "CHEMICAL", "entities": [ "Galangin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23535185", "text": "In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models.", "type": "CHEMICAL", "entities": [ "galangin" ], "offsets": [ [ 68, 76 ] ] }, { "pmid": "23535185", "text": "Galangin inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1).", "type": "CHEMICAL", "entities": [ "phorbol 12-mystate 13-acetate", "calcium", "Galangin", "histamine", "calcium" ], "offsets": [ [ 82, 111 ], [ 117, 124 ], [ 0, 8 ], [ 19, 28 ], [ 71, 78 ] ] }, { "pmid": "23535185", "text": "Galangin decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8.", "type": "CHEMICAL", "entities": [ "Galangin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23535185", "text": "The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1.", "type": "CHEMICAL", "entities": [ "galangin", "N" ], "offsets": [ [ 23, 31 ], [ 92, 93 ] ] }, { "pmid": "23535185", "text": "Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue.", "type": "CHEMICAL", "entities": [ "galangin", "histamine" ], "offsets": [ [ 10, 18 ], [ 95, 104 ] ] }, { "pmid": "23535185", "text": "The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug.", "type": "CHEMICAL", "entities": [ "galangin", "cromolyn" ], "offsets": [ [ 23, 31 ], [ 54, 62 ] ] }, { "pmid": "23535185", "text": "Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines.", "type": "CHEMICAL", "entities": [ "galangin", "histamine" ], "offsets": [ [ 21, 29 ], [ 107, 116 ] ] }, { "pmid": "23535185", "text": "In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent.", "type": "CHEMICAL", "entities": [ "galangin" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "23535288", "text": "Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls.", "type": "CHEMICAL", "entities": [ "caprolactam", "sulfadimethoxine", "SDM", "phenylethyl isothiocyanate", "butylated hydroxyanisole", "BHA", "catechol", "2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine", "chenodeoxycholic acid" ], "offsets": [ [ 313, 324 ], [ 29, 45 ], [ 47, 50 ], [ 70, 96 ], [ 112, 136 ], [ 138, 141 ], [ 163, 171 ], [ 189, 236 ], [ 241, 262 ] ] }, { "pmid": "23535288", "text": "HP1α responded only to BHA.", "type": "CHEMICAL", "entities": [ "BHA" ], "offsets": [ [ 21, 24 ] ] }, { "pmid": "23537747", "text": "Nobiletin attenuates metastasis via both ERK and PI3K/", "type": "CHEMICAL", "entities": [ "Nobiletin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23537747", "text": "We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis.", "type": "CHEMICAL", "entities": [ "apigenin", "tricetin", "tangeretin", "nobiletin" ], "offsets": [ [ 108, 116 ], [ 118, 126 ], [ 128, 138 ], [ 144, 153 ] ] }, { "pmid": "23537747", "text": "Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations.", "type": "CHEMICAL", "entities": [ "nobiletin" ], "offsets": [ [ 12, 21 ] ] }, { "pmid": "23537747", "text": "Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia.", "type": "CHEMICAL", "entities": [ "nobiletin" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "23537747", "text": "Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38.", "type": "CHEMICAL", "entities": [ "nobiletin" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "23537747", "text": "Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration.", "type": "CHEMICAL", "entities": [ "phospho", "phospho", "nobiletin" ], "offsets": [ [ 54, 61 ], [ 71, 78 ], [ 6, 15 ] ] }, { "pmid": "23537747", "text": "In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma.", "type": "CHEMICAL", "entities": [ "nobiletin" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "23539511", "text": "However, plasma pro-ANP and creatinine concentrations were closely correlated (P < .0001; r = 0.73).", "type": "CHEMICAL", "entities": [ "creatinine" ], "offsets": [ [ 28, 38 ] ] }, { "pmid": "23541086", "text": "T-Cells from HLA-B*57:01+ Human Subjects Are Activated with Abacavir through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms.\n", "type": "CHEMICAL", "entities": [ "Abacavir" ], "offsets": [ [ 60, 68 ] ] }, { "pmid": "23541086", "text": "The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between abacavir accumulation in antigen presenting cells and the T-cell response.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 194, 202 ] ] }, { "pmid": "23541086", "text": "Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to abacavir.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 148, 156 ] ] }, { "pmid": "23541086", "text": "Certain clones were activated with abacavir in the absence of antigen presenting cells.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 34, 42 ] ] }, { "pmid": "23541086", "text": "Overnight incubation of antigen presenting cells with abacavir, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation.", "type": "CHEMICAL", "entities": [ "abacavir", "glutaraldehyde" ], "offsets": [ [ 53, 61 ], [ 191, 205 ] ] }, { "pmid": "23541086", "text": "Accumulation of abacavir in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 15, 23 ] ] }, { "pmid": "23541086", "text": "However, intracellular abacavir was not detectable by mass spectrometry after pulsing.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 22, 30 ] ] }, { "pmid": "23541086", "text": "These data suggest that T-cells can be activated by abacavir through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23541086", "text": "With the former, abacavir seemingly participates in the MHC T-cell receptor binding interaction.", "type": "CHEMICAL", "entities": [ "abacavir" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "23541086", "text": "In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of abacavir exposure, but not abacavir itself.", "type": "CHEMICAL", "entities": [ "abacavir", "abacavir" ], "offsets": [ [ 98, 106 ], [ 125, 133 ] ] }, { "pmid": "23541982", "text": "Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid.\n", "type": "CHEMICAL", "entities": [ "oxysterols" ], "offsets": [ [ 48, 58 ] ] }, { "pmid": "23541982", "text": "The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover.", "type": "CHEMICAL", "entities": [ "cholesterol", "24OHC", "cholesterol", "cholesterol", "24S-hydroxycholesterol", "24OHC" ], "offsets": [ [ 18, 29 ], [ 215, 220 ], [ 307, 318 ], [ 67, 78 ], [ 84, 106 ], [ 108, 113 ] ] }, { "pmid": "23541982", "text": "In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC.", "type": "CHEMICAL", "entities": [ "24OHC" ], "offsets": [ [ 110, 115 ] ] }, { "pmid": "23541982", "text": "Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF)", "type": "CHEMICAL", "entities": [ "24OHC" ], "offsets": [ [ 45, 50 ] ] }, { "pmid": "23541982", "text": "whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier.", "type": "CHEMICAL", "entities": [ "27-hydroxycholesterol", "27OHC" ], "offsets": [ [ 19, 40 ], [ 42, 47 ] ] }, { "pmid": "23541982", "text": "Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction.", "type": "CHEMICAL", "entities": [ "oxysterols" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "23541982", "text": "In neurodegeneration, free cholesterol released from dying cells may engulf neurons.", "type": "CHEMICAL", "entities": [ "cholesterol" ], "offsets": [ [ 27, 38 ] ] }, { "pmid": "23541982", "text": "Cholesterol also increases Amyloid β (Aβ) deposition and tau pathology.", "type": "CHEMICAL", "entities": [ "Cholesterol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "23541982", "text": "ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples.", "type": "CHEMICAL", "entities": [ "24OHC" ], "offsets": [ [ 4, 9 ] ] }, { "pmid": "23541982", "text": "Excess of cholesterol converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and Tau.", "type": "CHEMICAL", "entities": [ "cholesterol", "24OHC" ], "offsets": [ [ 8, 19 ], [ 35, 40 ] ] }, { "pmid": "23541982", "text": "In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger.", "type": "CHEMICAL", "entities": [ "27OHC" ], "offsets": [ [ 109, 114 ] ] }, { "pmid": "23541982", "text": "Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and ApoE function in the pathogenesis of AD.", "type": "CHEMICAL", "entities": [ "oxysterols", "cholesterol" ], "offsets": [ [ 19, 29 ], [ 88, 99 ] ] }, { "pmid": "23543737", "text": "Loss of Calcium/Calmodulin-Dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP.\n", "type": "CHEMICAL", "entities": [ "ATP", "Calcium", "Glutamate" ], "offsets": [ [ 148, 151 ], [ 8, 15 ], [ 97, 106 ] ] }, { "pmid": "23543737", "text": "The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain following ischemia correlates with the extent of damage.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 14, 21 ] ] }, { "pmid": "23543737", "text": "We have previously shown that a loss of CaMKII activity in neurons is detrimental to neuronal viability by inducing excitotoxic glutamate release.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 128, 137 ] ] }, { "pmid": "23543737", "text": "In the current study, we extend these findings to show that the ability of astrocytes to buffer extracellular glutamate is reduced when CaMKII is inhibited.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 110, 119 ] ] }, { "pmid": "23543737", "text": "Furthermore, CaMKII inhibition in astrocytes is associated with the rapid onset of intracellular calcium oscillations.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 97, 104 ] ] }, { "pmid": "23543737", "text": "Surprisingly, this rapid calcium influx is blocked by the N-type calcium channel antagonist, omega-conotoxin.", "type": "CHEMICAL", "entities": [ "calcium", "N", "calcium" ], "offsets": [ [ 25, 32 ], [ 58, 59 ], [ 65, 72 ] ] }, { "pmid": "23543737", "text": "While the function of N-type calcium channels within astrocytes is controversial, these voltage-gated calcium channels have been linked to calcium-dependent vesicular gliotransmitter release.", "type": "CHEMICAL", "entities": [ "N", "calcium", "calcium", "calcium" ], "offsets": [ [ 22, 23 ], [ 29, 36 ], [ 102, 109 ], [ 139, 146 ] ] }, { "pmid": "23543737", "text": "When extracellular glutamate and ATP levels are measured following CaMKII inhibition within our enriched astrocyte cultures, no alterations in glutamate levels are observed, whereas ATP levels in the extracellular environment significantly increase.", "type": "CHEMICAL", "entities": [ "glutamate", "ATP", "glutamate", "ATP" ], "offsets": [ [ 19, 28 ], [ 33, 36 ], [ 143, 152 ], [ 182, 185 ] ] }, { "pmid": "23543737", "text": "Extracellular ATP accumulation associated with CaMKII inhibition contributes both to calcium oscillations within astrocytes and ultimately cortical neuron toxicity.", "type": "CHEMICAL", "entities": [ "ATP", "calcium" ], "offsets": [ [ 14, 17 ], [ 85, 92 ] ] }, { "pmid": "23543737", "text": "Thus, a loss of CaMKII signaling within astrocytes dysregulates glutamate uptake and supports ATP release, two processes that would compromise neuronal survival following ischemic/excitotoxic insults.", "type": "CHEMICAL", "entities": [ "glutamate", "ATP" ], "offsets": [ [ 64, 73 ], [ 94, 97 ] ] }, { "pmid": "23545568", "text": "Stable and high-rate overcharge protection for rechargeable lithium batteries.\n", "type": "CHEMICAL", "entities": [ "lithium" ], "offsets": [ [ 60, 67 ] ] }, { "pmid": "23545568", "text": "Rechargeable lithium or lithium-ion cells can be overcharge-protected by an electroactive polymer composite separator.", "type": "CHEMICAL", "entities": [ "lithium", "lithium" ], "offsets": [ [ 13, 20 ], [ 24, 31 ] ] }, { "pmid": "23545568", "text": "For the first time, stable overcharge protection for hundreds of cycles was demonstrated in several cell chemistries, including LiNi1/3Co1/3Mn1/3O2, LiFePO4, and spinel Li1.05Mn1.95O4", "type": "CHEMICAL", "entities": [ "LiNi1", "3Co1", "3Mn1", "3O2", "LiFePO4", "Li1.05Mn1.95O4" ], "offsets": [ [ 128, 133 ], [ 134, 138 ], [ 139, 143 ], [ 144, 147 ], [ 149, 156 ], [ 169, 183 ] ] }, { "pmid": "23547652", "text": "3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition.\n", "type": "CHEMICAL", "entities": [ "3-Hydroxypyridin-2-thione", "Zinc" ], "offsets": [ [ 0, 25 ], [ 35, 39 ] ] }, { "pmid": "23547652", "text": "Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date.", "type": "CHEMICAL", "entities": [ "zinc" ], "offsets": [ [ 47, 51 ] ] }, { "pmid": "23547652", "text": "However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs.", "type": "CHEMICAL", "entities": [ "hydroxamic acid" ], "offsets": [ [ 63, 78 ] ] }, { "pmid": "23547652", "text": "We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition.", "type": "CHEMICAL", "entities": [ "3-hydroxypyridin-2-thione", "3-HPT" ], "offsets": [ [ 19, 44 ], [ 46, 51 ] ] }, { "pmid": "23547652", "text": "3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively.", "type": "CHEMICAL", "entities": [ "3-HPT" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "23547652", "text": "Remarkably, 3-HPT gives no inhibition of HDAC 1.", "type": "CHEMICAL", "entities": [ "3-HPT" ], "offsets": [ [ 12, 17 ] ] }, { "pmid": "23547652", "text": "Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8.", "type": "CHEMICAL", "entities": [ "3HPT" ], "offsets": [ [ 45, 49 ] ] }, { "pmid": "23552260", "text": "Histological, ultrastructural and immunohistochemical studies on the protective effect of ginger extract against cisplatin-induced nephrotoxicity in male rats.\n", "type": "CHEMICAL", "entities": [ "cisplatin" ], "offsets": [ [ 113, 122 ] ] }, { "pmid": "23552260", "text": "Cisplatin (CP) is a widely used anticancer drug; however, it has several side effects such as nephrotoxicity.", "type": "CHEMICAL", "entities": [ "Cisplatin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23552260", "text": "CP group displayed a marked renal failure characterized by a significant increase in serum creatinine and blood urea nitrogen (BUN) levels in addition to severe histopathological and ultrastructural renal alterations.", "type": "CHEMICAL", "entities": [ "creatinine", "urea", "nitrogen" ], "offsets": [ [ 91, 101 ], [ 112, 116 ], [ 117, 125 ] ] }, { "pmid": "23552260", "text": "In contrast, GE+CP group showed significant decrease in the elevated serum creatinine and BUN levels and an improvement in the histopathological and ultrastructural renal injury induced by CP.", "type": "CHEMICAL", "entities": [ "creatinine" ], "offsets": [ [ 75, 85 ] ] }, { "pmid": "23553905", "text": "When using double staining with Alizarin red for mineralized matrix and Alcian blue for cartilaginous matrix, we observed previously that mineralization was totally absent at embryonic day 15.5 throughout the body in Runx2(-/-) mice, but was found in areas undergoing intramembranous ossification such as skull and clavicles in α1(II)-Cre;Runx2(flox/flox) mice.", "type": "CHEMICAL", "entities": [ "Alizarin red", "Alcian blue" ], "offsets": [ [ 28, 40 ], [ 68, 79 ] ] }, { "pmid": "23554071", "text": "Here we tested the effect of chronic supplementation with a mineral extract from red marine algae - rich in calcium (34%), magnesium, phosphorus, selenium and other trace minerals - in a clinically relevant model of spontaneous enterocolitis, interleukin (IL)-10(-/-) mice.", "type": "CHEMICAL", "entities": [ "calcium", "magnesium", "phosphorus", "selenium" ], "offsets": [ [ 108, 115 ], [ 123, 132 ], [ 134, 144 ], [ 146, 154 ] ] }, { "pmid": "23554574", "text": "Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.\n", "type": "CHEMICAL", "entities": [ "glucosylceramide" ], "offsets": [ [ 23, 39 ] ] }, { "pmid": "23554574", "text": "The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase).", "type": "CHEMICAL", "entities": [ "glucosylceramide", "UDP", "glucose", "ceramide" ], "offsets": [ [ 113, 129 ], [ 145, 148 ], [ 149, 156 ], [ 157, 165 ] ] }, { "pmid": "23554574", "text": "Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity.", "type": "CHEMICAL", "entities": [ "UDP", "glucose", "ceramide" ], "offsets": [ [ 76, 79 ], [ 80, 87 ], [ 88, 96 ] ] }, { "pmid": "23557688", "text": "Environmental pesticide exposure modulates cytokines, arginase and ornithine decarboxylase expression in human placenta.\n", "type": "CHEMICAL", "entities": [ "ornithine" ], "offsets": [ [ 67, 76 ] ] }, { "pmid": "23557688", "text": "To evaluate the cytokine balance and enzymatic alterations induced by environmental pesticide exposure during pregnancy, this transversal study explored placentas derived from non-exposed women (control group-CG), and from women living in a rural area (rural group-RG), collected during intensive organophosphate (OP) pesticide spraying season (RG-SS) and during non-spraying season (RG-NSS).", "type": "CHEMICAL", "entities": [ "organophosphate" ], "offsets": [ [ 297, 312 ] ] }, { "pmid": "23557688", "text": "Arginase and ornithine decarboxylase (ODC) enzymes were induced in syncytiotrophoblast and endothelial cells.", "type": "CHEMICAL", "entities": [ "ornithine" ], "offsets": [ [ 11, 20 ] ] }, { "pmid": "23558600", "text": "Native GLP-1 stimulates insulin secretion in a glucose-dependent manner, as well as suppressing glucagon production and slowing gastric emptying.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23561088", "text": "Maqui berry (Aristotelia chilensis) and the constituent delphinidin glycoside inhibit photoreceptor cell death induced by visible light.\n", "type": "CHEMICAL", "entities": [ "delphinidin glycoside" ], "offsets": [ [ 56, 77 ] ] }, { "pmid": "23561088", "text": "The protective effects of maqui berry (Aristotelia chilensis) extract (MBE) and its major anthocyanins [delphinidin 3,5-O-diglucoside (D3G5G) and delphinidin 3-O-sambubioside-5-O-glucoside (D3S5G)] against light-induced murine photoreceptor cells (661W) death were evaluated.", "type": "CHEMICAL", "entities": [ "anthocyanins", "delphinidin 3,5-O-diglucoside", "D3G5G", "delphinidin 3-O-sambubioside-5-O-glucoside", "D3S5G" ], "offsets": [ [ 90, 102 ], [ 104, 133 ], [ 135, 140 ], [ 146, 188 ], [ 190, 195 ] ] }, { "pmid": "23561088", "text": "Viability of 661W after light treatment for 24h, assessed by the tetrazolium salt (WST-8) assay and Hoechst 33342 nuclear staining, was improved by addition of MBE, D3G5G, and D3S5G. Intracellular radical activation in 661W, evaluated using the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester (CM-H2DCFDA), was reduced by MBE and its anthocyanins.", "type": "CHEMICAL", "entities": [ "5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester", "CM-H2DCFDA", "anthocyanins", "tetrazolium", "Hoechst 33342", "D3G5G", "D3S5G", "oxygen" ], "offsets": [ [ 291, 368 ], [ 370, 380 ], [ 410, 422 ], [ 65, 76 ], [ 100, 113 ], [ 165, 170 ], [ 176, 181 ], [ 254, 260 ] ] }, { "pmid": "23561088", "text": "These findings indicate that MBE and its anthocyanidins suppress the light-induced photoreceptor cell death by inhibiting ROS production, suggesting that the inhibition of phosphorylated-p38 may be involved in the underlying mechanism.", "type": "CHEMICAL", "entities": [ "anthocyanidins" ], "offsets": [ [ 41, 55 ] ] }, { "pmid": "23561115", "text": "Influence of triterpenoids present in apple peel on inflammatory gene expression associated with inflammatory bowel disease (IBD).\n", "type": "CHEMICAL", "entities": [ "triterpenoids" ], "offsets": [ [ 13, 26 ] ] }, { "pmid": "23561115", "text": "Various ursanic, oleanic and lupanic pentacyclic triterpenoids found in apple peel were studied for anti-inflammatory effects in vitro using T84 colon carcinoma cells.", "type": "CHEMICAL", "entities": [ "ursanic, oleanic and lupanic pentacyclic triterpenoids" ], "offsets": [ [ 8, 62 ] ] }, { "pmid": "23561115", "text": "After pretreatment with single triterpenoids, cells were stimulated with pro-inflammatory cytokines (TNF-α, INF-γ, IL-1β).", "type": "CHEMICAL", "entities": [ "triterpenoids" ], "offsets": [ [ 31, 44 ] ] }, { "pmid": "23561115", "text": "Furthermore, the effects of ursolic acid (UA) and oleanolic acid (OA) on the synthesis of certain pro-inflammatory proteins were examined.", "type": "CHEMICAL", "entities": [ "ursolic acid", "oleanolic acid" ], "offsets": [ [ 24, 36 ], [ 46, 60 ] ] }, { "pmid": "23561115", "text": "The present study confirms that triterpenoids present in apple peel and β-damascone may be implicated in the anti-inflammatory properties of apple constituents, suggesting that these substances might be helpful in the treatment of IBD as nutrient supplements.", "type": "CHEMICAL", "entities": [ "triterpenoids", "β-damascone" ], "offsets": [ [ 21, 34 ], [ 61, 72 ] ] }, { "pmid": "23561205", "text": "Curcumin inhibits invasion and metastasis in K1 papillary thyroid cancer cells.\n", "type": "CHEMICAL", "entities": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23561205", "text": "Curcumin, the active constituent of dietary spice turmeric, possesses a strong potential for cancer prevention and treatment.", "type": "CHEMICAL", "entities": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23561205", "text": "However, there is no study to address the effects of curcumin on invasion and metastasis of thyroid cancers.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 53, 61 ] ] }, { "pmid": "23561205", "text": "Here, for the first time it has been reported that curcumin inhibit multiple metastasis steps of K1 papillary thyroid cancer cells.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "23561205", "text": "Curcumin dose-dependently suppressed viability of K1 cells as well as its cell attachment, spreading, migration and invasion abilities.", "type": "CHEMICAL", "entities": [ "Curcumin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23561205", "text": "Moreover, curcumin could also down-regulate the expression and activity of matrix metalloproteinase-9 (MMP-9).", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 10, 18 ] ] }, { "pmid": "23561205", "text": "The findings showed that curcumin might be an effective tumouristatic agent for the treatment of aggressive papillary thyroid carcinomas.", "type": "CHEMICAL", "entities": [ "curcumin" ], "offsets": [ [ 25, 33 ] ] }, { "pmid": "23562365", "text": "Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction.\n", "type": "CHEMICAL", "entities": [ "Lignans" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "23562365", "text": "Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine.", "type": "CHEMICAL", "entities": [ "Evn-50", "lignan" ], "offsets": [ [ 0, 6 ], [ 12, 18 ] ] }, { "pmid": "23562365", "text": "This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound VB1 purified from EVn-50.", "type": "CHEMICAL", "entities": [ "EVn-50", "EVn-50", "lignan", "VB1", "EVn-50" ], "offsets": [ [ 68, 74 ], [ 193, 199 ], [ 209, 215 ], [ 225, 228 ], [ 243, 249 ] ] }, { "pmid": "23562365", "text": "The cytotoxic effect of EVn-50 and VB1 was determined with SRB assay using a panel of cancer cell lines.", "type": "CHEMICAL", "entities": [ "EVn-50", "VB1" ], "offsets": [ [ 24, 30 ], [ 35, 38 ] ] }, { "pmid": "23562365", "text": "Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or VB1 on cell cycle by flow cytometric analysis.", "type": "CHEMICAL", "entities": [ "EVn-50", "VB1" ], "offsets": [ [ 123, 129 ], [ 133, 136 ] ] }, { "pmid": "23562365", "text": "Apoptosis exerted by EVn-50 or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis.", "type": "CHEMICAL", "entities": [ "EVn-50", "VB1" ], "offsets": [ [ 21, 27 ], [ 31, 34 ] ] }, { "pmid": "23562365", "text": "EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml.", "type": "CHEMICAL", "entities": [ "EVn-50" ], "offsets": [ [ 0, 6 ] ] }, { "pmid": "23562365", "text": "Treatment with EVn-50 or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c.", "type": "CHEMICAL", "entities": [ "EVn-50", "VB1", "Ser", "Tyr" ], "offsets": [ [ 14, 20 ], [ 24, 27 ], [ 189, 192 ], [ 223, 226 ] ] }, { "pmid": "23562365", "text": "Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or VB1 caused obvious apoptosis of MDA-MB-435 cells.", "type": "CHEMICAL", "entities": [ "EVn-50", "VB1" ], "offsets": [ [ 55, 61 ], [ 65, 68 ] ] }, { "pmid": "23562365", "text": "Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis.", "type": "CHEMICAL", "entities": [ "lignan", "EVn-50" ], "offsets": [ [ 26, 32 ], [ 18, 24 ] ] }, { "pmid": "23562495", "text": "TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate.\n", "type": "CHEMICAL", "entities": [ "citronellyl acetate" ], "offsets": [ [ 60, 79 ] ] }, { "pmid": "23562495", "text": "Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities.", "type": "CHEMICAL", "entities": [ "CAT", "monoterpene", "Citronellyl acetate" ], "offsets": [ [ 32, 35 ], [ 40, 51 ], [ 11, 30 ] ] }, { "pmid": "23562495", "text": "Here, we used acute pain animal models to describe the antinociceptive action of CAT.", "type": "CHEMICAL", "entities": [ "CAT" ], "offsets": [ [ 81, 84 ] ] }, { "pmid": "23562495", "text": "Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism.", "type": "CHEMICAL", "entities": [ "acetic acid", "glutamate", "formalin", "CAT" ], "offsets": [ [ 12, 23 ], [ 108, 117 ], [ 122, 130 ], [ 189, 192 ] ] }, { "pmid": "23562495", "text": "Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg).", "type": "CHEMICAL", "entities": [ "CAT", "acetic acid" ], "offsets": [ [ 8, 11 ], [ 141, 152 ] ] }, { "pmid": "23562495", "text": "In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test.", "type": "CHEMICAL", "entities": [ "formalin", "CAT" ], "offsets": [ [ 7, 15 ], [ 35, 38 ] ] }, { "pmid": "23562495", "text": "The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT.", "type": "CHEMICAL", "entities": [ "glutamate", "CAT" ], "offsets": [ [ 4, 13 ], [ 94, 97 ] ] }, { "pmid": "23562495", "text": "Pretreatment with CAT did not alter locomotor activity or motor coordination.", "type": "CHEMICAL", "entities": [ "CAT" ], "offsets": [ [ 18, 21 ] ] }, { "pmid": "23562495", "text": "In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98).", "type": "CHEMICAL", "entities": [ "CAT", "capsaicin", "cinnamaldehyde", "menthol", "acetic acid" ], "offsets": [ [ 72, 75 ], [ 113, 122 ], [ 136, 150 ], [ 165, 172 ], [ 212, 223 ] ] }, { "pmid": "23562495", "text": "Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT.", "type": "CHEMICAL", "entities": [ "CAT" ], "offsets": [ [ 129, 132 ] ] }, { "pmid": "23562495", "text": "Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism.", "type": "CHEMICAL", "entities": [ "CAT", "glutamate", "CAT" ], "offsets": [ [ 102, 105 ], [ 173, 182 ], [ 221, 224 ] ] }, { "pmid": "23562496", "text": "2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells.\n", "type": "CHEMICAL", "entities": [ "2-Hydroxychalcone", "xanthohumol" ], "offsets": [ [ 0, 17 ], [ 22, 33 ] ] }, { "pmid": "23562496", "text": "In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis.", "type": "CHEMICAL", "entities": [ "estrogen", "progesterone" ], "offsets": [ [ 90, 98 ], [ 99, 111 ] ] }, { "pmid": "23562496", "text": "Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities.", "type": "CHEMICAL", "entities": [ "Chalcones", "flavonoids" ], "offsets": [ [ 0, 9 ], [ 42, 52 ] ] }, { "pmid": "23562496", "text": "Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells.", "type": "CHEMICAL", "entities": [ "chalcones", "chalcones" ], "offsets": [ [ 65, 74 ], [ 145, 154 ] ] }, { "pmid": "23562496", "text": "The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells.", "type": "CHEMICAL", "entities": [ "chalcone" ], "offsets": [ [ 54, 62 ] ] }, { "pmid": "23562496", "text": "Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively.", "type": "CHEMICAL", "entities": [ "chalcone", "2-hydroxychalcone", "xanthohumol" ], "offsets": [ [ 36, 44 ], [ 46, 63 ], [ 69, 80 ] ] }, { "pmid": "23562496", "text": "Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells.", "type": "CHEMICAL", "entities": [ "xanthohumol", "Chalcone", "2-hydroxychalcone", "Neohesperidin dihydrochalcone", "4-methoxychalcone", "hesperidin methylchalcone" ], "offsets": [ [ 43, 54 ], [ 10, 18 ], [ 20, 37 ], [ 116, 145 ], [ 147, 164 ], [ 170, 195 ] ] }, { "pmid": "23562496", "text": "Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation.", "type": "CHEMICAL", "entities": [ "2-hydroxychalcone" ], "offsets": [ [ 15, 32 ] ] }, { "pmid": "23562496", "text": "Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone.", "type": "CHEMICAL", "entities": [ "2-hydroxychalcone", "xanthohumol", "chalcone" ], "offsets": [ [ 12, 29 ], [ 34, 45 ], [ 166, 174 ] ] }, { "pmid": "23562496", "text": "These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC.", "type": "CHEMICAL", "entities": [ "chalcones" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "23566269", "text": "4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors.\n", "type": "CHEMICAL", "entities": [ "4-Hydroxypyridazin-3(2H)-one", "d-Amino Acid" ], "offsets": [ [ 0, 28 ], [ 50, 62 ] ] }, { "pmid": "23566269", "text": "d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor.", "type": "CHEMICAL", "entities": [ "d-serine", "d-Amino acid", "N-methyl-d-aspartate", "d-amino acids" ], "offsets": [ [ 79, 87 ], [ 0, 12 ], [ 108, 128 ], [ 55, 68 ] ] }, { "pmid": "23566269", "text": "We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design.", "type": "CHEMICAL", "entities": [ "4-hydroxypyridazin-3(2H)-one" ], "offsets": [ [ 26, 54 ] ] }, { "pmid": "23566269", "text": "Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner.", "type": "CHEMICAL", "entities": [ "Tyr" ], "offsets": [ [ 219, 222 ] ] }, { "pmid": "23566269", "text": "We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information.", "type": "CHEMICAL", "entities": [ "3-hydroxy-pyridine-2(1H)-one" ], "offsets": [ [ 57, 85 ] ] }, { "pmid": "23566269", "text": "3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays.", "type": "CHEMICAL", "entities": [ "3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one" ], "offsets": [ [ 0, 45 ] ] }, { "pmid": "23566269", "text": "We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity.", "type": "CHEMICAL", "entities": [ "4-hydroxypyridazin-3(2H)-one", "3-hydroxy-pyridine-2(1H)-one" ], "offsets": [ [ 36, 64 ], [ 106, 134 ] ] }, { "pmid": "23566269", "text": "6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.", "type": "CHEMICAL", "entities": [ "6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one", "MK-801" ], "offsets": [ [ 0, 60 ], [ 95, 101 ] ] }, { "pmid": "23567241", "text": "Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor.\n", "type": "CHEMICAL", "entities": [ "androgen", "parabens", "estrogen" ], "offsets": [ [ 103, 111 ], [ 52, 60 ], [ 73, 81 ] ] }, { "pmid": "23567241", "text": "The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated.", "type": "CHEMICAL", "entities": [ "estrogen", "androgen", "parabens" ], "offsets": [ [ 135, 143 ], [ 172, 180 ], [ 38, 46 ] ] }, { "pmid": "23567241", "text": "Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity.", "type": "CHEMICAL", "entities": [ "parabens", "parabens" ], "offsets": [ [ 10, 18 ], [ 121, 129 ] ] }, { "pmid": "23567241", "text": "Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12.", "type": "CHEMICAL", "entities": [ "heptylparaben", "pentylparaben", "alkyl" ], "offsets": [ [ 67, 80 ], [ 90, 103 ], [ 20, 25 ] ] }, { "pmid": "23567241", "text": "The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor.", "type": "CHEMICAL", "entities": [ "butylparaben" ], "offsets": [ [ 13, 25 ] ] }, { "pmid": "23567241", "text": "These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity.", "type": "CHEMICAL", "entities": [ "parabens", "alkyl" ], "offsets": [ [ 14, 22 ], [ 141, 146 ] ] }, { "pmid": "23567490", "text": "The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy.\n", "type": "CHEMICAL", "entities": [ "5-FU" ], "offsets": [ [ 119, 123 ] ] }, { "pmid": "23567490", "text": "Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019).", "type": "CHEMICAL", "entities": [ "5-fluorouracil" ], "offsets": [ [ 22, 36 ] ] }, { "pmid": "23567861", "text": "Evaluation of 7-O-galloyl-d-sedoheptulose, isolated from Corni Fructus, in the adipose tissue of type 2 diabetic db/db mice.\n", "type": "CHEMICAL", "entities": [ "7-O-galloyl-d-sedoheptulose" ], "offsets": [ [ 14, 41 ] ] }, { "pmid": "23567861", "text": "The aim of the present study was to evaluate the beneficial effects of 7-O-galloyl-d-sedoheptulose (GS), isolated from Corni Fructus, using type 2 diabetic mice.", "type": "CHEMICAL", "entities": [ "7-O-galloyl-d-sedoheptulose" ], "offsets": [ [ 71, 98 ] ] }, { "pmid": "23567861", "text": "The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, interleukin-6, triglycerides, total cholesterol, non-esterified fatty acids, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol/low-density lipoprotein cholesterol, reactive oxygen species (ROS), and thiobarbituric acid-reactive substance (TBARS) in serum were down-regulated, while adiponectin was augmented by GS treatment.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol", "oxygen", "thiobarbituric acid", "glucose", "triglycerides", "cholesterol", "fatty acids", "cholesterol" ], "offsets": [ [ 250, 261 ], [ 286, 297 ], [ 308, 314 ], [ 334, 353 ], [ 34, 41 ], [ 121, 134 ], [ 142, 153 ], [ 170, 181 ], [ 208, 219 ] ] }, { "pmid": "23567861", "text": "The administration of GS significantly decreased sterol regulatory element binding protein-1, nuclear factor-kappa ?>Bp65, cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemotactic protein-1, intracellular adhesion molecule-1, phosphor c-Jun N-terminal kinase, activator protein-1, transforming growth factor-β1, Bax, cytochrome c, and caspase-3 expressions.", "type": "CHEMICAL", "entities": [ "sterol", "nitric oxide", "N" ], "offsets": [ [ 46, 52 ], [ 148, 160 ], [ 253, 254 ] ] }, { "pmid": "23570615", "text": "Six new sesquiterpenoids, aristoyunnolins A-F (1-6), an artifact of isolation [7-O-ethyl madolin W (7)], and 12 known analogues were isolated from stems of Aristolochia yunnanensis.", "type": "CHEMICAL", "entities": [ "aristoyunnolins A-F", "7-O-ethyl madolin W", "sesquiterpenoids" ], "offsets": [ [ 26, 45 ], [ 79, 98 ], [ 8, 24 ] ] }, { "pmid": "23570615", "text": "Compounds 16 and 19 were more active than the positive control PD98059, a known inhibitor of the ERK1/2 signaling pathway.", "type": "CHEMICAL", "entities": [ "PD98059" ], "offsets": [ [ 63, 70 ] ] }, { "pmid": "23570999", "text": "In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats.\n", "type": "CHEMICAL", "entities": [ "pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside" ], "offsets": [ [ 52, 106 ] ] }, { "pmid": "23570999", "text": "Polyhydroxy pregnane glycoside (PPG), a steroidal glycoside was isolated from Wattakaka volubilis Linn.", "type": "CHEMICAL", "entities": [ "steroidal glycoside", "PPG" ], "offsets": [ [ 39, 58 ], [ 31, 34 ] ] }, { "pmid": "23570999", "text": "Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content.", "type": "CHEMICAL", "entities": [ "N-acetyl" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "23570999", "text": "PPG had a more effective response than the reference drug diclofenac sodium in both the models of inflammation.", "type": "CHEMICAL", "entities": [ "diclofenac sodium" ], "offsets": [ [ 57, 74 ] ] }, { "pmid": "23570999", "text": "Wattakaka volubilis steroidal glycoside mixture (WVSM) and PPG (1-50μM) significantly inhibited the COX-2 and iNOS enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells.", "type": "CHEMICAL", "entities": [ "steroidal glycoside", "PPG" ], "offsets": [ [ 19, 38 ], [ 58, 61 ] ] }, { "pmid": "23570999", "text": "Hence the study supports the traditional use of Wattakaka volubilis and its constituent PPG in treatment of inflammatory disorders.", "type": "CHEMICAL", "entities": [ "PPG" ], "offsets": [ [ 86, 89 ] ] }, { "pmid": "23572389", "text": "E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent interactions between adjacent epithelial cells.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "23572405", "text": "We aimed to investigate circulating levels of some major components of the system that regulates energy stores, glucose, and fat metabolism, during thyrotoxicosis compared to euthyroidism.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 112, 119 ] ] }, { "pmid": "23572405", "text": "Fasting serum ghrelin, leptin, adiponectin, insulin, glucagon, glucose, as well as body fat composition were analyzed during thyrotoxicosis in 40 hyperthyroid patients (50.5 ± 15.2 years old, 22 females, 31 with Graves disease, and 9 with toxic nodular goiter).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 63, 70 ] ] }, { "pmid": "23572405", "text": "Fasting serum glucose tended to be higher during thyrotoxicosis.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 9, 16 ] ] }, { "pmid": "23574729", "text": "Subclinical Cushing's syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing's syndrome (CS).", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 114, 122 ] ] }, { "pmid": "23574729", "text": "Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction.", "type": "CHEMICAL", "entities": [ "dexamethasone", "cortisol" ], "offsets": [ [ 74, 87 ], [ 166, 174 ] ] }, { "pmid": "23574729", "text": "Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 μg/dl (measured by radioimmunoassay", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 59, 67 ] ] }, { "pmid": "23574729", "text": "However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 μg/dl.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 199, 207 ] ] }, { "pmid": "23574729", "text": "One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 45, 53 ] ] }, { "pmid": "23574729", "text": "In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 μg/dl, similar to the American Endocrine Society's guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma.", "type": "CHEMICAL", "entities": [ "cortisol" ], "offsets": [ [ 73, 81 ] ] }, { "pmid": "23574729", "text": "Our findings indicate that serum cortisol levels ≥1.8 μg/dl after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/ml (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 μg/dl at 21:00 to 23:00 h.", "type": "CHEMICAL", "entities": [ "cortisol", "cortisol" ], "offsets": [ [ 28, 36 ], [ 268, 276 ] ] }, { "pmid": "23574729", "text": "If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation.", "type": "CHEMICAL", "entities": [ "dehydroepiandrosterone sulfate", "cortisol" ], "offsets": [ [ 123, 153 ], [ 173, 181 ] ] }, { "pmid": "23577589", "text": "Because of its peakless, extended and highly predictable glucose-lowering effect, once-daily dosing on a flexible schedule may be feasible with degludec.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 57, 64 ] ] }, { "pmid": "23578968", "text": "Evaluation of a predictive in vitro Leydig cell assay for anti-androgenicity of phthalate esters in the rat.\n", "type": "CHEMICAL", "entities": [ "phthalate esters" ], "offsets": [ [ 80, 96 ] ] }, { "pmid": "23578968", "text": "An in vitro assay using the rat Leydig cell line R2C was evaluated for its ability to quantitatively predict inhibition of testosterone synthesis.", "type": "CHEMICAL", "entities": [ "testosterone" ], "offsets": [ [ 123, 135 ] ] }, { "pmid": "23578968", "text": "Results obtained for endocrine active phthalates (MEHP, MBP), and inactive phthalates (MMP and MEP) were highly consistent with in vivo results based on tissue and media concentrations.", "type": "CHEMICAL", "entities": [ "MEP", "phthalates", "MEHP", "MBP", "phthalates", "MMP" ], "offsets": [ [ 95, 98 ], [ 38, 48 ], [ 50, 54 ], [ 56, 59 ], [ 75, 85 ], [ 87, 90 ] ] }, { "pmid": "23578968", "text": "Statistically significant inhibition of testosterone synthesis (p<0.05, 1-way ANOVA) was observed at 1μM MBP and 3μM MEHP, while MEP and MMP did not affect inhibition of testosterone synthesis until much higher concentrations (≫100μM).", "type": "CHEMICAL", "entities": [ "testosterone", "MBP", "MEHP", "MEP", "MMP", "testosterone" ], "offsets": [ [ 40, 52 ], [ 105, 108 ], [ 117, 121 ], [ 129, 132 ], [ 137, 140 ], [ 170, 182 ] ] }, { "pmid": "23578968", "text": "Concentrations causing 50% inhibition of testosterone synthesis for MBP and MEHP (3 and 6μM respectively), were similar to in vivo values (3 and 7μM).", "type": "CHEMICAL", "entities": [ "testosterone", "MBP", "MEHP" ], "offsets": [ [ 36, 48 ], [ 63, 66 ], [ 71, 75 ] ] }, { "pmid": "23578968", "text": "The R2C assay was used to determine the relative potency of 14 structurally diverse monoesters and oxidative metabolites of MEHP.", "type": "CHEMICAL", "entities": [ "monoesters", "MEHP" ], "offsets": [ [ 77, 87 ], [ 117, 121 ] ] }, { "pmid": "23578968", "text": "Monoesters with alkyl chains 4-5 carbons in length had the highest potency for testosterone inhibition, while 0-2 carbon alkyl chains were least potent.", "type": "CHEMICAL", "entities": [ "carbons", "testosterone", "carbon" ], "offsets": [ [ 26, 33 ], [ 72, 84 ], [ 107, 113 ] ] }, { "pmid": "23578968", "text": "Phase I metabolism did not completely inactivate MEHP, underscoring the need for metabolism data when interpreting in vitro pharmacodynamic data.", "type": "CHEMICAL", "entities": [ "MEHP" ], "offsets": [ [ 42, 46 ] ] }, { "pmid": "23578968", "text": "This steroid inhibition assay provides a predictive in vitro alternative to expensive and timeconsuming developmental rat studies for phthalate-induced antiandrogenicity.", "type": "CHEMICAL", "entities": [ "phthalate" ], "offsets": [ [ 127, 136 ] ] }, { "pmid": "23583009", "text": "Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO.\n", "type": "CHEMICAL", "entities": [ "Quercetin", "ethanol", "CO" ], "offsets": [ [ 0, 9 ], [ 38, 45 ], [ 99, 101 ] ] }, { "pmid": "23583009", "text": "Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect.", "type": "CHEMICAL", "entities": [ "ethanol", "heme", "carbon monoxide", "CO", "quercetin" ], "offsets": [ [ 55, 62 ], [ 93, 97 ], [ 131, 146 ], [ 148, 150 ], [ 19, 28 ] ] }, { "pmid": "23583009", "text": "However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear.", "type": "CHEMICAL", "entities": [ "ethanol", "quercetin" ], "offsets": [ [ 78, 85 ], [ 40, 49 ] ] }, { "pmid": "23583009", "text": "To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days.", "type": "CHEMICAL", "entities": [ "ethanol" ], "offsets": [ [ 44, 51 ] ] }, { "pmid": "23583009", "text": "Our data showed that chronic ethanol over-activated CYP2E1 but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.).", "type": "CHEMICAL", "entities": [ "ethanol", "quercetin" ], "offsets": [ [ 29, 36 ], [ 155, 164 ] ] }, { "pmid": "23583009", "text": "Quercetin (100μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes.", "type": "CHEMICAL", "entities": [ "Quercetin" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23583009", "text": "Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation.", "type": "CHEMICAL", "entities": [ "quercetin", "heme" ], "offsets": [ [ 64, 73 ], [ 129, 133 ] ] }, { "pmid": "23583009", "text": "CO scavenging blocked the suppression of quercetin only on CYP2E1 activity.", "type": "CHEMICAL", "entities": [ "quercetin" ], "offsets": [ [ 40, 49 ] ] }, { "pmid": "23583009", "text": "CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger.", "type": "CHEMICAL", "entities": [ "ethanol", "CO" ], "offsets": [ [ 47, 54 ], [ 130, 132 ] ] }, { "pmid": "23583009", "text": "Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction.", "type": "CHEMICAL", "entities": [ "ethanol", "quercetin" ], "offsets": [ [ 21, 28 ], [ 62, 71 ] ] }, { "pmid": "23583009", "text": "Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively.", "type": "CHEMICAL", "entities": [ "CO" ], "offsets": [ [ 22, 24 ] ] }, { "pmid": "23583510", "text": "Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors.\n", "type": "CHEMICAL", "entities": [ "tetrahydrocurcuminoid dihydropyrimidinone" ], "offsets": [ [ 14, 55 ] ] }, { "pmid": "23583510", "text": "The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst.", "type": "CHEMICAL", "entities": [ "THDC", "tetrahydrobisdemethoxycurcumin", "THBDC", "dihydropyrimidinone", "DHPM", "tetrahydrocurcumin", "copper sulphate", "THC", "tetrahydrodemethoxycurcumin" ], "offsets": [ [ 83, 87 ], [ 94, 124 ], [ 127, 132 ], [ 135, 154 ], [ 156, 160 ], [ 25, 43 ], [ 256, 271 ], [ 46, 49 ], [ 53, 80 ] ] }, { "pmid": "23583510", "text": "THBDC-DHPM demonstrated the most potent inhibitory activity with an IC50 value of 1.34±0.03μM which was more active than the approved drug galanthamine (IC50=1.45±0.04μM).", "type": "CHEMICAL", "entities": [ "THBDC-DHPM", "galanthamine" ], "offsets": [ [ 0, 10 ], [ 139, 151 ] ] }, { "pmid": "23583603", "text": "Agonistic activity of ICI 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle.\n", "type": "CHEMICAL", "entities": [ "ICI 182 780" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "23583603", "text": "We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle.", "type": "CHEMICAL", "entities": [ "ICI 182,780", "ICI" ], "offsets": [ [ 26, 37 ], [ 39, 42 ] ] }, { "pmid": "23583603", "text": "Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus.", "type": "CHEMICAL", "entities": [ "ICI" ], "offsets": [ [ 103, 106 ] ] }, { "pmid": "23583603", "text": "Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay.", "type": "CHEMICAL", "entities": [ "progesterone" ], "offsets": [ [ 18, 30 ] ] }, { "pmid": "23583603", "text": "Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals.", "type": "CHEMICAL", "entities": [ "ICI", "estrogen", "progesterone" ], "offsets": [ [ 4, 7 ], [ 71, 79 ], [ 135, 147 ] ] }, { "pmid": "23583603", "text": "Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β)", "type": "CHEMICAL", "entities": [ "ICI" ], "offsets": [ [ 28, 31 ] ] }, { "pmid": "23583603", "text": "We observed that the administration of ICI at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00h on estrus day had no effect on these parameters.", "type": "CHEMICAL", "entities": [ "ICI", "Ser", "ICI" ], "offsets": [ [ 36, 39 ], [ 216, 219 ], [ 272, 275 ] ] }, { "pmid": "23583603", "text": "The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model.", "type": "CHEMICAL", "entities": [ "ICI" ], "offsets": [ [ 31, 34 ] ] }, { "pmid": "23583910", "text": "Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors.\n", "type": "CHEMICAL", "entities": [ "Aminopropylindenes", "Grundmann's ketone" ], "offsets": [ [ 0, 18 ], [ 32, 50 ] ] }, { "pmid": "23583910", "text": "A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone.", "type": "CHEMICAL", "entities": [ "aminopropylindenes", "2,3-oxidosqualen", "lanosterol", "Grundmann's ketone", "oxidosqualene" ], "offsets": [ [ 12, 30 ], [ 152, 168 ], [ 172, 182 ], [ 201, 219 ], [ 97, 110 ] ] }, { "pmid": "23583910", "text": "A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.", "type": "CHEMICAL", "entities": [ "N,N-dimethylaminopropyl", "cholesterol" ], "offsets": [ [ 2, 25 ], [ 164, 175 ] ] }, { "pmid": "23583931", "text": "The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels.\n", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "23583931", "text": "During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation.", "type": "CHEMICAL", "entities": [ "ATP", "Ca(2+)" ], "offsets": [ [ 64, 67 ], [ 126, 132 ] ] }, { "pmid": "23583931", "text": "We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs).", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "23583931", "text": "Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles.", "type": "CHEMICAL", "entities": [ "dihydropyridine", "ryanodine" ], "offsets": [ [ 116, 131 ], [ 136, 145 ] ] }, { "pmid": "23583931", "text": "Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation.", "type": "CHEMICAL", "entities": [ "ethidium", "Etd(+)", "ATP" ], "offsets": [ [ 27, 35 ], [ 37, 43 ], [ 78, 81 ] ] }, { "pmid": "23583931", "text": "Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade.", "type": "CHEMICAL", "entities": [ "glucose", "2-NBDG", "glucose", "glucose" ], "offsets": [ [ 20, 27 ], [ 63, 69 ], [ 85, 92 ], [ 143, 150 ] ] }, { "pmid": "23583931", "text": "ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice.", "type": "CHEMICAL", "entities": [ "Etd(+)", "ATP" ], "offsets": [ [ 13, 19 ], [ 0, 3 ] ] }, { "pmid": "23583931", "text": "MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors.", "type": "CHEMICAL", "entities": [ "ATP" ], "offsets": [ [ 113, 116 ] ] }, { "pmid": "23583931", "text": "Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening.", "type": "CHEMICAL", "entities": [ "Ser", "Thr" ], "offsets": [ [ 19, 22 ], [ 27, 30 ] ] }, { "pmid": "23583931", "text": "Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction.", "type": "CHEMICAL", "entities": [ "ATP", "glucose", "Ca(2+)" ], "offsets": [ [ 67, 70 ], [ 82, 89 ], [ 103, 109 ] ] }, { "pmid": "23585332", "text": "tert-Butylhydroquinone reduces lipid accumulation in C57BL/6 mice with lower body weight gain.\n", "type": "CHEMICAL", "entities": [ "tert-Butylhydroquinone" ], "offsets": [ [ 0, 22 ] ] }, { "pmid": "23585332", "text": "tert-Butylhydroquinone (tBHQ) is a commonly used antioxidant additive that is approved for human use by both the Food and Agriculture Organization and the World Health Organization (FAO/WHO).", "type": "CHEMICAL", "entities": [ "tert-Butylhydroquinone", "tBHQ" ], "offsets": [ [ 0, 22 ], [ 24, 28 ] ] }, { "pmid": "23585332", "text": "In this study, we examined the effect of tBHQ on body weight gain and found that food supplementation with 0.001 % (w/w) tBHQ inhibited 61.4 % (P < 0.01) of body weight gain in high-fat diet (HFD)-induced C57BL/6 mice, and the oral administration of tBHQ (1.5 mg/kg) reduced 47.5 % (P < 0.05) of body weight gain in normal diet fed db/db mice.", "type": "CHEMICAL", "entities": [ "tBHQ", "tBHQ", "tBHQ" ], "offsets": [ [ 41, 45 ], [ 121, 125 ], [ 250, 254 ] ] }, { "pmid": "23585332", "text": "The HFD increased lipid deposit in adipocytes, but these were reduced significantly by tBHQ treatment in C57BL/6 mice.", "type": "CHEMICAL", "entities": [ "tBHQ", "tBHQ" ], "offsets": [ [ 79, 83 ], [ 111, 115 ] ] }, { "pmid": "23585332", "text": "tBHQ supplementation significantly lowered the plasma triglyceride and total cholesterol, with reduced size of accumulated fat mass.", "type": "CHEMICAL", "entities": [ "triglyceride", "cholesterol" ], "offsets": [ [ 46, 58 ], [ 69, 80 ] ] }, { "pmid": "23585332", "text": "The rate limiting enzyme of beta-oxidation (ACOX1) was significantly over-expressed in the liver with tBHQ treatment.", "type": "CHEMICAL", "entities": [ "tBHQ" ], "offsets": [ [ 94, 98 ] ] }, { "pmid": "23585332", "text": "These results indicate that tBHQ suppresses body weight gain in mice, possibly at least related to the up-regulation of ACOX1 gene expression.", "type": "CHEMICAL", "entities": [ "tBHQ" ], "offsets": [ [ 20, 24 ] ] }, { "pmid": "23585380", "text": "An optimized electrodropping system produces homogeneous core-shell microcapsules (C-S MCs) by using poly(L-lactic-co-glycolic acid) (PLGA) and alginate.", "type": "CHEMICAL", "entities": [ "poly(L-lactic-co-glycolic acid)", "PLGA" ], "offsets": [ [ 101, 132 ], [ 134, 138 ] ] }, { "pmid": "23585380", "text": "For release control, the use of high-molecular-weight PLGA (HMW 270 000) restrains the initial burst release of protein compared to that of low-MW PLGA (LMW 40 000).", "type": "CHEMICAL", "entities": [ "PLGA", "PLGA" ], "offsets": [ [ 54, 58 ], [ 147, 151 ] ] }, { "pmid": "23585380", "text": "The difference of cumulative albumin release between HMW (7-layer LBL) and LMW (0-layer LBL) PLGA is determined to be more than 40% on day 5.", "type": "CHEMICAL", "entities": [ "PLGA" ], "offsets": [ [ 93, 97 ] ] }, { "pmid": "23585380", "text": "When dual angiogenic growth factors (GFs), such as platelet-derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the VEGF release rate is much greater than that of PDGF, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core PLGA and more than 45% with HMW core PLGA.", "type": "CHEMICAL", "entities": [ "PLGA", "PLGA" ], "offsets": [ [ 356, 360 ], [ 393, 397 ] ] }, { "pmid": "23587425", "text": "Potency switch between CHK1 and MK2: Discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors.\n", "type": "CHEMICAL", "entities": [ "imidazo[1,2-a]pyrazine", "imidazo[1,2-c]pyrimidine" ], "offsets": [ [ 50, 72 ], [ 78, 102 ] ] }, { "pmid": "23587425", "text": "Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines.", "type": "CHEMICAL", "entities": [ "imidazo[1,2-a]pyrazines", "imidazo[1,2-c]pyrimidines" ], "offsets": [ [ 44, 67 ], [ 72, 97 ] ] }, { "pmid": "23589302", "text": "The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced Stat3 phosphorylation, colony formation in soft agar and tumor growth in vivo.\n", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 8, 16 ] ] }, { "pmid": "23589302", "text": "Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 21, 29 ] ] }, { "pmid": "23589302", "text": "In the present report, we show that Fer associates with the activated PDGFbeta receptor (PDGFRbeta) through multiple autophosphorylation sites, i.e. Tyr579, Tyr581, Tyr740 and Tyr1021.", "type": "CHEMICAL", "entities": [ "Tyr", "Tyr", "Tyr", "Tyr" ], "offsets": [ [ 149, 152 ], [ 157, 160 ], [ 165, 168 ], [ 176, 179 ] ] }, { "pmid": "23591110", "text": "Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part I).\n", "type": "CHEMICAL", "entities": [ "aryl ureas", "aryl amides", "histamine" ], "offsets": [ [ 13, 23 ], [ 28, 39 ], [ 64, 73 ] ] }, { "pmid": "23591110", "text": "A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists.", "type": "CHEMICAL", "entities": [ "histamine", "aryl ureas" ], "offsets": [ [ 101, 110 ], [ 31, 41 ] ] }, { "pmid": "23591590", "text": "Structure and energetics of gas phase halogen-bonding in mono-, bi-, and tri-dentate anion receptors as studied by BIRD.\n", "type": "CHEMICAL", "entities": [ "halogen" ], "offsets": [ [ 38, 45 ] ] }, { "pmid": "23591590", "text": "Complexes of mono-, bi- (RB), and tridentate (RT) receptors with a range of anions (Cl(-), Br(-), I(-), NO3(-), H2PO4(-), HSO4(-), and tosylate (TsO(-))) have been studied in the gas phase by both experimental and theoretical methods.", "type": "CHEMICAL", "entities": [ "NO3(-)", "Cl(-)", "Br(-)", "I(-)", "H2PO4(-)", "HSO4(-)", "tosylate", "TsO(-)" ], "offsets": [ [ 104, 110 ], [ 84, 89 ], [ 91, 96 ], [ 98, 102 ], [ 112, 120 ], [ 122, 129 ], [ 135, 143 ], [ 145, 151 ] ] }, { "pmid": "23591590", "text": "Temperature dependent blackbody infrared radiative dissociation (BIRD) experiments were performed on complexes of C8F17I with Br(-) and I(-), RB with I(-), NO3(-), HSO4(-), H2PO4(-), and TsO(-), and RT with I(-), HSO4(-) and TsO(-) and the observed Arrhenius parameters are reported here.", "type": "CHEMICAL", "entities": [ "C8F17I", "Br(-)", "I(-)", "I(-)", "NO3(-)", "HSO4(-)", "H2PO4(-)", "TsO(-)", "I(-)", "HSO4(-)", "TsO(-)" ], "offsets": [ [ 114, 120 ], [ 126, 131 ], [ 136, 140 ], [ 150, 154 ], [ 156, 162 ], [ 164, 171 ], [ 173, 181 ], [ 187, 193 ], [ 207, 211 ], [ 213, 220 ], [ 225, 231 ] ] }, { "pmid": "23591590", "text": "Results were examined in terms of the binding order of various anions as well as the added binding strength from additional halogen bonding (XB) interactions.", "type": "CHEMICAL", "entities": [ "halogen" ], "offsets": [ [ 124, 131 ] ] }, { "pmid": "23591590", "text": "The relative binding energies of ions were generally consistent with the ordering previously reported from solution phase experiments; however, the relatively strong binding of H2PO4(-) to the bidentate receptor contrasted the solution phase observation of oxoanions having weaker interactions when compared to halides.", "type": "CHEMICAL", "entities": [ "H2PO4(-)", "oxo", "halides" ], "offsets": [ [ 177, 185 ], [ 257, 260 ], [ 311, 318 ] ] }, { "pmid": "23591590", "text": "An increase in the energy required to remove the same anion from the tridentate receptor when compared to the bidentate and monodentate receptors is explained as being due to the increase in halogen bonding interactions.", "type": "CHEMICAL", "entities": [ "halogen" ], "offsets": [ [ 191, 198 ] ] }, { "pmid": "23591590", "text": "The possibility of mixed halogen and hydrogen bonded complexes were considered.", "type": "CHEMICAL", "entities": [ "halogen", "hydrogen" ], "offsets": [ [ 25, 32 ], [ 37, 45 ] ] }, { "pmid": "23597506", "text": "Anandamide deficiency and heightened neuropathic pain in aged mice.\n", "type": "CHEMICAL", "entities": [ "Anandamide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23597506", "text": "We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain.", "type": "CHEMICAL", "entities": [ "R-flurbiprofen" ], "offsets": [ [ 74, 88 ] ] }, { "pmid": "23597506", "text": "R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing anandamide.", "type": "CHEMICAL", "entities": [ "R-flurbiprofen", "anandamide" ], "offsets": [ [ 0, 14 ], [ 106, 116 ] ] }, { "pmid": "23597506", "text": "This was associated with low anandamide levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury.", "type": "CHEMICAL", "entities": [ "anandamide" ], "offsets": [ [ 29, 39 ] ] }, { "pmid": "23597506", "text": "In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal anandamide levels after nerve injury.", "type": "CHEMICAL", "entities": [ "R-flurbiprofen", "anandamide" ], "offsets": [ [ 14, 28 ], [ 100, 110 ] ] }, { "pmid": "23597506", "text": "In terms of the mechanisms, we found that fatty acid amide hydrolase (FAAH) which degrades anandamide, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences.", "type": "CHEMICAL", "entities": [ "fatty acid", "amide", "anandamide" ], "offsets": [ [ 42, 52 ], [ 53, 58 ], [ 91, 101 ] ] }, { "pmid": "23597506", "text": "However, enzymes contributing to oxidative metabolism of anandamide, namely cyclooxygenase-1 and Cyp2D6, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of anandamide.", "type": "CHEMICAL", "entities": [ "anandamide", "anandamide" ], "offsets": [ [ 57, 67 ], [ 193, 203 ] ] }, { "pmid": "23597506", "text": "This may overwhelm the capacity of R-flurbiprofen to restore anandamide homeostasis and may contribute to the heightened risk for neuropathic pain at old age.", "type": "CHEMICAL", "entities": [ "R-flurbiprofen", "anandamide" ], "offsets": [ [ 35, 49 ], [ 61, 71 ] ] }, { "pmid": "23600667", "text": "The attachment of inert polymers, such as polyethyleneglycol, to proteins has driven the emergence of a multibillion dollar biotechnology industry.", "type": "CHEMICAL", "entities": [ "polyethyleneglycol" ], "offsets": [ [ 42, 60 ] ] }, { "pmid": "23600667", "text": "Poly(2-(dimethylamino)ethyl methacrylate) changes in conformation with altered temperature and pH. Growing the polymer from the surface of chymotrypsin we were able to demonstrate that changes in temperature or pH can change predictably the conformation of the polymer surrounding the enzyme, which in turn enabled the rational tailoring of enzyme activity and stability.", "type": "CHEMICAL", "entities": [ "Poly(2-(dimethylamino)ethyl methacrylate)" ], "offsets": [ [ 0, 41 ] ] }, { "pmid": "23600914", "text": "24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1.\n", "type": "CHEMICAL", "entities": [ "24(S)-hydroxycholesterol" ], "offsets": [ [ 0, 24 ] ] }, { "pmid": "23600914", "text": "High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning.", "type": "CHEMICAL", "entities": [ "cholesterol", "cholesterol" ], "offsets": [ [ 39, 50 ], [ 5, 16 ] ] }, { "pmid": "23600914", "text": "Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells.", "type": "CHEMICAL", "entities": [ "24(S)-hydroxycholesterol", "24-OHC" ], "offsets": [ [ 8, 32 ], [ 34, 40 ] ] }, { "pmid": "23600914", "text": "Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation.", "type": "CHEMICAL", "entities": [ "24-OHC" ], "offsets": [ [ 85, 91 ] ] }, { "pmid": "23600914", "text": "The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR.", "type": "CHEMICAL", "entities": [ "retinoic acid", "24-OHC", "TO901317" ], "offsets": [ [ 81, 94 ], [ 49, 55 ], [ 68, 76 ] ] }, { "pmid": "23600914", "text": "When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor.", "type": "CHEMICAL", "entities": [ "24-OHC" ], "offsets": [ [ 52, 58 ] ] }, { "pmid": "23600914", "text": "To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal.", "type": "CHEMICAL", "entities": [ "24-OHC" ], "offsets": [ [ 126, 132 ] ] }, { "pmid": "23600914", "text": "Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC.", "type": "CHEMICAL", "entities": [ "24-OHC" ], "offsets": [ [ 103, 109 ] ] }, { "pmid": "23600914", "text": "These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells.", "type": "CHEMICAL", "entities": [ "24-OHC" ], "offsets": [ [ 53, 59 ] ] }, { "pmid": "23601203", "text": "Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system.\n", "type": "CHEMICAL", "entities": [ "catecholamine" ], "offsets": [ [ 47, 60 ] ] }, { "pmid": "23601203", "text": "Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm.", "type": "CHEMICAL", "entities": [ "Catecholamine", "EDTA-bis(tyramide)" ], "offsets": [ [ 0, 13 ], [ 22, 40 ] ] }, { "pmid": "23601203", "text": "Molecular docking studies were performed with Human Serum Albumin (HSA: PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target.", "type": "CHEMICAL", "entities": [ "amino acid", "Arg", "Arg", "Lys" ], "offsets": [ [ 111, 121 ], [ 131, 134 ], [ 139, 142 ], [ 150, 153 ] ] }, { "pmid": "23601203", "text": "Finally, EDTA-bis(tyramide) labeled with (99m)", "type": "CHEMICAL", "entities": [ "EDTA-bis(tyramide)", "(99m) Tc" ], "offsets": [ [ 6, 24 ], [ 38, 46 ] ] }, { "pmid": "23602864", "text": "Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia.\n", "type": "CHEMICAL", "entities": [ "HPMA" ], "offsets": [ [ 93, 97 ] ] }, { "pmid": "23602864", "text": "In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates.", "type": "CHEMICAL", "entities": [ "N-(2-hydroxypropyl)methacrylamide", "HPMA" ], "offsets": [ [ 127, 160 ], [ 162, 166 ] ] }, { "pmid": "23602864", "text": "Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78kDa (GRP78) was utilized for targeted drug therapy.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 84, 91 ] ] }, { "pmid": "23602864", "text": "Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized.", "type": "CHEMICAL", "entities": [ "aminohexylgeldanamycin", "AHGDM", "docetaxel", "DOC", "cisplatin" ], "offsets": [ [ 41, 63 ], [ 65, 70 ], [ 73, 82 ], [ 84, 87 ], [ 93, 102 ] ] }, { "pmid": "23602864", "text": "HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide.", "type": "CHEMICAL", "entities": [ "AHGDM", "DOC" ], "offsets": [ [ 13, 18 ], [ 23, 26 ] ] }, { "pmid": "23602864", "text": "HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC50 of 2.4nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively.", "type": "CHEMICAL", "entities": [ "DOC", "AHGDM", "DOC" ], "offsets": [ [ 12, 15 ], [ 106, 111 ], [ 116, 119 ] ] }, { "pmid": "23602864", "text": "Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation.", "type": "CHEMICAL", "entities": [ "DOC" ], "offsets": [ [ 36, 39 ] ] }, { "pmid": "23602864", "text": "In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10mg/kg resulted in maintained tumor regression for a period of 30days.", "type": "CHEMICAL", "entities": [ "HPMA", "docetaxel" ], "offsets": [ [ 183, 187 ], [ 198, 207 ] ] }, { "pmid": "23602989", "text": "Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner.\n", "type": "CHEMICAL", "entities": [ "Ca(2+)", "dopamine" ], "offsets": [ [ 111, 117 ], [ 30, 38 ] ] }, { "pmid": "23602989", "text": "In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 141, 147 ] ] }, { "pmid": "23602989", "text": "In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "ionomycin", "K(+)", "cAMP", "dopamine" ], "offsets": [ [ 58, 64 ], [ 66, 75 ], [ 80, 84 ], [ 139, 143 ], [ 192, 200 ] ] }, { "pmid": "23602989", "text": "The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization.", "type": "CHEMICAL", "entities": [ "KN-62", "ionomycin", "K(+)" ], "offsets": [ [ 29, 34 ], [ 69, 78 ], [ 83, 87 ] ] }, { "pmid": "23602989", "text": "Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization.", "type": "CHEMICAL", "entities": [ "Ca(2)", "Ca(2+)", "nifedipine", "K(+)" ], "offsets": [ [ 17, 22 ], [ 61, 67 ], [ 76, 86 ], [ 126, 130 ] ] }, { "pmid": "23602989", "text": "Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors.", "type": "CHEMICAL", "entities": [ "KN-62", "K(+)" ], "offsets": [ [ 86, 91 ], [ 27, 31 ] ] }, { "pmid": "23602989", "text": "In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62.", "type": "CHEMICAL", "entities": [ "[(3)H]GABA", "KN-62" ], "offsets": [ [ 83, 93 ], [ 137, 142 ] ] }, { "pmid": "23602989", "text": "In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release.", "type": "CHEMICAL", "entities": [ "KN-62", "PD 128,907", "SKF 38393", "KN-62", "dopamine", "[(3)H]GABA" ], "offsets": [ [ 217, 222 ], [ 53, 63 ], [ 100, 109 ], [ 127, 132 ], [ 162, 170 ], [ 197, 207 ] ] }, { "pmid": "23602989", "text": "KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses.", "type": "CHEMICAL", "entities": [ "dopamine", "KN-62" ], "offsets": [ [ 15, 23 ], [ 43, 48 ] ] }, { "pmid": "23602989", "text": "These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "GABA" ], "offsets": [ [ 98, 104 ], [ 159, 163 ] ] }, { "pmid": "23602989", "text": "These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 118, 126 ] ] }, { "pmid": "23603381", "text": "Ellagic acid attenuates bleomycin and cyclophosphamide-induced pulmonary toxicity in Wistar rats.\n", "type": "CHEMICAL", "entities": [ "Ellagic acid", "bleomycin", "cyclophosphamide" ], "offsets": [ [ 0, 12 ], [ 24, 33 ], [ 38, 54 ] ] }, { "pmid": "23603381", "text": "Use of bleomycin (BLM) and cyclophosphamide (CP) as chemotherapeutic drugs is associated with side effects including toxicity to respiratory system.", "type": "CHEMICAL", "entities": [ "BLM", "cyclophosphamide", "bleomycin" ], "offsets": [ [ 18, 21 ], [ 27, 43 ], [ 7, 16 ] ] }, { "pmid": "23603381", "text": "Ellagic acid (EA), a polyphenolic compound present in many fruits and nuts in addition to walnut has shown promising protective effect against toxicity of drugs and chemicals.", "type": "CHEMICAL", "entities": [ "Ellagic acid" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23603381", "text": "and BLM (10U/kgb.w., i.t.).", "type": "CHEMICAL", "entities": [ "BLM" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "23603381", "text": "EA (15mg/kgb.w., p.o.×14days) treatment modulated enhanced hydroxyproline level, lipid peroxidation, myeloperoxidase activity, nitric oxide production and protein carbonyl formation in lungs of rats exposed to toxic anticancer drugs.", "type": "CHEMICAL", "entities": [ "hydroxyproline", "nitric oxide", "carbonyl" ], "offsets": [ [ 59, 73 ], [ 127, 139 ], [ 163, 171 ] ] }, { "pmid": "23603381", "text": "There was a marked decrease in GSH content and activities of antioxidant enzymes as a result of BLM and CP treatment.", "type": "CHEMICAL", "entities": [ "BLM", "GSH" ], "offsets": [ [ 95, 98 ], [ 30, 33 ] ] }, { "pmid": "23605050", "text": "Effects of High Iron and Glucose Concentrations over the Relative Expression of Bcl2, Bax, and Mfn2 in MIN6 Cells.\n", "type": "CHEMICAL", "entities": [ "Iron", "Glucose" ], "offsets": [ [ 16, 20 ], [ 25, 32 ] ] }, { "pmid": "23605050", "text": "The purpose of this study was to describe the effect of different iron and/or glucose concentrations over Mfn2, Bax, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells).", "type": "CHEMICAL", "entities": [ "iron", "glucose" ], "offsets": [ [ 65, 69 ], [ 77, 84 ] ] }, { "pmid": "23605050", "text": "MIN6 cells were pre-incubated with different iron and/or glucose concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR.", "type": "CHEMICAL", "entities": [ "iron", "glucose" ], "offsets": [ [ 43, 47 ], [ 55, 62 ] ] }, { "pmid": "23605050", "text": "Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined.", "type": "CHEMICAL", "entities": [ "iron", "superoxide", "glutathione" ], "offsets": [ [ 28, 32 ], [ 41, 51 ], [ 76, 87 ] ] }, { "pmid": "23605050", "text": "The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after glucose stimulation.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 77, 84 ] ] }, { "pmid": "23605050", "text": "These effects were higher when glucose and iron were incubated together.", "type": "CHEMICAL", "entities": [ "glucose", "iron" ], "offsets": [ [ 29, 36 ], [ 41, 45 ] ] }, { "pmid": "23605050", "text": "Additionally, treatment with glucose/iron showed a higher HO activity.", "type": "CHEMICAL", "entities": [ "glucose", "iron" ], "offsets": [ [ 27, 34 ], [ 35, 39 ] ] }, { "pmid": "23605050", "text": "Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis.", "type": "CHEMICAL", "entities": [ "glucose", "Fe" ], "offsets": [ [ 27, 34 ], [ 35, 37 ] ] }, { "pmid": "23607523", "text": "Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156.\n", "type": "CHEMICAL", "entities": [ "Pyralomicin" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "23607523", "text": "The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156.", "type": "CHEMICAL", "entities": [ "pyralomicin" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "23607523", "text": "The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis.", "type": "CHEMICAL", "entities": [ "pyralomicin" ], "offsets": [ [ 85, 96 ] ] }, { "pmid": "23607523", "text": "This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure.", "type": "CHEMICAL", "entities": [ "benzopyranopyrrole", "O", "N" ], "offsets": [ [ 119, 137 ], [ 217, 218 ], [ 245, 246 ] ] }, { "pmid": "23607523", "text": "The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone.", "type": "CHEMICAL", "entities": [ "cyclitol", "N", "glucose" ], "offsets": [ [ 84, 92 ], [ 4, 5 ], [ 58, 65 ] ] }, { "pmid": "23607523", "text": "A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs.", "type": "CHEMICAL", "entities": [ "C7", "cyclitol", "benzopyranopyrrole" ], "offsets": [ [ 25, 27 ], [ 28, 36 ], [ 89, 107 ] ] }, { "pmid": "23607523", "text": "Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety.", "type": "CHEMICAL", "entities": [ "N", "pyralomicin", "sugar", "phosphate", "C7", "cyclitol" ], "offsets": [ [ 45, 46 ], [ 84, 95 ], [ 185, 190 ], [ 191, 200 ], [ 242, 244 ], [ 245, 253 ] ] }, { "pmid": "23607712", "text": "Synaptotagmin 1 is required for vesicular Ca(2+) /H(+) -antiport activity.\n", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)" ], "offsets": [ [ 42, 48 ], [ 50, 54 ] ] }, { "pmid": "23607712", "text": "A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)" ], "offsets": [ [ 15, 21 ], [ 23, 27 ] ] }, { "pmid": "23607712", "text": "Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "calcium" ], "offsets": [ [ 82, 88 ], [ 167, 174 ] ] }, { "pmid": "23607712", "text": "Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca(2+) /H(+) -antiport.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)" ], "offsets": [ [ 82, 88 ], [ 90, 94 ] ] }, { "pmid": "23607712", "text": "We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)", "Ca(2+)", "H(+)", "bafilomycin", "calcium", "calcium" ], "offsets": [ [ 12, 18 ], [ 20, 24 ], [ 122, 128 ], [ 167, 171 ], [ 187, 198 ], [ 209, 216 ], [ 254, 261 ] ] }, { "pmid": "23607712", "text": "Ca(2+) /H(+)", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)" ], "offsets": [ [ 0, 6 ], [ 8, 12 ] ] }, { "pmid": "23607712", "text": "In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "H(+)" ], "offsets": [ [ 153, 159 ], [ 161, 165 ] ] }, { "pmid": "23607712", "text": "Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)", "H(+)" ], "offsets": [ [ 111, 117 ], [ 142, 148 ], [ 150, 154 ] ] }, { "pmid": "23608737", "text": "Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha.\n", "type": "CHEMICAL", "entities": [ "Estradiol", "cocaine", "estrogen" ], "offsets": [ [ 0, 9 ], [ 31, 38 ], [ 92, 100 ] ] }, { "pmid": "23608737", "text": "Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown.", "type": "CHEMICAL", "entities": [ "Estradiol" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23608737", "text": "This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods.", "type": "CHEMICAL", "entities": [ "estradiol", "cocaine" ], "offsets": [ [ 81, 90 ], [ 108, 115 ] ] }, { "pmid": "23608737", "text": "The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 151, 158 ] ] }, { "pmid": "23608737", "text": "Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects.", "type": "CHEMICAL", "entities": [ "17β-estradiol", "cocaine" ], "offsets": [ [ 52, 65 ], [ 103, 110 ] ] }, { "pmid": "23608737", "text": "To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either ERα (αERKO) or ERβ (βERKO) were compared to WT littermates.", "type": "CHEMICAL", "entities": [ "estradiol", "PPT", "DPN" ], "offsets": [ [ 31, 40 ], [ 117, 120 ], [ 150, 153 ] ] }, { "pmid": "23608737", "text": "Ovx mice exhibited fewer ambulations during habituation than Sham females.", "type": "CHEMICAL", "entities": [ "Cocaine" ], "offsets": [ [ 67, 74 ] ] }, { "pmid": "23608737", "text": "Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels.", "type": "CHEMICAL", "entities": [ "cocaine", "PPT" ], "offsets": [ [ 56, 63 ], [ 90, 93 ] ] }, { "pmid": "23608737", "text": "PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice.", "type": "CHEMICAL", "entities": [ "cocaine", "DPN" ], "offsets": [ [ 26, 33 ], [ 67, 70 ] ] }, { "pmid": "23608737", "text": "αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 68, 75 ] ] }, { "pmid": "23608737", "text": "These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 26, 33 ] ] }, { "pmid": "23609128", "text": "Here, we investigate the water cations [(H2 O)n = 2-6 (+) ] with density functional theory (DFT), Möller-Plesset second-order perturbation theory (MP2), and coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)].", "type": "CHEMICAL", "entities": [ "(H2 O)n" ], "offsets": [ [ 40, 47 ] ] }, { "pmid": "23609128", "text": "The characteristics of structures and spectra of the water cluster cations reflect the formation of the hydronium cation moiety (H3 O(+) ) and the hydroxyl radical.", "type": "CHEMICAL", "entities": [ "hydronium", "H3 O(+)", "hydroxyl" ], "offsets": [ [ 99, 108 ], [ 124, 131 ], [ 142, 150 ] ] }, { "pmid": "23609128", "text": "On ionization, the water clusters tend to have an Eigen-like form with the hydronium cation instead of a Zundel-like form, based on reliable BOMD simulations.", "type": "CHEMICAL", "entities": [ "hydronium" ], "offsets": [ [ 70, 79 ] ] }, { "pmid": "23609128", "text": "For the vertically ionized water hexamer, the relatively stable (H2 O)5 (+) (5sL4A) cluster tends to form with a detached water molecule (H2 O).", "type": "CHEMICAL", "entities": [ "(H2 O)5 (+)", "H2 O" ], "offsets": [ [ 59, 70 ], [ 133, 137 ] ] }, { "pmid": "23609438", "text": "The Intermediate-conductance Calcium-activated Potassium Channel KCa3.1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent Signaling.\n", "type": "CHEMICAL", "entities": [ "Calcium", "Calcium", "Potassium" ], "offsets": [ [ 140, 147 ], [ 29, 36 ], [ 47, 56 ] ] }, { "pmid": "23609438", "text": "The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis and vascular remodeling.", "type": "CHEMICAL", "entities": [ "calcium", "potassium" ], "offsets": [ [ 29, 36 ], [ 47, 56 ] ] }, { "pmid": "23609438", "text": "Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 135, 141 ], [ 158, 164 ], [ 199, 205 ] ] }, { "pmid": "23609438", "text": "KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP response element binding protein (CREB), c-fos and neuron-derived orphan receptor-1 (NOR-1).", "type": "CHEMICAL", "entities": [ "Ca(2+)", "cAMP" ], "offsets": [ [ 81, 87 ], [ 139, 143 ] ] }, { "pmid": "23609438", "text": "This anti-proliferative effect was abolished by elevating [Ca(2+)]i.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 59, 65 ] ] }, { "pmid": "23609438", "text": "Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by inhibiting the rise in [Ca(2+)]i and abolishing the expression and activity of KCa3.1 and PDGF β-receptors.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 103, 109 ] ] }, { "pmid": "23609438", "text": "In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 83, 89 ] ] }, { "pmid": "23610086", "text": "Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-based Inverse Agonists of the Ghrelin Receptor.\n", "type": "CHEMICAL", "entities": [ "Imidazo- and 2-Methylimidazo[2,1-b]thiazole" ], "offsets": [ [ 40, 83 ] ] }, { "pmid": "23610086", "text": "The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure.", "type": "CHEMICAL", "entities": [ "1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone", "imidazo[2,1-b]thiazole", "1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone" ], "offsets": [ [ 219, 344 ], [ 369, 391 ], [ 93, 210 ] ] }, { "pmid": "23610086", "text": "Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species.", "type": "CHEMICAL", "entities": [ "NADPH", "glutathione", "glutathione" ], "offsets": [ [ 49, 54 ], [ 60, 71 ], [ 117, 128 ] ] }, { "pmid": "23610086", "text": "Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle.", "type": "CHEMICAL", "entities": [ "glutathionyl", "thiol", "thiazole" ], "offsets": [ [ 90, 102 ], [ 117, 122 ], [ 145, 153 ] ] }, { "pmid": "23610086", "text": "Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1.", "type": "CHEMICAL", "entities": [ "glutathione", "imidazo[2,1-b]thiazole" ], "offsets": [ [ 4, 15 ], [ 51, 73 ] ] }, { "pmid": "23610086", "text": "One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct.", "type": "CHEMICAL", "entities": [ "glutathione", "glutathione", "S-oxide", "glutathione-S-oxide" ], "offsets": [ [ 170, 181 ], [ 52, 63 ], [ 78, 85 ], [ 208, 227 ] ] }, { "pmid": "23610086", "text": "In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step.", "type": "CHEMICAL", "entities": [ "2-methylimidazo[2,1-b]thiazole", "glutathione", "thiazole" ], "offsets": [ [ 19, 49 ], [ 60, 71 ], [ 152, 160 ] ] }, { "pmid": "23610086", "text": "Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide.", "type": "CHEMICAL", "entities": [ "18O", "potassium cyanide" ], "offsets": [ [ 57, 60 ], [ 96, 113 ] ] }, { "pmid": "23610086", "text": "The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3).", "type": "CHEMICAL", "entities": [ "-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone", "thiazole", "1,2,4-thiadiazole" ], "offsets": [ [ 223, 357 ], [ 169, 177 ], [ 190, 207 ] ] }, { "pmid": "23614728", "text": "Adenovirus-delivered angiopoietin-1 treatment for phosgene-induced acute lung injury.\n", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 50, 58 ] ] }, { "pmid": "23614728", "text": "Abstract Context: Exposure to phosgene can result in an acute lung injury, leading to pulmonary edema and even death.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 30, 38 ] ] }, { "pmid": "23614728", "text": "In this study, the histopathological changes of the lungs after exposure to phosgene and the effect of Ang1 treatment were examined.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 76, 84 ] ] }, { "pmid": "23614728", "text": "Materials and methods: Rats were exposed to phosgene gas at 8.33 g/m(3) for 5 min. Ang1 overexpressing rats were established by an intravenous injection of adenovirus-Ang1 (Ad/Ang1).", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 44, 52 ] ] }, { "pmid": "23614728", "text": "The histological changes of the lung were examined by Haematoxylin-Eosin (H&E) staining and fluorescence microscopy.", "type": "CHEMICAL", "entities": [ "Haematoxylin", "Eosin" ], "offsets": [ [ 50, 62 ], [ 63, 68 ] ] }, { "pmid": "23614728", "text": "The lung injury induced by phosgene was markedly reduced after the injection of Ad/Ang1.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 23, 31 ] ] }, { "pmid": "23614728", "text": "The increase of IL-1β and IL-17 and decrease of vascular endothelial growth factor in the serum and bronchoalveolar lavage fluid of phosgene-exposed animals were abolished by the administration of Ad/Ang1.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 128, 136 ] ] }, { "pmid": "23614728", "text": "Discussion and conclusions: Ang1 has the beneficial effects on phosgene-induced lung injury.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 58, 66 ] ] }, { "pmid": "23614728", "text": "The adenovirus-delivered Ang1 may have the potential as a novel approach for the treatment of the acute lung injury caused by phosgene gas inhalation in humans.", "type": "CHEMICAL", "entities": [ "phosgene" ], "offsets": [ [ 121, 129 ] ] }, { "pmid": "23617725", "text": "Probing the Role of the Vancomycin E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues.\n", "type": "CHEMICAL", "entities": [ "Vancomycin", "Aryl Chloride" ], "offsets": [ [ 24, 34 ], [ 42, 55 ] ] }, { "pmid": "23617725", "text": "The selective functionalization of a vancomycin aglycon derivative through direct conversion of the E-ring aryl chloride to a reactive boronic acid, and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described.", "type": "CHEMICAL", "entities": [ "aryl chloride", "boronic acid", "vancomycin", "vancomycin" ], "offsets": [ [ 107, 120 ], [ 135, 147 ], [ 204, 214 ], [ 37, 47 ] ] }, { "pmid": "23617725", "text": "The series of analogues was used to examine the impact of the E-ring chloride in binding D-Ala-D-Ala and on antimicrobial activity.", "type": "CHEMICAL", "entities": [ "D-Ala-D-Ala" ], "offsets": [ [ 89, 100 ] ] }, { "pmid": "23617725", "text": "In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively non-polar substituents approach or match the chloro substituted vancomycin and was insensitive to the electronic character of the substituent (e.g. Cl vs CN or OMe), whereas highly polar substituents fail to provide the enhancements.", "type": "CHEMICAL", "entities": [ "Cl", "CN", "OMe", "chloro substituted vancomycin" ], "offsets": [ [ 252, 254 ], [ 258, 260 ], [ 264, 267 ], [ 149, 178 ] ] }, { "pmid": "23617725", "text": "Moreover, the active permethylated vancomycin aglycon derivatives examined exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria.", "type": "CHEMICAL", "entities": [ "vancomycin", "VanB" ], "offsets": [ [ 35, 45 ], [ 83, 87 ] ] }, { "pmid": "23617725", "text": "The robust borylation reaction also enabled the selective functionalization of a minimally protected vancomycin aglycon (N-Boc vancomycin aglycon), and provides a direct method for the preparation of previously inaccessible analogues.", "type": "CHEMICAL", "entities": [ "vancomycin", "N-Boc", "vancomycin" ], "offsets": [ [ 101, 111 ], [ 121, 126 ], [ 127, 137 ] ] }, { "pmid": "23619606", "text": "Exposure to DEHP decreased four fatty acid levels in plasma of prepartum mice.\n", "type": "CHEMICAL", "entities": [ "DEHP", "fatty acid" ], "offsets": [ [ 12, 16 ], [ 32, 42 ] ] }, { "pmid": "23619606", "text": "Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice.", "type": "CHEMICAL", "entities": [ "di(2-ethylhexyl) phthalate", "DEHP", "triglyceride" ], "offsets": [ [ 21, 47 ], [ 49, 53 ], [ 76, 88 ] ] }, { "pmid": "23619606", "text": "To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPARα), peroxisome proliferator-activated receptor α-null (Pparα-null) and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% DEHP.", "type": "CHEMICAL", "entities": [ "DEHP", "fatty acid" ], "offsets": [ [ 287, 291 ], [ 16, 26 ] ] }, { "pmid": "23619606", "text": "The plasma levels of linoleic acid, α-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPARa mice than in Ppara-null and hPPARa mice.", "type": "CHEMICAL", "entities": [ "linoleic acid", "α-linolenic acid", "palmitic acid", "oleic acid", "DEHP" ], "offsets": [ [ 16, 29 ], [ 31, 47 ], [ 49, 62 ], [ 67, 77 ], [ 162, 166 ] ] }, { "pmid": "23619606", "text": "Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups.", "type": "CHEMICAL", "entities": [ "DEHP" ], "offsets": [ [ 161, 165 ] ] }, { "pmid": "23619606", "text": "DEHP exposure slightly increased hepatic arachidonic acid, α-linolenic acid, palmitoleic acid and oleic acid in fetuses, but not in pups.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "α-linolenic acid", "palmitoleic acid", "oleic acid" ], "offsets": [ [ 34, 50 ], [ 52, 68 ], [ 70, 86 ], [ 91, 101 ] ] }, { "pmid": "23619606", "text": "However, DEHP exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice.", "type": "CHEMICAL", "entities": [ "DEHP" ], "offsets": [ [ 1, 5 ] ] }, { "pmid": "23619606", "text": "Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant mPPARα mice than in other genotypes, and DEHP exposure decreased these specific FA concentrations only in mPPARα mice, similarly to triglyceride levels.", "type": "CHEMICAL", "entities": [ "triglyceride", "carbon", "DEHP" ], "offsets": [ [ 221, 233 ], [ 51, 57 ], [ 130, 134 ] ] }, { "pmid": "23619613", "text": "Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity.", "type": "CHEMICAL", "entities": [ "polySia", "polysialic acid" ], "offsets": [ [ 95, 102 ], [ 78, 93 ] ] }, { "pmid": "23619613", "text": "Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung.", "type": "CHEMICAL", "entities": [ "polySia" ], "offsets": [ [ 59, 66 ] ] }, { "pmid": "23619613", "text": "In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells.", "type": "CHEMICAL", "entities": [ "polySia" ], "offsets": [ [ 41, 48 ] ] }, { "pmid": "23619613", "text": "In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed.", "type": "CHEMICAL", "entities": [ "polySia" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "23619613", "text": "Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β.", "type": "CHEMICAL", "entities": [ "bleomycin" ], "offsets": [ [ 69, 78 ] ] }, { "pmid": "23619613", "text": "As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM.", "type": "CHEMICAL", "entities": [ "polySia", "polySia" ], "offsets": [ [ 257, 264 ], [ 33, 40 ] ] }, { "pmid": "23619613", "text": "Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing \"neutrophil extracellular traps\", which are formed during invasion of microorganisms.", "type": "CHEMICAL", "entities": [ "polySia" ], "offsets": [ [ 13, 20 ] ] }, { "pmid": "23619613", "text": "Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.", "type": "CHEMICAL", "entities": [ "polySia" ], "offsets": [ [ 16, 23 ] ] }, { "pmid": "23620256", "text": "A double-labeling fluorescent technique (yo pro-1 and propidium iodide) was used to validate the findings revealed by the FRET-based caspase sensor.", "type": "CHEMICAL", "entities": [ "yo pro-1", "propidium iodide" ], "offsets": [ [ 41, 49 ], [ 54, 70 ] ] }, { "pmid": "23620256", "text": "The results show high rates of apoptosis and necrosis of endothelial cells when high glucose concentration was applied in our hemodynamic microfluidic chip combined with an exhaustive pulsatile flow profile.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 85, 92 ] ] }, { "pmid": "23620256", "text": "Furthermore, the activation of the FRET biosensor also confirms the endothelial cell apoptosis induced by the abnormal pulsatile shear stress and high glucose concentration is through caspase-3 pathway.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 151, 158 ] ] }, { "pmid": "23620256", "text": "A 12% apoptotic rate (nearly a 4-fold increase compared to the static condition) was observed when the endothelial cells were exposed to a high glucose concentration of 20 mM under 2 h exhaustive pulsatile shear stress of 30 dyne cm(-2) and followed with another 10 h normal pulsatile shear stress of 15 dyne cm(-2).", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 144, 151 ] ] }, { "pmid": "23620256", "text": "This finding may provide new insight into how glucose causes endothelial cell dysfunction, which is the major cause of diabetes-derived complications.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 46, 53 ] ] }, { "pmid": "23620529", "text": "Fetal renal excretion of sodium was increased while urine volume decreased in HSD group.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 25, 31 ] ] }, { "pmid": "23620529", "text": "Fetal blood urea nitrogen was increased, while kidney/body weight ratio decreased in HSD group.", "type": "CHEMICAL", "entities": [ "urea", "nitrogen" ], "offsets": [ [ 12, 16 ], [ 17, 25 ] ] }, { "pmid": "23623491", "text": "Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents.\n", "type": "CHEMICAL", "entities": [ "pyrazolo[1,5-a]pyrimidine", "aminobenzothiazole" ], "offsets": [ [ 13, 38 ], [ 46, 64 ] ] }, { "pmid": "23623491", "text": "A series of pyrazolo[1,5-a]pyrimidine linked 2-aminobenzothizole conjugates (6a-t) were synthesized and evaluated for their anticancer activity against five human cancer cell lines.", "type": "CHEMICAL", "entities": [ "pyrazolo[1,5-a]pyrimidine", "2-aminobenzothizole" ], "offsets": [ [ 12, 37 ], [ 45, 64 ] ] }, { "pmid": "23624419", "text": "Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to metformin in type 2 diabetic patients.\n", "type": "CHEMICAL", "entities": [ "metformin", "vildagliptin" ], "offsets": [ [ 112, 121 ], [ 84, 96 ] ] }, { "pmid": "23624419", "text": "We evaluated the positive effects of vildagliptin in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients.", "type": "CHEMICAL", "entities": [ "vildagliptin", "metformin" ], "offsets": [ [ 36, 48 ], [ 64, 73 ] ] }, { "pmid": "23624419", "text": "One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months.", "type": "CHEMICAL", "entities": [ "vildaglipin", "metformin" ], "offsets": [ [ 74, 85 ], [ 117, 126 ] ] }, { "pmid": "23624419", "text": "Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation.", "type": "CHEMICAL", "entities": [ "arginine", "vildagliptin" ], "offsets": [ [ 160, 168 ], [ 47, 59 ] ] }, { "pmid": "23624419", "text": "Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements.", "type": "CHEMICAL", "entities": [ "metformin", "metformin" ], "offsets": [ [ 10, 19 ], [ 53, 62 ] ] }, { "pmid": "23624419", "text": "Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 10, 19 ] ] }, { "pmid": "23624419", "text": "We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin.", "type": "CHEMICAL", "entities": [ "vildagliptin", "metformin" ], "offsets": [ [ 129, 141 ], [ 142, 151 ] ] }, { "pmid": "23624419", "text": "Vildagliptin, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements.", "type": "CHEMICAL", "entities": [ "metformin" ], "offsets": [ [ 24, 33 ] ] }, { "pmid": "23624423", "text": "4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells.\n", "type": "CHEMICAL", "entities": [ "4-Hydroxytamoxifen" ], "offsets": [ [ 0, 18 ] ] }, { "pmid": "23624423", "text": "17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells.", "type": "CHEMICAL", "entities": [ "17β-Estradiol" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "23624423", "text": "Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 40, 48 ] ] }, { "pmid": "23624423", "text": "We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα).", "type": "CHEMICAL", "entities": [ "tamoxifen", "estrogen", "estrogen" ], "offsets": [ [ 42, 51 ], [ 121, 129 ], [ 224, 232 ] ] }, { "pmid": "23624423", "text": "4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration.", "type": "CHEMICAL", "entities": [ "OHT", "tamoxifen" ], "offsets": [ [ 17, 20 ], [ 22, 31 ] ] }, { "pmid": "23624423", "text": "Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30.", "type": "CHEMICAL", "entities": [ "OHT" ], "offsets": [ [ 8, 11 ] ] }, { "pmid": "23624423", "text": "In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling.", "type": "CHEMICAL", "entities": [ "OHT" ], "offsets": [ [ 60, 63 ] ] }, { "pmid": "23624423", "text": "Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells.", "type": "CHEMICAL", "entities": [ "OHT" ], "offsets": [ [ 32, 35 ] ] }, { "pmid": "23625804", "text": "Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants.\n", "type": "CHEMICAL", "entities": [ "Disulfide", "Cu(I)" ], "offsets": [ [ 115, 124 ], [ 71, 76 ] ] }, { "pmid": "23625804", "text": "Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer.", "type": "CHEMICAL", "entities": [ "Superoxide" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "23625804", "text": "We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1).", "type": "CHEMICAL", "entities": [ "copper" ], "offsets": [ [ 82, 88 ] ] }, { "pmid": "23625804", "text": "The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1.", "type": "CHEMICAL", "entities": [ "copper(I)" ], "offsets": [ [ 34, 43 ] ] }, { "pmid": "23625804", "text": "NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 copper acquisition.", "type": "CHEMICAL", "entities": [ "disulfide", "cysteines" ], "offsets": [ [ 141, 150 ], [ 207, 216 ] ] }, { "pmid": "23625804", "text": "Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1.", "type": "CHEMICAL", "entities": [ "copper" ], "offsets": [ [ 167, 173 ] ] }, { "pmid": "23626400", "text": "Novel pentablock copolymer (PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery: Effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles.\n", "type": "CHEMICAL", "entities": [ "PLA", "PCL", "PEG", "PCL", "PLA" ], "offsets": [ [ 28, 31 ], [ 32, 35 ], [ 36, 39 ], [ 40, 43 ], [ 44, 47 ] ] }, { "pmid": "23626400", "text": "The purpose of this investigation was to design novel pentablock copolymers (polylatide-polycaprolactone-polyethylene glycol- polycaprolactone-polylatide) (PLA-PCL-PEG-PCL-PLA) to prepare nanoparticle formulations which provide continuous delivery of steroids over a longer duration with minimal burst effect.", "type": "CHEMICAL", "entities": [ "steroids", "polylatide", "polycaprolactone", "polyethylene glycol", "polycaprolactone", "polylatide", "PLA", "PCL", "PEG", "PCL", "PLA" ], "offsets": [ [ 251, 259 ], [ 77, 87 ], [ 88, 104 ], [ 105, 124 ], [ 126, 142 ], [ 143, 153 ], [ 156, 159 ], [ 160, 163 ], [ 164, 167 ], [ 168, 171 ], [ 172, 175 ] ] }, { "pmid": "23626400", "text": "Another purpose was to evaluate the effect of poly (L-lactide) (PLLA) or poly (D, L-lactide) (PDLLA) incorporation on crystallinity of pentablock copolymers and in vitro release profile of triamcinolone acetonide (selected as model drug) from nanoparticles.", "type": "CHEMICAL", "entities": [ "poly (L-lactide)", "PLLA", "poly (D, L-lactide)", "PDLLA", "triamcinolone acetonide" ], "offsets": [ [ 46, 62 ], [ 64, 68 ], [ 73, 92 ], [ 94, 99 ], [ 189, 212 ] ] }, { "pmid": "23626400", "text": "PLA-PCL-PEG-PCL-PLA copolymers with different block ratio of PCL/PLA segment were synthesized.", "type": "CHEMICAL", "entities": [ "PLA", "PCL", "PEG", "PCL", "PLA", "PCL", "PLA" ], "offsets": [ [ 0, 3 ], [ 4, 7 ], [ 8, 11 ], [ 12, 15 ], [ 16, 19 ], [ 61, 64 ], [ 65, 68 ] ] }, { "pmid": "23626400", "text": "Release of triamcinolone acetonide from nanoparticles was significantly affected by crystallinity of the copolymers.", "type": "CHEMICAL", "entities": [ "triamcinolone acetonide" ], "offsets": [ [ 11, 34 ] ] }, { "pmid": "23626400", "text": "Burst release of triamcinolone acetonide from nanoparticles was significantly minimized with incorporation of proper ratio of PDLLA in the existing triblock (PCL-PEG-PCL) copolymer.", "type": "CHEMICAL", "entities": [ "triamcinolone acetonide", "PDLLA", "PCL", "PEG", "PCL" ], "offsets": [ [ 17, 40 ], [ 126, 131 ], [ 158, 161 ], [ 162, 165 ], [ 166, 169 ] ] }, { "pmid": "23626400", "text": "Moreover, pentablock copolymer based nanoparticles exhibited continuous release of triamcinolone acetonide.", "type": "CHEMICAL", "entities": [ "triamcinolone acetonide" ], "offsets": [ [ 83, 106 ] ] }, { "pmid": "23630454", "text": "PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance.\n", "type": "CHEMICAL", "entities": [ "Glucose" ], "offsets": [ [ 100, 107 ] ] }, { "pmid": "23630454", "text": "Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 84, 91 ] ] }, { "pmid": "23631463", "text": "Design, Synthesis and Biological Evaluation of Aminoalkylindole Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse.\n", "type": "CHEMICAL", "entities": [ "Alcohol", "Aminoalkylindole" ], "offsets": [ [ 140, 147 ], [ 47, 63 ] ] }, { "pmid": "23631463", "text": "Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse.", "type": "CHEMICAL", "entities": [ "alcohol" ], "offsets": [ [ 139, 146 ] ] }, { "pmid": "23631463", "text": "We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies.", "type": "CHEMICAL", "entities": [ "aminoalkylindole", "JHW-073", "alcohol" ], "offsets": [ [ 79, 95 ], [ 108, 115 ], [ 234, 241 ] ] }, { "pmid": "23631463", "text": "In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity.", "type": "CHEMICAL", "entities": [ "aminoalkylindole" ], "offsets": [ [ 65, 81 ] ] }, { "pmid": "23631463", "text": "Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference.", "type": "CHEMICAL", "entities": [ "alcohol", "alcohol" ], "offsets": [ [ 93, 100 ], [ 188, 195 ] ] }, { "pmid": "23631463", "text": "Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse.", "type": "CHEMICAL", "entities": [ "alcohol", "aminoalkylindoles" ], "offsets": [ [ 257, 264 ], [ 88, 105 ] ] }, { "pmid": "23632310", "text": "Immunoregulatory effects of Glycyrrhizic acid exerts anti-asthmatic effects via modulation of Th1/Th2 cytokines and enhancement of CD4(+)CD25(+)Foxp3(+) regulatory T cells in ovalbumin-sensitized mice.\n", "type": "CHEMICAL", "entities": [ "Glycyrrhizic acid" ], "offsets": [ [ 28, 45 ] ] }, { "pmid": "23632310", "text": "ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizic acid (GA) is the main bioactive ingredient of licorice (Glycyrrhiza glabra), and has been found to be associated with multiple therapeutic properties.", "type": "CHEMICAL", "entities": [ "Glycyrrhizic acid" ], "offsets": [ [ 32, 49 ] ] }, { "pmid": "23632310", "text": "AIM OF THE STUDY: In this study, we investigated immunoregulatory effects of glycyrrhizic acid on anti-asthmatic effects and underlying mechanisms.", "type": "CHEMICAL", "entities": [ "glycyrrhizic acid" ], "offsets": [ [ 77, 94 ] ] }, { "pmid": "23632310", "text": "A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg) and GA (10mg/kg, 20mg/kg, 40mg/kg).", "type": "CHEMICAL", "entities": [ "dexamethasone" ], "offsets": [ [ 86, 99 ] ] }, { "pmid": "23632310", "text": "Airway resistance (Raw) were measured by the forced oscillation technique, histological studies were evaluated by The hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was evaluated by Flow Cytometry (FCM), the forkhead/winged helix transcription factor (Foxp3) was evaluated by western blotting.", "type": "CHEMICAL", "entities": [ "hematoxylin", "eosin" ], "offsets": [ [ 118, 129 ], [ 134, 139 ] ] }, { "pmid": "23636640", "text": "Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model.\n", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 123, 135 ] ] }, { "pmid": "23636640", "text": "After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months.", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 66, 78 ] ] }, { "pmid": "23636640", "text": "Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets.", "type": "CHEMICAL", "entities": [ "glucose", "vildagliptin" ], "offsets": [ [ 20, 27 ], [ 69, 81 ] ] }, { "pmid": "23636640", "text": "In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls.", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 104, 116 ] ] }, { "pmid": "23636640", "text": "Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment.", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 189, 201 ] ] }, { "pmid": "23636640", "text": "Chronic vildagliptin treatment also improved survival rates for HFD-fed mice.", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 5, 17 ] ] }, { "pmid": "23636640", "text": "The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.", "type": "CHEMICAL", "entities": [ "vildagliptin" ], "offsets": [ [ 65, 77 ] ] }, { "pmid": "23639187", "text": "Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis).\n", "type": "CHEMICAL", "entities": [ "palmitate" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "23639187", "text": "Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver.", "type": "CHEMICAL", "entities": [ "free fatty acids", "FFAs", "saturated free fatty acids", "palmitate" ], "offsets": [ [ 20, 36 ], [ 38, 42 ], [ 58, 84 ], [ 93, 102 ] ] }, { "pmid": "23639187", "text": "Skeletal muscle, responsible for up to 80% of the glucose disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs.", "type": "CHEMICAL", "entities": [ "glucose", "FFAs" ], "offsets": [ [ 50, 57 ], [ 160, 164 ] ] }, { "pmid": "23639187", "text": "Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance.", "type": "CHEMICAL", "entities": [ "dihydrochalcone C-glucoside", "aspalathin" ], "offsets": [ [ 45, 72 ], [ 74, 84 ] ] }, { "pmid": "23639187", "text": "Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood glucose lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE).", "type": "CHEMICAL", "entities": [ "Palmitate", "aspalathin", "glucose" ], "offsets": [ [ 0, 9 ], [ 69, 79 ], [ 163, 170 ] ] }, { "pmid": "23639187", "text": "Glucose uptake and mitochondrial activity were measured using 2-deoxy-[(3)H]-d-glucose, MTT and ATP assays, respectively.", "type": "CHEMICAL", "entities": [ "2-deoxy-[(3)H]-d-glucose", "Glucose", "MTT", "ATP" ], "offsets": [ [ 62, 86 ], [ 0, 7 ], [ 88, 91 ], [ 96, 99 ] ] }, { "pmid": "23639187", "text": "Expression of proteins relevant to glucose metabolism was analysed by Western blot.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 35, 42 ] ] }, { "pmid": "23639187", "text": "GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside.", "type": "CHEMICAL", "entities": [ "phenylpyruvic acid-2-O-glucoside", "luteolin-7-O-glucoside" ], "offsets": [ [ 64, 96 ], [ 101, 123 ] ] }, { "pmid": "23639187", "text": "Both rooibos extracts increased glucose uptake, mitochondrial activity and ATP production.", "type": "CHEMICAL", "entities": [ "glucose", "ATP" ], "offsets": [ [ 32, 39 ], [ 75, 78 ] ] }, { "pmid": "23639187", "text": "Compared to FRE, GRE was more effective at increasing glucose uptake and ATP production.", "type": "CHEMICAL", "entities": [ "ATP", "glucose" ], "offsets": [ [ 73, 76 ], [ 54, 61 ] ] }, { "pmid": "23639187", "text": "At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance.", "type": "CHEMICAL", "entities": [ "palmitate" ], "offsets": [ [ 95, 104 ] ] }, { "pmid": "23639187", "text": "Protein levels of the glucose transporter (GLUT4) involved in glucose transport via these two pathways were also increased.", "type": "CHEMICAL", "entities": [ "glucose", "glucose" ], "offsets": [ [ 21, 28 ], [ 61, 68 ] ] }, { "pmid": "23639187", "text": "This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells.", "type": "CHEMICAL", "entities": [ "palmitate" ], "offsets": [ [ 66, 75 ] ] }, { "pmid": "23639192", "text": "Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation.\n", "type": "CHEMICAL", "entities": [ "Puerarin" ], "offsets": [ [ 0, 8 ] ] }, { "pmid": "23639192", "text": "Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.)", "type": "CHEMICAL", "entities": [ "Puerarin", "isoflavone glycoside" ], "offsets": [ [ 0, 8 ], [ 19, 39 ] ] }, { "pmid": "23639192", "text": "Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 27, 35 ] ] }, { "pmid": "23639192", "text": "Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 29, 37 ] ] }, { "pmid": "23639192", "text": "Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms.", "type": "CHEMICAL", "entities": [ "cisplatin", "estrogen", "puerarin" ], "offsets": [ [ 83, 92 ], [ 160, 168 ], [ 18, 26 ] ] }, { "pmid": "23639192", "text": "Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression.", "type": "CHEMICAL", "entities": [ "Puerarin", "puerarin" ], "offsets": [ [ 0, 8 ], [ 76, 84 ] ] }, { "pmid": "23639192", "text": "Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells.", "type": "CHEMICAL", "entities": [ "ICI 182,780", "puerarin" ], "offsets": [ [ 33, 44 ], [ 76, 84 ] ] }, { "pmid": "23639192", "text": "Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 99, 107 ] ] }, { "pmid": "23639192", "text": "Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 33, 41 ] ] }, { "pmid": "23639192", "text": "This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen.", "type": "CHEMICAL", "entities": [ "estrogen" ], "offsets": [ [ 85, 93 ] ] }, { "pmid": "23639192", "text": "Therefore, puerarin will be a promising agent that prevents or retards osteoporosis.", "type": "CHEMICAL", "entities": [ "puerarin" ], "offsets": [ [ 9, 17 ] ] }, { "pmid": "23639248", "text": "Bone Morphogenetic Protein-7 inhibits silica-induced pulmonary fibrosis in rats.\n", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 38, 44 ] ] }, { "pmid": "23639248", "text": "There is no study to investigate BMP-7's role in the development of pulmonary fibrosis induced by silica.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 98, 104 ] ] }, { "pmid": "23639248", "text": "In the current study, we used the rat model to explore the potential antifibrotic role of BMP-7 and its underlying mechanism in silica-induced pulmonary fibrosis.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 128, 134 ] ] }, { "pmid": "23639248", "text": "Control group received saline, silica group received silica and BMP-7 treated group received silica and BMP-7.", "type": "CHEMICAL", "entities": [ "silica", "silica", "silica" ], "offsets": [ [ 31, 37 ], [ 53, 59 ], [ 93, 99 ] ] }, { "pmid": "23639248", "text": "BMP-7 was administered to silica-treated rats intraperitoneally at a dose of 300μg/kg/injection from day 8 to day 30 every other day.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 26, 32 ] ] }, { "pmid": "23639248", "text": "After the animals were sacrificed on day 15 and 30, hydroxyproline levels, the protein expressions of BMP/Smad and TGF-β/Smad signaling, and histopathology in lung tissues were analyzed.", "type": "CHEMICAL", "entities": [ "hydroxyproline" ], "offsets": [ [ 51, 65 ] ] }, { "pmid": "23639248", "text": "The hydroxyproline contents in BMP-7 treated groups were significantly lower than the silica groups (P<0.05).", "type": "CHEMICAL", "entities": [ "hydroxyproline", "silica" ], "offsets": [ [ 2, 16 ], [ 84, 90 ] ] }, { "pmid": "23639248", "text": "Histopathological results showed BMP-7 could reduce the progression of silica induced fibrosis.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 69, 75 ] ] }, { "pmid": "23639248", "text": "Furthermore, the expression of p-Smad1/5/8, a marker of BMP/Smad signaling, was significantly up-regulated in BMP-7 treated groups (P<0.05) compared with the silica groups.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 156, 162 ] ] }, { "pmid": "23639248", "text": "On the contrary, the expression of p-Smad2/3, a marker for TGF-β/Smad signaling, reduced significantly in BMP-7-treated groups compared with silica groups (P<0.05).", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 139, 145 ] ] }, { "pmid": "23639248", "text": "In conclusion, the pulmonary fibrosis induced by silica in rats was significantly reduced with the therapeutic treatment of BMP-7.", "type": "CHEMICAL", "entities": [ "silica" ], "offsets": [ [ 46, 52 ] ] }, { "pmid": "23639572", "text": "The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis.\n", "type": "CHEMICAL", "entities": [ "phosphatidylinositol", "free fatty acid" ], "offsets": [ [ 132, 152 ], [ 60, 75 ] ] }, { "pmid": "23639572", "text": "Linoleic acid (LA) was used as a representative free fatty acid.", "type": "CHEMICAL", "entities": [ "Linoleic acid", "free fatty acid" ], "offsets": [ [ 0, 13 ], [ 48, 63 ] ] }, { "pmid": "23639572", "text": "Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL.", "type": "CHEMICAL", "entities": [ "deoxyribonucleotide", "deoxyuridine triphosphate", "poly (ADP-ribose)" ], "offsets": [ [ 67, 86 ], [ 108, 133 ], [ 217, 234 ] ] }, { "pmid": "23639572", "text": "The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway.", "type": "CHEMICAL", "entities": [ "NO", "nitric oxide" ], "offsets": [ [ 97, 99 ], [ 44, 56 ] ] }, { "pmid": "23639572", "text": "Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, wortmannin.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol", "wortmannin" ], "offsets": [ [ 151, 171 ], [ 205, 215 ] ] }, { "pmid": "23639572", "text": "Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner.", "type": "CHEMICAL", "entities": [ "nitric oxide" ], "offsets": [ [ 111, 123 ] ] }, { "pmid": "23640471", "text": "A series of 1-butyl-3-methylimidazolium ([C4MIM](+)) based ILs was investigated by Positron Annihilation Lifetime Spectroscopy (PALS).", "type": "CHEMICAL", "entities": [ "1-butyl-3-methylimidazolium", "[C4MIM](+)" ], "offsets": [ [ 12, 39 ], [ 41, 51 ] ] }, { "pmid": "23640471", "text": "The phase transition and dynamic properties of the ILs [C4MIM][X] with [X](-) =", "type": "CHEMICAL", "entities": [ "C4MIM" ], "offsets": [ [ 56, 61 ] ] }, { "pmid": "23640471", "text": "[Cl](-), [BF4](-), [PF6](-), [OTf](-), [NTf2](-) and [B(hfip)4](-) were reported recently (Yu et al., Phys.", "type": "CHEMICAL", "entities": [ "[Cl](-)", "[BF4](-)", "[PF6](-)", "[OTf](-)", "[NTf2](-)", "[B(hfip)4](-)" ], "offsets": [ [ 0, 7 ], [ 9, 17 ], [ 19, 27 ], [ 29, 37 ], [ 39, 48 ], [ 53, 66 ] ] }, { "pmid": "23640471", "text": "Linear correlations of 〈vh〉 at the \"knee\" temperature (〈vh〉(Tk)) with Vm,scaled and Vvdw gave good results for the [C4MIM](+) series.", "type": "CHEMICAL", "entities": [ "[C4MIM](+)" ], "offsets": [ [ 111, 121 ] ] }, { "pmid": "23640884", "text": "Distinct role of PYK2 in mediating thromboxane generation downstream of both G12/13 and integrin αiibβ in platelets.\n", "type": "CHEMICAL", "entities": [ "thromboxane" ], "offsets": [ [ 35, 46 ] ] }, { "pmid": "23640884", "text": "Proline-rich tyrosine kinase 2 (Pyk2) is activated by various agonists in platelets.", "type": "CHEMICAL", "entities": [ "tyrosine" ], "offsets": [ [ 11, 19 ] ] }, { "pmid": "23640884", "text": "We found that platelet aggregation and secretion in response to 2-MeSADP and AYPGKF were diminished in the presence of Pyk2 inhibitors or in Pyk2-deficient platelets, suggesting that Pyk2 plays a positive regulatory role in platelet functional responses.", "type": "CHEMICAL", "entities": [ "2-MeSADP" ], "offsets": [ [ 62, 70 ] ] }, { "pmid": "23640884", "text": "It has been shown that ADP-, but not thrombin-, induced thromboxane (TxA2) generation depends on integrin signaling.", "type": "CHEMICAL", "entities": [ "ADP", "thromboxane", "TxA2" ], "offsets": [ [ 21, 24 ], [ 54, 65 ], [ 67, 71 ] ] }, { "pmid": "23640884", "text": "Unlike ADP, thrombin activates G12/13 pathways, and G12/13 pathways can substitute for integrin signaling for TxA2 generation.", "type": "CHEMICAL", "entities": [ "ADP", "TxA2" ], "offsets": [ [ 5, 8 ], [ 108, 112 ] ] }, { "pmid": "23640884", "text": "We found that Pyk2 was activated downstream of both G12/13 and integrin-mediated pathways, and both 2-MeSADP- and AYPGKF-induced TxA2 generation was significantly diminished in Pyk2-deficient platelets.", "type": "CHEMICAL", "entities": [ "2-MeSADP", "TxA2" ], "offsets": [ [ 98, 106 ], [ 127, 131 ] ] }, { "pmid": "23640884", "text": "In addition, TxA2 generation induced by co-stimulation of Gi and Gz pathways, which is dependent on integrin signaling, was inhibited by blocking Pyk2.", "type": "CHEMICAL", "entities": [ "TxA2" ], "offsets": [ [ 11, 15 ] ] }, { "pmid": "23640884", "text": "Furthermore, inhibition of 2-MeSADP-induced TxA2 generation by fibrinogen receptor antagonist was not rescued by co-stimulation of G12/13 pathways in the presence of Pyk2 inhibitor.", "type": "CHEMICAL", "entities": [ "2-MeSADP", "TxA2" ], "offsets": [ [ 25, 33 ], [ 42, 46 ] ] }, { "pmid": "23640884", "text": "We conclude that Pyk2 is a common signaling effector downstream of both G12/13 and integrin αIIbβ3 signaling which contributes to thromboxane generation.", "type": "CHEMICAL", "entities": [ "thromboxane" ], "offsets": [ [ 128, 139 ] ] }, { "pmid": "23643725", "text": "Therefore, biofilms were grown in channels for 38 days and then exposed to different concentrations (0-150μgL(-1)) of the herbicide oxyfluorfen for 5 more weeks.", "type": "CHEMICAL", "entities": [ "oxyfluorfen" ], "offsets": [ [ 132, 143 ] ] }, { "pmid": "23643725", "text": "Under control conditions, the AEA of biofilms were found to change throughout time with a significant increase in ascorbate peroxidase (APX) activity during the exponential growth and a more important role of catalase (CAT) and glutathione reductase (GR) activities during the slow growth phase.", "type": "CHEMICAL", "entities": [ "ascorbate", "glutathione" ], "offsets": [ [ 113, 122 ], [ 227, 238 ] ] }, { "pmid": "23643725", "text": "Chronic exposure to oxyfluorfen led to slight variations in AEA, however, the ranges of variability of AEA in controls and exposed communities were similar, highlighting the difficulty of a direct interpretation of AEA values.", "type": "CHEMICAL", "entities": [ "oxyfluorfen" ], "offsets": [ [ 19, 30 ] ] }, { "pmid": "23643725", "text": "After 5 weeks of exposure to oxyfluorfen, no clear effects were observed on chl-a concentration or on the composition of other pigments suggesting that algal group composition was not affected.", "type": "CHEMICAL", "entities": [ "oxyfluorfen", "chl-a" ], "offsets": [ [ 28, 39 ], [ 75, 80 ] ] }, { "pmid": "23643725", "text": "In addition, during acute exposure tests performed at the end of the chronic exposure, biofilms chronically exposed to 75 and 150μgL(-1) oxyfluorfen showed a higher CAT activity than controls.", "type": "CHEMICAL", "entities": [ "oxyfluorfen" ], "offsets": [ [ 136, 147 ] ] }, { "pmid": "23643725", "text": "Chronic exposure to oxyfluorfen provoked then structural changes but also functional changes in the capacity of biofilm CAT activity to respond to a sudden increase in concentration, suggesting a selection of species with higher antioxidant capacity.", "type": "CHEMICAL", "entities": [ "oxyfluorfen" ], "offsets": [ [ 18, 29 ] ] }, { "pmid": "23643745", "text": "A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 109, 117 ] ] }, { "pmid": "23643745", "text": "The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice.", "type": "CHEMICAL", "entities": [ "SCH23390", "raclopride", "amisulpride", "S33084" ], "offsets": [ [ 157, 165 ], [ 175, 185 ], [ 187, 198 ], [ 208, 214 ] ] }, { "pmid": "23643745", "text": "Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride.", "type": "CHEMICAL", "entities": [ "raclopride", "amisulpride" ], "offsets": [ [ 48, 58 ], [ 99, 110 ] ] }, { "pmid": "23643745", "text": "Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it.", "type": "CHEMICAL", "entities": [ "Amisulpride", "pramipexole", "dopamine", "L-3,4-dihydroxyphenylalanine", "raclopride", "S33084" ], "offsets": [ [ 0, 11 ], [ 85, 96 ], [ 101, 109 ], [ 120, 148 ], [ 158, 168 ], [ 174, 180 ] ] }, { "pmid": "23643745", "text": "Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice.", "type": "CHEMICAL", "entities": [ "pramipexole" ], "offsets": [ [ 170, 181 ] ] }, { "pmid": "23643745", "text": "We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine.", "type": "CHEMICAL", "entities": [ "dopamine" ], "offsets": [ [ 95, 103 ] ] }, { "pmid": "23643747", "text": "Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1.\n", "type": "CHEMICAL", "entities": [ "Haloperidol", "dopamine", "cAMP" ], "offsets": [ [ 0, 11 ], [ 82, 90 ], [ 96, 100 ] ] }, { "pmid": "23643747", "text": "Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders.", "type": "CHEMICAL", "entities": [ "haloperidol", "Ser" ], "offsets": [ [ 42, 53 ], [ 119, 122 ] ] }, { "pmid": "23643747", "text": "Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs).", "type": "CHEMICAL", "entities": [ "Ser", "GABA", "dopamine", "haloperidol" ], "offsets": [ [ 40, 43 ], [ 89, 93 ], [ 143, 151 ], [ 18, 29 ] ] }, { "pmid": "23643747", "text": "This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1).", "type": "CHEMICAL", "entities": [ "rapamycin", "rapamycin", "PF470867" ], "offsets": [ [ 29, 38 ], [ 80, 89 ], [ 116, 124 ] ] }, { "pmid": "23643747", "text": "We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1).", "type": "CHEMICAL", "entities": [ "haloperidol", "Ser", "dopamine", "cAMP" ], "offsets": [ [ 33, 44 ], [ 48, 51 ], [ 119, 127 ], [ 133, 137 ] ] }, { "pmid": "23643747", "text": "In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation.", "type": "CHEMICAL", "entities": [ "okadaic acid", "calyculin A", "Ser" ], "offsets": [ [ 66, 78 ], [ 83, 94 ], [ 130, 133 ] ] }, { "pmid": "23643747", "text": "These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs.", "type": "CHEMICAL", "entities": [ "haloperidol", "Ser" ], "offsets": [ [ 24, 35 ], [ 99, 102 ] ] }, { "pmid": "23643747", "text": "They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1.", "type": "CHEMICAL", "entities": [ "Ser" ], "offsets": [ [ 83, 86 ] ] }, { "pmid": "23644191", "text": "Designing, structural elucidation, comparison of DNA binding, cleavage, radical scavenging activity and anticancer activity of copper(I) complex with 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one Schiff base ligand.\n", "type": "CHEMICAL", "entities": [ "copper(I)", "5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one", "Schiff base" ], "offsets": [ [ 127, 136 ], [ 150, 229 ], [ 230, 241 ] ] }, { "pmid": "23644191", "text": "Single crystal X-ray diffraction studies revealed that the copper(I) complex [CuCl(PPh3)L] has a distorted tetrahedral geometry around the central copper(I) ion.", "type": "CHEMICAL", "entities": [ "copper(I)", "[CuCl(PPh3)L]", "copper(I)" ], "offsets": [ [ 58, 67 ], [ 76, 89 ], [ 146, 155 ] ] }, { "pmid": "23644191", "text": "The antioxidative properties showed that the copper(I) complex has a strong radical-scavenging potency than ligands.", "type": "CHEMICAL", "entities": [ "copper(I)" ], "offsets": [ [ 44, 53 ] ] }, { "pmid": "23644213", "text": "These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity.", "type": "CHEMICAL", "entities": [ "rivaroxaban", "Arg-Gly-Asp" ], "offsets": [ [ 103, 114 ], [ 135, 146 ] ] }, { "pmid": "23644213", "text": "Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described.", "type": "CHEMICAL", "entities": [ "1,2,4-oxadiazol-5(4H)-one" ], "offsets": [ [ 119, 144 ] ] }, { "pmid": "23645211", "text": "Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats.\n", "type": "CHEMICAL", "entities": [ "cadmium", "quercetin" ], "offsets": [ [ 21, 28 ], [ 8, 17 ] ] }, { "pmid": "23645211", "text": "The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats.", "type": "CHEMICAL", "entities": [ "quercetin", "cadmium", "Cd" ], "offsets": [ [ 76, 85 ], [ 109, 116 ], [ 118, 120 ] ] }, { "pmid": "23645211", "text": "A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, Cd treated and Cd treated with QE.", "type": "CHEMICAL", "entities": [ "Cd", "Cd" ], "offsets": [ [ 114, 116 ], [ 129, 131 ] ] }, { "pmid": "23645211", "text": "The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd.", "type": "CHEMICAL", "entities": [ "Cd", "cadmium chloride", "CdCl2", "Cd" ], "offsets": [ [ 4, 6 ], [ 54, 70 ], [ 72, 77 ], [ 170, 172 ] ] }, { "pmid": "23645211", "text": "The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to Cd injection, during the study period.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 121, 123 ] ] }, { "pmid": "23645211", "text": "To date, there is no available information on the effect of QE on neuronal injury after Cd exposure.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 88, 90 ] ] }, { "pmid": "23645211", "text": "Rats intoxicated with Cd for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue.", "type": "CHEMICAL", "entities": [ "superoxide", "Cd", "malondialdehyde", "MDA", "glutathione" ], "offsets": [ [ 149, 159 ], [ 22, 24 ], [ 69, 84 ], [ 86, 89 ], [ 171, 182 ] ] }, { "pmid": "23645211", "text": "Administration of QE with Cd significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue.", "type": "CHEMICAL", "entities": [ "Cd", "MDA" ], "offsets": [ [ 26, 28 ], [ 68, 71 ] ] }, { "pmid": "23645211", "text": "The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 95, 97 ] ] }, { "pmid": "23645211", "text": "The caspase-3 immunopositivity was increased in degenerating neurons of the Cd group.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 76, 78 ] ] }, { "pmid": "23645211", "text": "In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 99, 101 ] ] }, { "pmid": "23645211", "text": "We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after Cd exposure in rats.", "type": "CHEMICAL", "entities": [ "Cd" ], "offsets": [ [ 149, 151 ] ] }, { "pmid": "23645248", "text": "Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?\n", "type": "CHEMICAL", "entities": [ "Oestrogen" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "23645248", "text": "Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 59, 68 ] ] }, { "pmid": "23645248", "text": "This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are a target of oestrogen action.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 116, 125 ] ] }, { "pmid": "23645248", "text": "In thyroid stem/progenitor cells derived from nodular goitres the ability of 17beta-oestradiol to induce thyrosphere formation, the expression of oestrogen receptors and the effect of 17beta-oestradiol on growth, expression of marker of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin, sodium iodide symporter expression) were analysed.", "type": "CHEMICAL", "entities": [ "17beta-oestradiol", "sodium iodide", "17beta-oestradiol", "oestrogen" ], "offsets": [ [ 184, 201 ], [ 323, 336 ], [ 77, 94 ], [ 146, 155 ] ] }, { "pmid": "23645248", "text": "17beta-oestradiol induced thyrosphere formation, albeit to lower extent than other growth factors.", "type": "CHEMICAL", "entities": [ "17beta-oestradiol" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "23645248", "text": "Thyroid stem and progenitor cells expressed oestrogen receptor alpha and beta with an 8 time higher expression level of oestrogen receptor alpha mRNA", "type": "CHEMICAL", "entities": [ "oestrogen", "oestrogen" ], "offsets": [ [ 44, 53 ], [ 120, 129 ] ] }, { "pmid": "23645248", "text": "17beta-oestradiol was a potent stimulator of thyroid stem/ progenitor cell growth.", "type": "CHEMICAL", "entities": [ "17beta-oestradiol" ], "offsets": [ [ 0, 17 ] ] }, { "pmid": "23645248", "text": "In contrast, TSH-induced differentiation of progenitor cells, in particular the expression of the sodium iodide symporter, was significantly inhibited by 17beta-oestradiol.", "type": "CHEMICAL", "entities": [ "sodium iodide", "17beta-oestradiol" ], "offsets": [ [ 98, 111 ], [ 154, 171 ] ] }, { "pmid": "23645248", "text": "In conclusion, oestrogen stimulated growth and simultaneously inhibited differentiation of thyroid nodules derived stem/progenitor cells.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "23645248", "text": "From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to a selection of a progeny of growth-prone cells with a decreased differentiation.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 104, 113 ] ] }, { "pmid": "23645360", "text": "Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated).", "type": "CHEMICAL", "entities": [ "lincomycin", "norflurazon" ], "offsets": [ [ 174, 184 ], [ 191, 202 ] ] }, { "pmid": "23645360", "text": "By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings.", "type": "CHEMICAL", "entities": [ "lincomycin" ], "offsets": [ [ 206, 216 ] ] }, { "pmid": "23645360", "text": "The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings.", "type": "CHEMICAL", "entities": [ "norflurazon" ], "offsets": [ [ 67, 78 ] ] }, { "pmid": "23645360", "text": "In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by lincomycin, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings.", "type": "CHEMICAL", "entities": [ "lincomycin" ], "offsets": [ [ 110, 120 ] ] }, { "pmid": "23703578", "text": "Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors.\n", "type": "CHEMICAL", "entities": [ "HMG-CoA" ], "offsets": [ [ 31, 38 ] ] }, { "pmid": "23703578", "text": "The HMG-CoA reductase inhibitors are a class of drugs also known as statins.", "type": "CHEMICAL", "entities": [ "HMG-CoA" ], "offsets": [ [ 4, 11 ] ] }, { "pmid": "23703578", "text": "Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.", "type": "CHEMICAL", "entities": [ "atorvastatin", "fluvastatin", "lovastatin", "pitavastatin", "pravastatin", "rosuvastatin", "simvastatin" ], "offsets": [ [ 39, 51 ], [ 53, 64 ], [ 66, 76 ], [ 78, 90 ], [ 92, 103 ], [ 105, 117 ], [ 122, 133 ] ] }, { "pmid": "23703578", "text": "Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP.", "type": "CHEMICAL", "entities": [ "simvastatin", "lovastatin", "atorvastatin" ], "offsets": [ [ 74, 85 ], [ 87, 97 ], [ 102, 114 ] ] }, { "pmid": "23703578", "text": "All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties.", "type": "CHEMICAL", "entities": [ "nelfinavir", "ritonavir" ], "offsets": [ [ 19, 29 ], [ 68, 77 ] ] }, { "pmid": "23703578", "text": "The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions.", "type": "CHEMICAL", "entities": [ "boceprevir", "telaprevir" ], "offsets": [ [ 12, 22 ], [ 27, 37 ] ] }, { "pmid": "23703578", "text": "Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated.", "type": "CHEMICAL", "entities": [ "boceprevir", "Simvastatin", "lovastatin", "ritonavir", "cobicistat", "telaprevir" ], "offsets": [ [ 230, 240 ], [ 0, 11 ], [ 16, 26 ], [ 141, 150 ], [ 155, 165 ], [ 216, 226 ] ] }, { "pmid": "23703578", "text": "Atorvastatin is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors.", "type": "CHEMICAL", "entities": [ "Atorvastatin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "23742252", "text": "Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.\n", "type": "CHEMICAL", "entities": [ "5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine", "LDK378" ], "offsets": [ [ 143, 259 ], [ 261, 267 ] ] }, { "pmid": "23742252", "text": "The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described.", "type": "CHEMICAL", "entities": [ "LDK378" ], "offsets": [ [ 150, 156 ] ] }, { "pmid": "23742252", "text": "In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684).", "type": "CHEMICAL", "entities": [ "TAE684" ], "offsets": [ [ 221, 227 ] ] }, { "pmid": "2450203", "text": "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture.\n", "type": "CHEMICAL", "entities": [ "Benzodiazepines", "beta carbolines" ], "offsets": [ [ 0, 15 ], [ 25, 40 ] ] }, { "pmid": "2450203", "text": "Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques.", "type": "CHEMICAL", "entities": [ "BDZs", "beta carbolines", "beta CCs", "benzodiazepines" ], "offsets": [ [ 28, 32 ], [ 38, 53 ], [ 55, 63 ], [ 11, 26 ] ] }, { "pmid": "2450203", "text": "Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations.", "type": "CHEMICAL", "entities": [ "BDZs", "diazepam", "clonazepam", "nitrazepam", "lorazepam", "BDZ", "BDZ", "Ro 5-4864", "BDZ", "Ro 15-1788" ], "offsets": [ [ 53, 57 ], [ 59, 67 ], [ 69, 79 ], [ 81, 91 ], [ 96, 105 ], [ 163, 166 ], [ 204, 207 ], [ 219, 228 ], [ 272, 275 ], [ 307, 317 ] ] }, { "pmid": "2450203", "text": "The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials.", "type": "CHEMICAL", "entities": [ "sodium" ], "offsets": [ [ 112, 118 ] ] }, { "pmid": "2450203", "text": "Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs.", "type": "CHEMICAL", "entities": [ "BDZ", "diazepam", "Ro 15-1788", "beta CCs" ], "offsets": [ [ 185, 188 ], [ 120, 128 ], [ 209, 219 ], [ 228, 236 ] ] }, { "pmid": "2450203", "text": "These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation.", "type": "CHEMICAL", "entities": [ "sodium", "BDZs", "beta CCs", "sodium", "BDZ", "BDZs" ], "offsets": [ [ 229, 235 ], [ 73, 77 ], [ 87, 95 ], [ 118, 124 ], [ 167, 170 ], [ 191, 195 ] ] }, { "pmid": "2450203", "text": "We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus.", "type": "CHEMICAL", "entities": [ "BDZs" ], "offsets": [ [ 72, 76 ] ] }, { "pmid": "2521824", "text": "Androgens directly stimulate proliferation of bone cells in vitro.\n", "type": "CHEMICAL", "entities": [ "Androgens" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "2521824", "text": "This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture.", "type": "CHEMICAL", "entities": [ "androgens" ], "offsets": [ [ 76, 85 ] ] }, { "pmid": "2521824", "text": "[3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation.", "type": "CHEMICAL", "entities": [ "[3H]thymidine" ], "offsets": [ [ 0, 13 ] ] }, { "pmid": "2521824", "text": "Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89.", "type": "CHEMICAL", "entities": [ "Dihydrotestosterone", "DHT", "DHT" ], "offsets": [ [ 0, 19 ], [ 21, 24 ], [ 192, 195 ] ] }, { "pmid": "2521824", "text": "Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system.", "type": "CHEMICAL", "entities": [ "steroid", "methenolone", "steroid", "Testosterone", "fluoxymesterone" ], "offsets": [ [ 54, 61 ], [ 67, 78 ], [ 92, 99 ], [ 0, 12 ], [ 14, 29 ] ] }, { "pmid": "2521824", "text": "The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor.", "type": "CHEMICAL", "entities": [ "DHT", "hydroxyflutamide", "cyproterone acetate", "androgen" ], "offsets": [ [ 24, 27 ], [ 74, 90 ], [ 95, 114 ], [ 149, 157 ] ] }, { "pmid": "2521824", "text": "In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens.", "type": "CHEMICAL", "entities": [ "DHT" ], "offsets": [ [ 46, 49 ] ] }, { "pmid": "2521824", "text": "We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an androgen receptor mediated mechanism.", "type": "CHEMICAL", "entities": [ "androgens", "androgen" ], "offsets": [ [ 17, 26 ], [ 190, 198 ] ] }, { "pmid": "2569356", "text": "The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma.\n", "type": "CHEMICAL", "entities": [ "histamine", "terfenadine", "AMP" ], "offsets": [ [ 14, 23 ], [ 52, 63 ], [ 89, 92 ] ] }, { "pmid": "2569356", "text": "Selective histamine-H1 receptor antagonists inhibit adenosine 5'-monophosphate (AMP)-induced bronchoconstriction by greater than 80% when expressed as a percentage inhibition of the FEV1 time-response curve following inhalation of the provocation concentration of AMP required to produce a 20% decrease in FEV1 from baseline (PC20).", "type": "CHEMICAL", "entities": [ "histamine", "AMP", "adenosine 5'-monophosphate", "AMP" ], "offsets": [ [ 10, 19 ], [ 264, 267 ], [ 52, 78 ], [ 80, 83 ] ] }, { "pmid": "2569356", "text": "To investigate this further we have determined that, in eight mild atopic asthmatic subjects, terfenadine (180 mg), administered 3 hr pre-challenge, increases the geometric mean PC20 for histamine from 0.4 (range 0.03-3) mg/ml after placebo, to 20.2 (range 0.6-64) mg/ml following active treatment (P less than 0.0001).", "type": "CHEMICAL", "entities": [ "terfenadine", "histamine" ], "offsets": [ [ 94, 105 ], [ 187, 196 ] ] }, { "pmid": "2569356", "text": "For AMP, the PC20 increased from 9.3 (range 1.0-113.3) mg/ml after placebo, to 150.2 (range 32.1-1177.7) mg/ml with terfenadine (P less than 0.0001).", "type": "CHEMICAL", "entities": [ "AMP", "terfenadine" ], "offsets": [ [ 4, 7 ], [ 116, 127 ] ] }, { "pmid": "2569356", "text": "This 16.2-fold (range, 5.5-47.9) displacement to the right of the AMP concentration-response curve by a selective histamine-H1 receptor antagonist emphasizes the central role of histamine in the airways response to this nucleotide.", "type": "CHEMICAL", "entities": [ "histamine", "histamine", "AMP" ], "offsets": [ [ 114, 123 ], [ 178, 187 ], [ 66, 69 ] ] }, { "pmid": "25802231", "text": "Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia.\n", "type": "CHEMICAL", "entities": [ "Ibrutinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "25802231", "text": "Ibrutinib (Imbruvica(R)) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK.", "type": "CHEMICAL", "entities": [ "Ibrutinib", "tyrosine", "Imbruvica(R)" ], "offsets": [ [ 0, 9 ], [ 106, 114 ], [ 11, 23 ] ] }, { "pmid": "25802231", "text": "Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation.", "type": "CHEMICAL", "entities": [ "ibrutinib" ], "offsets": [ [ 5, 14 ] ] }, { "pmid": "25802231", "text": "This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications.", "type": "CHEMICAL", "entities": [ "ibrutinib" ], "offsets": [ [ 95, 104 ] ] }, { "pmid": "25802231", "text": "In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study).", "type": "CHEMICAL", "entities": [ "ibrutinib" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "25802231", "text": "In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis.", "type": "CHEMICAL", "entities": [ "ibrutinib" ], "offsets": [ [ 13, 22 ] ] }, { "pmid": "25802231", "text": "Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events.", "type": "CHEMICAL", "entities": [ "Ibrutinib" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "25802231", "text": "Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation.", "type": "CHEMICAL", "entities": [ "ibrutinib" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "2859531", "text": "To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 113, 124 ] ] }, { "pmid": "2859531", "text": "[no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years.", "type": "CHEMICAL", "entities": [ "alprenolol", "mepindolol", "(+/-)-[125I]-iodocyanopindolol", "ICYP" ], "offsets": [ [ 47, 57 ], [ 73, 83 ], [ 152, 182 ], [ 184, 188 ] ] }, { "pmid": "2859531", "text": "Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced.", "type": "CHEMICAL", "entities": [ "Propranolol" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "2859531", "text": "After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced.", "type": "CHEMICAL", "entities": [ "propranolol" ], "offsets": [ [ 20, 31 ] ] }, { "pmid": "2859531", "text": "Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment.", "type": "CHEMICAL", "entities": [ "propranolol", "ICYP" ], "offsets": [ [ 113, 124 ], [ 182, 186 ] ] }, { "pmid": "2859531", "text": "Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment.", "type": "CHEMICAL", "entities": [ "Mepindolol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "2859531", "text": "The KD-values for ICYP, however, were not changed.", "type": "CHEMICAL", "entities": [ "ICYP" ], "offsets": [ [ 18, 22 ] ] }, { "pmid": "2859531", "text": "Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density.", "type": "CHEMICAL", "entities": [ "Alprenolol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "2882965", "text": "Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid.\n", "type": "CHEMICAL", "entities": [ "5-aminosalicylic acid", "arachidonic acid", "sulfasalazine" ], "offsets": [ [ 110, 131 ], [ 40, 56 ], [ 92, 105 ] ] }, { "pmid": "2882965", "text": "The possible effect of sulfasalazine, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous arachidonic acid release and metabolism was studied in human polymorphonuclear leukocytes (PMNs).", "type": "CHEMICAL", "entities": [ "acetyl-5-aminosalicylic acid", "arachidonic acid", "sulfasalazine", "5-aminosalicylic acid" ], "offsets": [ [ 65, 93 ], [ 108, 124 ], [ 23, 36 ], [ 38, 59 ] ] }, { "pmid": "2882965", "text": "A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr).", "type": "CHEMICAL", "entities": [ "[1-14C]arachidonic acid" ], "offsets": [ [ 39, 62 ] ] }, { "pmid": "2882965", "text": "After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry.", "type": "CHEMICAL", "entities": [ "calcium ionophore A23187", "eicosanoids" ], "offsets": [ [ 65, 89 ], [ 104, 115 ] ] }, { "pmid": "2882965", "text": "Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and 5-aminosalicylic acid.", "type": "CHEMICAL", "entities": [ "leukotriene B4", "5-hydroxyeicosatetraenoic acid", "5-HETE", "sulfasalazine", "5-aminosalicylic acid" ], "offsets": [ [ 56, 70 ], [ 75, 105 ], [ 107, 113 ], [ 158, 171 ], [ 176, 197 ] ] }, { "pmid": "2882965", "text": "The acetylated derivative of 5-aminosalicylic acid was ineffective.", "type": "CHEMICAL", "entities": [ "acetylated derivative of 5-aminosalicylic acid" ], "offsets": [ [ 4, 50 ] ] }, { "pmid": "2882965", "text": "The present data suggest that inhibition of arachidonic acid lipoxygenation may be an essential action of sulfasalazine and its active metabolite, 5-aminosalicylic acid.", "type": "CHEMICAL", "entities": [ "arachidonic acid", "sulfasalazine", "5-aminosalicylic acid" ], "offsets": [ [ 44, 60 ], [ 106, 119 ], [ 147, 168 ] ] }, { "pmid": "2882965", "text": "Interference with lipoxygenase enzymes, rather than a steroid-like inhibition of arachidonic acid release from intracellular phospholipids, seems to be the mode of action.", "type": "CHEMICAL", "entities": [ "steroid", "arachidonic acid" ], "offsets": [ [ 54, 61 ], [ 81, 97 ] ] }, { "pmid": "2888789", "text": "Bevantolol: a beta-1 adrenoceptor antagonist with unique additional actions.\n", "type": "CHEMICAL", "entities": [ "Bevantolol" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "2888789", "text": "UNLABELLED: Bevantolol is a beta-1 adrenoceptor antagonist that has been shown to be as effective as other beta blockers for the treatment of angina pectoris and hypertension.", "type": "CHEMICAL", "entities": [ "Bevantolol" ], "offsets": [ [ 12, 22 ] ] }, { "pmid": "2888789", "text": "In addition, bevantolol has electrophysiologic effects, including bradycardia by a direct action on the sinus node and a class 1 antiarrhythmic action.", "type": "CHEMICAL", "entities": [ "bevantolol" ], "offsets": [ [ 13, 23 ] ] }, { "pmid": "2888789", "text": "Investigations in humans have shown that although bevantolol has a short half-life, good control of hypertension can be achieved on once-a-day dosing.", "type": "CHEMICAL", "entities": [ "bevantolol" ], "offsets": [ [ 50, 60 ] ] }, { "pmid": "2888789", "text": "SAFETY: bevantolol has remarkably few side effects, does not cause cold extremities, and does not significantly affect glomerular filtration rate in patients with renal impairment.", "type": "CHEMICAL", "entities": [ "bevantolol" ], "offsets": [ [ 8, 18 ] ] }, { "pmid": "2888789", "text": "Evidence has been obtained in man for interaction with alpha-adrenoceptors in the brain; and in the peripheral circulation bevantolol does not, as do other beta blockers, increase peripheral vascular resistance, but reduces it.", "type": "CHEMICAL", "entities": [ "bevantolol" ], "offsets": [ [ 123, 133 ] ] }, { "pmid": "2888789", "text": "It is suggested that all the additional actions of bevantolol can be attributed to a partial agonist action on alpha-adrenoceptors.", "type": "CHEMICAL", "entities": [ "bevantolol" ], "offsets": [ [ 51, 61 ] ] }, { "pmid": "2889803", "text": "Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose alprazolam.\n", "type": "CHEMICAL", "entities": [ "Benzodiazepine", "alprazolam", "triazolobenzodiazepines" ], "offsets": [ [ 0, 14 ], [ 108, 118 ], [ 35, 58 ] ] }, { "pmid": "2889803", "text": "Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics.", "type": "CHEMICAL", "entities": [ "Triazolobenzodiazepines" ], "offsets": [ [ 0, 23 ] ] }, { "pmid": "2889803", "text": "We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam.", "type": "CHEMICAL", "entities": [ "alprazolam", "triazolam", "estazolam" ], "offsets": [ [ 65, 75 ], [ 77, 86 ], [ 92, 101 ] ] }, { "pmid": "2889803", "text": "In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds.", "type": "CHEMICAL", "entities": [ "estazolam", "triazolam", "[3H]Ro15-1788" ], "offsets": [ [ 113, 122 ], [ 127, 136 ], [ 63, 76 ] ] }, { "pmid": "2889803", "text": "Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam.", "type": "CHEMICAL", "entities": [ "Triazolam", "estazolam" ], "offsets": [ [ 0, 9 ], [ 99, 108 ] ] }, { "pmid": "2889803", "text": "At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug.", "type": "CHEMICAL", "entities": [ "alprazolam", "[3H]Ro15-1788" ], "offsets": [ [ 19, 29 ], [ 76, 89 ] ] }, { "pmid": "2889803", "text": "However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions.", "type": "CHEMICAL", "entities": [ "alprazolam" ], "offsets": [ [ 27, 37 ] ] }, { "pmid": "2889803", "text": "The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)", "type": "CHEMICAL", "entities": [ "benzodiazepine", "clonazepam", "alprazolam", "alprazolam" ], "offsets": [ [ 25, 39 ], [ 54, 64 ], [ 83, 93 ], [ 202, 212 ] ] }, { "pmid": "2899826", "text": "Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites.\n", "type": "CHEMICAL", "entities": [ "histamine", "phenothiazine" ], "offsets": [ [ 27, 36 ], [ 60, 73 ] ] }, { "pmid": "2899826", "text": "In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories.", "type": "CHEMICAL", "entities": [ "fluphenazine", "levomepromazine", "perphenazine", "dopamine", "chlorpromazine" ], "offsets": [ [ 47, 59 ], [ 61, 76 ], [ 78, 90 ], [ 125, 133 ], [ 31, 45 ] ] }, { "pmid": "2899826", "text": "The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands.", "type": "CHEMICAL", "entities": [ "histamine", "3H-quinuclidinyl benzilate", "3H-mepyramine" ], "offsets": [ [ 125, 134 ], [ 168, 194 ], [ 199, 212 ] ] }, { "pmid": "2899826", "text": "Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites.", "type": "CHEMICAL", "entities": [ "levomepromazine", "fluphenazine", "perphenazine", "Chlorpromazine" ], "offsets": [ [ 16, 31 ], [ 138, 150 ], [ 152, 164 ], [ 0, 14 ] ] }, { "pmid": "2899826", "text": "Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding.", "type": "CHEMICAL", "entities": [ "Levomepromazine", "fluphenazine", "histamine" ], "offsets": [ [ 0, 15 ], [ 40, 52 ], [ 91, 100 ] ] }, { "pmid": "2899826", "text": "7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system.", "type": "CHEMICAL", "entities": [ "7-Hydroxy levomepromazine", "3-hydroxy levomepromazine", "7-hydroxy fluphenazine", "histamine", "7-hydroxy", "chlorpromazine", "perphenazine" ], "offsets": [ [ 0, 25 ], [ 27, 52 ], [ 57, 79 ], [ 130, 139 ], [ 171, 180 ], [ 196, 210 ], [ 215, 227 ] ] }, { "pmid": "2899826", "text": "Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine.", "type": "CHEMICAL", "entities": [ "histamine", "chlorpromazine", "levomepromazine" ], "offsets": [ [ 6, 15 ], [ 115, 129 ], [ 134, 149 ] ] }, { "pmid": "2922761", "text": "Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K.\n", "type": "CHEMICAL", "entities": [ "Retinoid", "vitamin K" ], "offsets": [ [ 0, 8 ], [ 79, 88 ] ] }, { "pmid": "2922761", "text": "The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects.", "type": "CHEMICAL", "entities": [ "vitamin A" ], "offsets": [ [ 53, 62 ] ] }, { "pmid": "2922761", "text": "Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K.", "type": "CHEMICAL", "entities": [ "vitamin K", "13-cis-retinoic acid", "13cisRA", "retinyl acetate", "ROAc", "N-(4-hydroxyphenyl)retinamide", "4HPR", "vitamin K", "menadione", "vitamin K3", "menadione", "vitamin K" ], "offsets": [ [ 70, 79 ], [ 124, 144 ], [ 146, 153 ], [ 156, 171 ], [ 173, 177 ], [ 184, 213 ], [ 215, 219 ], [ 300, 309 ], [ 368, 377 ], [ 387, 397 ], [ 437, 446 ], [ 486, 495 ] ] }, { "pmid": "2922761", "text": "The retinoids had no effect on prothrombin times of animals fed the supplemented diet.", "type": "CHEMICAL", "entities": [ "retinoids" ], "offsets": [ [ 4, 13 ] ] }, { "pmid": "2922761", "text": "When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times.", "type": "CHEMICAL", "entities": [ "menadione", "4HPR" ], "offsets": [ [ 5, 14 ], [ 51, 55 ] ] }, { "pmid": "2922761", "text": "13cisRA-dosed animals showed no change in prothrombin times.", "type": "CHEMICAL", "entities": [ "13cisRA" ], "offsets": [ [ 0, 7 ] ] }, { "pmid": "2922761", "text": "In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing.", "type": "CHEMICAL", "entities": [ "ROAc" ], "offsets": [ [ 17, 21 ] ] }, { "pmid": "2922761", "text": "In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels.", "type": "CHEMICAL", "entities": [ "13cisRA", "ROAc" ], "offsets": [ [ 33, 40 ], [ 45, 49 ] ] }, { "pmid": "2922761", "text": "In contrast, 4HPR administered at the highest dose induced only one fracture in one animal.", "type": "CHEMICAL", "entities": [ "4HPR" ], "offsets": [ [ 13, 17 ] ] }, { "pmid": "2922761", "text": "For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 8, 16 ] ] }, { "pmid": "2922761", "text": "The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths.", "type": "CHEMICAL", "entities": [ "4HPR", "ROAc", "13cisRA" ], "offsets": [ [ 24, 28 ], [ 42, 46 ], [ 60, 67 ] ] }, { "pmid": "2922761", "text": "Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet.", "type": "CHEMICAL", "entities": [ "retinoid", "vitamin K" ], "offsets": [ [ 21, 29 ], [ 116, 125 ] ] }, { "pmid": "2922761", "text": "13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects.", "type": "CHEMICAL", "entities": [ "13cisRA", "ROAc", "4HPR", "retinoid" ], "offsets": [ [ 0, 7 ], [ 12, 16 ], [ 26, 30 ], [ 120, 128 ] ] }, { "pmid": "2922761", "text": "In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc.", "type": "CHEMICAL", "entities": [ "13cisRA", "4HPR", "ROAc" ], "offsets": [ [ 75, 82 ], [ 86, 90 ], [ 118, 122 ] ] }, { "pmid": "2922761", "text": "For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals.", "type": "CHEMICAL", "entities": [ "ROAc" ], "offsets": [ [ 134, 138 ] ] }, { "pmid": "2922761", "text": "Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase.", "type": "CHEMICAL", "entities": [ "retinoid" ], "offsets": [ [ 51, 59 ] ] }, { "pmid": "2982865", "text": "The existence of multiple affinity states for the opiate receptor in neuroblastoma x glioma NG108-15 hybrid cells has been demonstrated by competition binding studies with tritiated diprenorphine and [D-Ala2, D-Leu5]enkephalin (DADLE).", "type": "CHEMICAL", "entities": [ "[D-Ala2, D-Leu5]enkephalin", "DADLE", "tritiated diprenorphine" ], "offsets": [ [ 200, 226 ], [ 228, 233 ], [ 172, 195 ] ] }, { "pmid": "2982865", "text": "In the presence of 10 mM Mg2+, all receptors exist in a high affinity state with Kd = 1.88 +/- 0.16 nM. Addition of 10 microM guanyl-5'-yl imidodiphosphate (Gpp(NH)p) decreased the affinity of DADLE to Kd = 8.08 +/- 0.93 nM. However, in the presence of 100 mM Na+, which is required for opiate inhibition of adenylate cyclase activity, analysis of competition binding data revealed three sites: the first, consisting of 17.5% of total receptor population has a Kd = 0.38 +/- 0.18 nM; the second, 50.6% of the population, has a Kd = 6.8 +/- 2.2 nM; and the third, 31.9% of the population, has a Kd of 410 +/-", "type": "CHEMICAL", "entities": [ "Mg2+", "guanyl-5'-yl imidodiphosphate", "Gpp(NH)p", "DADLE", "Na+", "adenylate" ], "offsets": [ [ 25, 29 ], [ 126, 155 ], [ 157, 165 ], [ 193, 198 ], [ 260, 263 ], [ 308, 317 ] ] }, { "pmid": "2982865", "text": "110 nM. Thus, in the presence of sodium, a high affinity complex between receptor (R), GTP binding component (Ni), and ligand (L) was formed which was different from that formed in the absence of sodium.", "type": "CHEMICAL", "entities": [ "sodium", "sodium", "GTP" ], "offsets": [ [ 196, 202 ], [ 33, 39 ], [ 87, 90 ] ] }, { "pmid": "2982865", "text": "These multiple affinity states of receptor in the hybrid cells are agonist-specific, and the percentage of total opiate receptor in high affinity state is relatively constant in various concentrations of Na+.", "type": "CHEMICAL", "entities": [ "Na+" ], "offsets": [ [ 204, 207 ] ] }, { "pmid": "2982865", "text": "Multiple affinity states of opiate receptor can be demonstrated further by Scatchard analysis of saturation binding studies with [3H]DADLE.", "type": "CHEMICAL", "entities": [ "[3H]DADLE" ], "offsets": [ [ 129, 138 ] ] }, { "pmid": "2982865", "text": "In the presence of Mg2+, or Gpp(NH)p, analysis of [3H]DADLE binding demonstrates that opiate receptor can exist in a single affinity state, with apparent Kd values of [3H]DADLE in 10 mM Mg2+ = 1.75 +/- 0.28 nM", "type": "CHEMICAL", "entities": [ "Mg2+", "Gpp(NH)p", "[3H]DADLE", "[3H]DADLE" ], "offsets": [ [ 19, 23 ], [ 28, 36 ], [ 50, 59 ], [ 167, 176 ] ] }, { "pmid": "2982865", "text": "and in 10 microM Gpp(NH)p = 0.85 +/- 0.12 nM. There is a reduction of Bmax value from 0.19 +/- 0.02 nM in the presence of Mg2+ to 0.14 +/- 0.03 nM in the presence of Gpp(NH)p.", "type": "CHEMICAL", "entities": [ "Mg2+", "Gpp(NH)p", "Gpp(NH)p" ], "offsets": [ [ 122, 126 ], [ 166, 174 ], [ 17, 25 ] ] }, { "pmid": "2982865", "text": "In the presence of 100 mM Na+, Scatchard analysis of saturation binding of [3H]DADLE reveals nonlinear plots; two-site analysis of the curves yields Kd = 0.43 +/- 0.09 and 7.9 +/- 3.2 nM. These Kd values are analogous to that obtained with competition binding studies.", "type": "CHEMICAL", "entities": [ "Na+", "[3H]DADLE" ], "offsets": [ [ 26, 29 ], [ 75, 84 ] ] }, { "pmid": "2982865", "text": "Again, this conversion of single site binding Scatchard plots to multiple sites binding plots in the presence of Na+ is restricted to 3H-agonist binding only.(ABSTRACT TRUNCATED AT 400 WORDS)", "type": "CHEMICAL", "entities": [ "Na+", "3H" ], "offsets": [ [ 113, 116 ], [ 134, 136 ] ] }, { "pmid": "3004501", "text": "Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor.\n", "type": "CHEMICAL", "entities": [ "diethylcarbamazine", "piriprost", "leukotriene", "diethylcarbamazine" ], "offsets": [ [ 117, 135 ], [ 140, 149 ], [ 18, 29 ], [ 75, 93 ] ] }, { "pmid": "3004501", "text": "Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM).", "type": "CHEMICAL", "entities": [ "sulfidopeptide leukotrienes", "Diethylcarbamazine" ], "offsets": [ [ 46, 73 ], [ 0, 18 ] ] }, { "pmid": "3004501", "text": "Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione.", "type": "CHEMICAL", "entities": [ "leukotriene C4", "LTC4", "LTA4", "glutathione" ], "offsets": [ [ 55, 69 ], [ 71, 75 ], [ 193, 197 ], [ 201, 212 ] ] }, { "pmid": "3004501", "text": "By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor.", "type": "CHEMICAL", "entities": [ "LTA4", "LTC4" ], "offsets": [ [ 31, 35 ], [ 39, 43 ] ] }, { "pmid": "3004501", "text": "The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4.", "type": "CHEMICAL", "entities": [ "leukotriene C", "LTA4", "LTA4", "LTA4" ], "offsets": [ [ 31, 44 ], [ 102, 106 ], [ 174, 178 ], [ 207, 211 ] ] }, { "pmid": "3004501", "text": "Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4.", "type": "CHEMICAL", "entities": [ "leukotriene C", "diethylcarbamazine", "LTA4" ], "offsets": [ [ 53, 66 ], [ 90, 108 ], [ 141, 145 ] ] }, { "pmid": "3004501", "text": "In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells.", "type": "CHEMICAL", "entities": [ "diethylcarbamazine", "piriprost", "U-60,257", "6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1", "sulfidopeptide leuktrienes", "leukotriene" ], "offsets": [ [ 15, 33 ], [ 35, 44 ], [ 46, 54 ], [ 56, 112 ], [ 147, 173 ], [ 251, 262 ] ] }, { "pmid": "3004501", "text": "On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine.", "type": "CHEMICAL", "entities": [ "piriprost", "leukotriene", "diethylcarbamazine" ], "offsets": [ [ 41, 50 ], [ 101, 112 ], [ 185, 203 ] ] }, { "pmid": "3004501", "text": "These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction.", "type": "CHEMICAL", "entities": [ "LTA4", "leukotriene C", "piriprost", "diethylcarbamazine", "leukotriene" ], "offsets": [ [ 281, 285 ], [ 293, 306 ], [ 63, 72 ], [ 77, 95 ], [ 104, 115 ] ] }, { "pmid": "3089818", "text": "Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation.\n", "type": "CHEMICAL", "entities": [ "lactose" ], "offsets": [ [ 28, 35 ] ] }, { "pmid": "3089818", "text": "Changes in intestinal permeability and lactose hydrolysis have been investigated in three adults and fifteen infants with acute rotaviral gastroenteritis by differential sugar absorption.", "type": "CHEMICAL", "entities": [ "lactose" ], "offsets": [ [ 39, 46 ] ] }, { "pmid": "3089818", "text": "The method involves chromatographic measurement of urinary lactose, lactulose and L-rhamnose excretion following combined ingestion in an iso-osmolar test solution.", "type": "CHEMICAL", "entities": [ "lactose", "lactulose", "L-rhamnose" ], "offsets": [ [ 59, 66 ], [ 68, 77 ], [ 82, 92 ] ] }, { "pmid": "3089818", "text": "All patients had abnormal intestinal permeability indicated by raised urine lactulose/L-rhamnose excretion, ratio of percentages recovered in 5 h, of 0.462 (0.100-1.227) mean and range, compared with 0.027 (0.008-0.052) for healthy controls (P less than 0.001).", "type": "CHEMICAL", "entities": [ "lactulose", "L-rhamnose" ], "offsets": [ [ 76, 85 ], [ 86, 96 ] ] }, { "pmid": "3089818", "text": "Ten patients also had urinary lactose/lactulose excretion ratios raised above the normal range (0.014-0.41, mean 0.258) during their acute illness, indicating impaired intestinal lactose hydrolysis.", "type": "CHEMICAL", "entities": [ "lactose", "lactulose", "lactose" ], "offsets": [ [ 30, 37 ], [ 38, 47 ], [ 179, 186 ] ] }, { "pmid": "3089818", "text": "The test procedure was verified with respect to intestinal lactose hydrolysis by demonstrating a linear relationship between lactose/lactulose excretion and log jejunal mucosal lactase activity by in vitro assay (R2 = 0.95) in a further group of subjects.", "type": "CHEMICAL", "entities": [ "lactose", "lactose", "lactulose" ], "offsets": [ [ 59, 66 ], [ 125, 132 ], [ 133, 142 ] ] }, { "pmid": "3089818", "text": "Differential lactose/lactulose/L-rhamnose absorption provides a non-invasive and sensitive index of small intestinal integrity of value for the interpretation of prolonged or otherwise complicated enteritis and the distinction of primary secondary intestinal lactase deficiency.", "type": "CHEMICAL", "entities": [ "lactose", "lactulose", "L-rhamnose" ], "offsets": [ [ 13, 20 ], [ 21, 30 ], [ 31, 41 ] ] }, { "pmid": "3134891", "text": "Characteristics of the binding of phenoxybenzamine to calmodulin.\n", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 34, 50 ] ] }, { "pmid": "3134891", "text": "To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "phenoxybenzamine" ], "offsets": [ [ 64, 80 ], [ 112, 128 ] ] }, { "pmid": "3134891", "text": "This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin.", "type": "CHEMICAL", "entities": [ "phenothiazines" ], "offsets": [ [ 85, 99 ] ] }, { "pmid": "3134891", "text": "It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 46, 62 ] ] }, { "pmid": "3134891", "text": "It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0.", "type": "CHEMICAL", "entities": [ "calcium" ], "offsets": [ [ 82, 89 ] ] }, { "pmid": "3134891", "text": "The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "penfluridol", "pimozide", "spiroperidol", "phenoxybenzamine" ], "offsets": [ [ 18, 34 ], [ 162, 173 ], [ 175, 183 ], [ 188, 200 ], [ 227, 243 ] ] }, { "pmid": "3134891", "text": "However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly.", "type": "CHEMICAL", "entities": [ "phenothiazines", "phenoxybenzamine" ], "offsets": [ [ 55, 69 ], [ 85, 101 ] ] }, { "pmid": "3134891", "text": "The binding of phenoxybenzamine to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "prazosin", "yohimbine", "clonidine" ], "offsets": [ [ 15, 31 ], [ 113, 121 ], [ 123, 132 ], [ 137, 146 ] ] }, { "pmid": "3134891", "text": "In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "calcium" ], "offsets": [ [ 13, 29 ], [ 50, 57 ] ] }, { "pmid": "3134891", "text": "The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 33, 49 ] ] }, { "pmid": "3320565", "text": "Pharmacological and clinical studies of the antiandrogen Anandron.\n", "type": "CHEMICAL", "entities": [ "Anandron" ], "offsets": [ [ 57, 65 ] ] }, { "pmid": "3320565", "text": "This paper summarizes the animal and human studies with Anandron available at the time of the meeting.", "type": "CHEMICAL", "entities": [ "Anandron" ], "offsets": [ [ 56, 64 ] ] }, { "pmid": "3320565", "text": "The following was demonstrated in the rat and confirmed in man: interaction of Anandron with the prostatic androgen receptor, antiandrogen activity against testosterone (in particular against the early transient rise induced by LHRH analogs) and adrenal androgens.", "type": "CHEMICAL", "entities": [ "Anandron", "androgen", "testosterone", "androgens" ], "offsets": [ [ 79, 87 ], [ 107, 115 ], [ 156, 168 ], [ 254, 263 ] ] }, { "pmid": "3320565", "text": "Thus, as shown in 4 different double blind studies performed in stage D2 prostrate cancer patients, the combination of Anandron with surgical or chemical castration enhanced the beneficial effects of castration alone and thus seems a step forward in the hormonal treatment of prostatic carcinoma.", "type": "CHEMICAL", "entities": [ "Anandron" ], "offsets": [ [ 119, 127 ] ] }, { "pmid": "3588607", "text": "Adenosine receptors: development of selective agonists and antagonists.\n", "type": "CHEMICAL", "entities": [ "Adenosine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "3588607", "text": "Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase.", "type": "CHEMICAL", "entities": [ "adenylate", "Adenosine", "adenosine" ], "offsets": [ [ 181, 190 ], [ 0, 9 ], [ 92, 101 ] ] }, { "pmid": "3588607", "text": "The involvement of adenylate cyclase in these responses remains unresolved.", "type": "CHEMICAL", "entities": [ "adenylate" ], "offsets": [ [ 19, 28 ] ] }, { "pmid": "3588607", "text": "Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors.", "type": "CHEMICAL", "entities": [ "Adenosine", "N6" ], "offsets": [ [ 0, 9 ], [ 36, 38 ] ] }, { "pmid": "3588607", "text": "The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity.", "type": "CHEMICAL", "entities": [ "adenosine", "N6", "phenyl" ], "offsets": [ [ 21, 30 ], [ 64, 66 ], [ 146, 152 ] ] }, { "pmid": "3588607", "text": "A series of para-substituted N6-phenyladenosines have been synthesized based on a \"functionalized congener\" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain.", "type": "CHEMICAL", "entities": [ "N6-phenyladenosines", "amine", "carboxylic acid" ], "offsets": [ [ 29, 48 ], [ 166, 171 ], [ 175, 190 ] ] }, { "pmid": "3588607", "text": "Certain of the adenosine conjugates are highly selective for A1 receptors.", "type": "CHEMICAL", "entities": [ "adenosine" ], "offsets": [ [ 15, 24 ] ] }, { "pmid": "3588607", "text": "Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors.", "type": "CHEMICAL", "entities": [ "Xanthines", "adenosine", "adenosine" ], "offsets": [ [ 0, 9 ], [ 40, 49 ], [ 128, 137 ] ] }, { "pmid": "3588607", "text": "Caffeine and theophylline are virtually non-selective for A2 and A2 receptors.", "type": "CHEMICAL", "entities": [ "Caffeine", "theophylline" ], "offsets": [ [ 0, 8 ], [ 13, 25 ] ] }, { "pmid": "3588607", "text": "Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety.", "type": "CHEMICAL", "entities": [ "n-propyl", "alkyl", "xanthines", "8-phenyl", "methyl", "theophylline" ], "offsets": [ [ 54, 62 ], [ 73, 78 ], [ 93, 102 ], [ 173, 181 ], [ 19, 25 ], [ 36, 48 ] ] }, { "pmid": "3588607", "text": "Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity.", "type": "CHEMICAL", "entities": [ "1,3-dialkyl-8-phenyl xanthines", "aryl", "sulfo", "carboxy" ], "offsets": [ [ 5, 35 ], [ 83, 87 ], [ 110, 115 ], [ 119, 126 ] ] }, { "pmid": "3588607", "text": "A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the \"functionalized congener\" approach.", "type": "CHEMICAL", "entities": [ "1,3-dipropyl-8-phenylxanthines" ], "offsets": [ [ 33, 63 ] ] }, { "pmid": "3588607", "text": "Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models.", "type": "CHEMICAL", "entities": [ "8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine" ], "offsets": [ [ 22, 74 ] ] }, { "pmid": "3588607", "text": "Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors.", "type": "CHEMICAL", "entities": [ "caffeine", "methyl", "propyl" ], "offsets": [ [ 19, 27 ], [ 41, 47 ], [ 110, 116 ] ] }, { "pmid": "3588607", "text": "The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.", "type": "CHEMICAL", "entities": [ "adenosine", "xanthine", "adenosine" ], "offsets": [ [ 27, 36 ], [ 51, 59 ], [ 108, 117 ] ] }, { "pmid": "3735252", "text": "Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers.\n", "type": "CHEMICAL", "entities": [ "gossypol" ], "offsets": [ [ 66, 74 ] ] }, { "pmid": "3735252", "text": "The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro.", "type": "CHEMICAL", "entities": [ "(+)-, (-)-, (+/-)-gossypol", "(+/-)-gossypol acetic acid" ], "offsets": [ [ 25, 51 ], [ 56, 82 ] ] }, { "pmid": "3735252", "text": "Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster.", "type": "CHEMICAL", "entities": [ "Gossypol acetic acid" ], "offsets": [ [ 0, 20 ] ] }, { "pmid": "3735252", "text": "LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol.", "type": "CHEMICAL", "entities": [ "gossypol" ], "offsets": [ [ 78, 86 ] ] }, { "pmid": "3735252", "text": "Gossypol and its isomers were non-competitive inhibitors of human and hamster LDH-X with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate.", "type": "CHEMICAL", "entities": [ "Gossypol", "NADH", "alpha-ketobutyrate" ], "offsets": [ [ 0, 8 ], [ 113, 117 ], [ 246, 264 ] ] }, { "pmid": "3735252", "text": "Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster LDH-X from gossypol.", "type": "CHEMICAL", "entities": [ "gossypol", "poly-L-lysine", "lysine" ], "offsets": [ [ 110, 118 ], [ 42, 55 ], [ 64, 70 ] ] }, { "pmid": "3917545", "text": "Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone.", "type": "CHEMICAL", "entities": [ "prostaglandin H", "prostacyclin", "phenylbutazone" ], "offsets": [ [ 16, 31 ], [ 45, 57 ], [ 70, 84 ] ] }, { "pmid": "3917545", "text": "Phenylbutazone (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS).", "type": "CHEMICAL", "entities": [ "PB", "Phenylbutazone", "prostaglandin H" ], "offsets": [ [ 16, 18 ], [ 0, 14 ], [ 125, 140 ] ] }, { "pmid": "3917545", "text": "Most reducing cofactors for the peroxidase protect PHS and prostacyclin synthase from inactivation by hydroperoxides.", "type": "CHEMICAL", "entities": [ "prostacyclin", "hydroperoxides" ], "offsets": [ [ 59, 71 ], [ 102, 116 ] ] }, { "pmid": "3917545", "text": "PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation.", "type": "CHEMICAL", "entities": [ "PB", "hydroperoxide" ], "offsets": [ [ 0, 2 ], [ 71, 84 ] ] }, { "pmid": "3917545", "text": "Using ram seminal vesicle microsomes as a source of PHS and prostacyclin synthase, we have examined the interaction of PB and exogenous hydroperoxides.", "type": "CHEMICAL", "entities": [ "prostacyclin", "PB", "hydroperoxides" ], "offsets": [ [ 60, 72 ], [ 119, 121 ], [ 136, 150 ] ] }, { "pmid": "3917545", "text": "Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of PHS is markedly increased in the presence of 100 microM H2O2.", "type": "CHEMICAL", "entities": [ "14C-labeled arachidonic acid", "PB", "H2O2" ], "offsets": [ [ 46, 74 ], [ 104, 106 ], [ 189, 193 ] ] }, { "pmid": "3917545", "text": "This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB.", "type": "CHEMICAL", "entities": [ "PB" ], "offsets": [ [ 42, 44 ] ] }, { "pmid": "3917545", "text": "Prostacyclin synthase is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM.", "type": "CHEMICAL", "entities": [ "Prostacyclin", "PB", "PB", "H2O2" ], "offsets": [ [ 0, 12 ], [ 144, 146 ], [ 77, 79 ], [ 84, 88 ] ] }, { "pmid": "3917545", "text": "This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase.", "type": "CHEMICAL", "entities": [ "PB", "H2O2", "PGH2", "arachidonic acid", "prostacyclin" ], "offsets": [ [ 5, 7 ], [ 13, 17 ], [ 65, 69 ], [ 96, 112 ], [ 185, 197 ] ] }, { "pmid": "3917545", "text": "As PB undergoes peroxide-dependent co-oxygenation catalyzed by PHS, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of PHS and prostacyclin synthase.", "type": "CHEMICAL", "entities": [ "peroxide", "PB", "prostacyclin", "PB" ], "offsets": [ [ 16, 24 ], [ 118, 120 ], [ 208, 220 ], [ 3, 5 ] ] }, { "pmid": "3917545", "text": "Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal.", "type": "CHEMICAL", "entities": [ "Nafazatrom", "PB", "PB", "H2O2" ], "offsets": [ [ 0, 10 ], [ 39, 41 ], [ 84, 86 ], [ 91, 95 ] ] }, { "pmid": "3994963", "text": "Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and calmodulin.\n", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 81, 97 ] ] }, { "pmid": "3994963", "text": "Phenoxybenzamine, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels calmodulin in the presence of calcium.", "type": "CHEMICAL", "entities": [ "Phenoxybenzamine", "calcium", "(chloroethyl)amine" ], "offsets": [ [ 0, 16 ], [ 125, 132 ], [ 62, 80 ] ] }, { "pmid": "3994963", "text": "The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "chlorpromazine" ], "offsets": [ [ 41, 55 ] ] }, { "pmid": "3994963", "text": "Adducts of calmodulin and phenoxybenzamine were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine" ], "offsets": [ [ 26, 42 ] ] }, { "pmid": "3994963", "text": "Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of phenoxybenzamine incorporation into each adduct.", "type": "CHEMICAL", "entities": [ "cyclic nucleotide", "chlorpromazine", "phenoxybenzamine", "phenoxybenzamine" ], "offsets": [ [ 46, 63 ], [ 121, 135 ], [ 162, 178 ], [ 231, 247 ] ] }, { "pmid": "3994963", "text": "Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained phenoxybenzamine label.", "type": "CHEMICAL", "entities": [ "phenoxybenzamine", "phenoxybenzamine" ], "offsets": [ [ 56, 72 ], [ 178, 194 ] ] }, { "pmid": "6150080", "text": "Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane.\n", "type": "CHEMICAL", "entities": [ "Amine", "clorgyline", "semicarbazide" ], "offsets": [ [ 0, 5 ], [ 104, 114 ], [ 79, 92 ] ] }, { "pmid": "6150080", "text": "Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells.", "type": "CHEMICAL", "entities": [ "Amine" ], "offsets": [ [ 0, 5 ] ] }, { "pmid": "6150080", "text": "It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue.", "type": "CHEMICAL", "entities": [ "monoamine", "semicarbazide", "clorgyline" ], "offsets": [ [ 50, 59 ], [ 87, 100 ], [ 111, 121 ] ] }, { "pmid": "6150080", "text": "In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I.", "type": "CHEMICAL", "entities": [ "borate" ], "offsets": [ [ 68, 74 ] ] }, { "pmid": "6150080", "text": "Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine.", "type": "CHEMICAL", "entities": [ "tryptamine" ], "offsets": [ [ 85, 95 ] ] }, { "pmid": "6150080", "text": "Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine.", "type": "CHEMICAL", "entities": [ "tyramine", "benzylamine" ], "offsets": [ [ 88, 96 ], [ 101, 112 ] ] }, { "pmid": "6150080", "text": "Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide.", "type": "CHEMICAL", "entities": [ "hydralazine", "semicarbazide" ], "offsets": [ [ 115, 126 ], [ 164, 177 ] ] }, { "pmid": "6311012", "text": "Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death.\n", "type": "CHEMICAL", "entities": [ "Penicillin", "amdinocillin" ], "offsets": [ [ 0, 10 ], [ 40, 52 ] ] }, { "pmid": "6311012", "text": "The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis.", "type": "CHEMICAL", "entities": [ "penicillins" ], "offsets": [ [ 16, 27 ] ] }, { "pmid": "6311012", "text": "These proteins have been designated penicillin-binding proteins.", "type": "CHEMICAL", "entities": [ "penicillin" ], "offsets": [ [ 36, 46 ] ] }, { "pmid": "6311012", "text": "They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6.", "type": "CHEMICAL", "entities": [ "acrylamide", "14C-labeled penicillin G", "penicillin" ], "offsets": [ [ 64, 74 ], [ 122, 146 ], [ 212, 222 ] ] }, { "pmid": "6311012", "text": "Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs.", "type": "CHEMICAL", "entities": [ "penicillin", "penicillin", "penicillin", "penicillin" ], "offsets": [ [ 72, 82 ], [ 124, 134 ], [ 192, 202 ], [ 255, 265 ] ] }, { "pmid": "6311012", "text": "Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme.", "type": "CHEMICAL", "entities": [ "Penicillin", "penicillin" ], "offsets": [ [ 0, 10 ], [ 74, 84 ] ] }, { "pmid": "6311012", "text": "Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival.", "type": "CHEMICAL", "entities": [ "Penicillin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "6311012", "text": "Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments.", "type": "CHEMICAL", "entities": [ "penicillin", "penicillin", "penicillins", "penicillin" ], "offsets": [ [ 84, 94 ], [ 150, 160 ], [ 11, 22 ], [ 26, 36 ] ] }, { "pmid": "6311012", "text": "Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2.", "type": "CHEMICAL", "entities": [ "Amdinocillin", "beta-amidino penicillanic acid", "penicillin" ], "offsets": [ [ 0, 12 ], [ 18, 48 ], [ 87, 97 ] ] }, { "pmid": "6311012", "text": "The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins.", "type": "CHEMICAL", "entities": [ "ampicillin", "penicillins" ], "offsets": [ [ 48, 58 ], [ 129, 140 ] ] }, { "pmid": "6311012", "text": "Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa.", "type": "CHEMICAL", "entities": [ "Amdinocillin", "indole" ], "offsets": [ [ 0, 12 ], [ 81, 87 ] ] }, { "pmid": "6311012", "text": "Amdinocillin produces spherical bacterial cells that eventually lyse.", "type": "CHEMICAL", "entities": [ "Amdinocillin" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "6311012", "text": "This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall.", "type": "CHEMICAL", "entities": [ "penicillins", "ampicillin", "carbenicillin", "cephalosporins", "cefazolin", "cefamandole", "cefoxitin" ], "offsets": [ [ 42, 53 ], [ 63, 73 ], [ 75, 88 ], [ 113, 127 ], [ 129, 138 ], [ 140, 151 ], [ 156, 165 ] ] }, { "pmid": "6311012", "text": "Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections.", "type": "CHEMICAL", "entities": [ "Amdinocillin", "beta-lactams" ], "offsets": [ [ 0, 12 ], [ 146, 158 ] ] }, { "pmid": "6319437", "text": "Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides.\n", "type": "CHEMICAL", "entities": [ "naphthalene sulfonamides", "phenothiazines" ], "offsets": [ [ 104, 128 ], [ 85, 99 ] ] }, { "pmid": "6319437", "text": "We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts.", "type": "CHEMICAL", "entities": [ "naphthalenesulfonamides", "N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide", "W-7", "phenothiazines", "trifluoperazine", "TFP" ], "offsets": [ [ 27, 50 ], [ 58, 108 ], [ 110, 113 ], [ 120, 134 ], [ 142, 157 ], [ 159, 162 ] ] }, { "pmid": "6319437", "text": "The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed.", "type": "CHEMICAL", "entities": [ "W-7" ], "offsets": [ [ 130, 133 ] ] }, { "pmid": "6319437", "text": "W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane.", "type": "CHEMICAL", "entities": [ "W-7", "W-7" ], "offsets": [ [ 0, 3 ], [ 179, 182 ] ] }, { "pmid": "6319437", "text": "Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors.", "type": "CHEMICAL", "entities": [ "TFP", "W-7" ], "offsets": [ [ 11, 14 ], [ 19, 22 ] ] }, { "pmid": "6319437", "text": "Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin.", "type": "CHEMICAL", "entities": [ "W-7", "rhodamine", "W-7", "rhodamine", "Promethazine", "phenothiazine", "TFP" ], "offsets": [ [ 433, 436 ], [ 584, 593 ], [ 641, 644 ], [ 890, 899 ], [ 128, 140 ], [ 144, 157 ], [ 224, 227 ] ] }, { "pmid": "6621777", "text": "The effect of various amino acids and drugs on the para- and meta-hydroxyphenylacetic acid concentrations in the mouse caudate nucleus.\n", "type": "CHEMICAL", "entities": [ "amino acids", "para- and meta-hydroxyphenylacetic acid" ], "offsets": [ [ 22, 33 ], [ 51, 90 ] ] }, { "pmid": "6621777", "text": "Injection of L-p-tyrosine (800 mg/kg, 2 h) increased the mouse striatal para-hydroxyphenylacetic acid (p-HPAA) concentrations.", "type": "CHEMICAL", "entities": [ "para-hydroxyphenylacetic acid", "p-HPAA", "L-p-tyrosine" ], "offsets": [ [ 72, 101 ], [ 103, 109 ], [ 13, 25 ] ] }, { "pmid": "6621777", "text": "A smaller dose of D,L-m-tyrosine (20 mg/kg, 2 h) produced a larger increase in mouse striatal meta-hydroxyphenylacetic acid (m-HPAA) concentrations.", "type": "CHEMICAL", "entities": [ "D,L-m-tyrosine", "meta-hydroxyphenylacetic acid", "m-HPAA" ], "offsets": [ [ 18, 32 ], [ 94, 123 ], [ 125, 131 ] ] }, { "pmid": "6621777", "text": "The administration of L-phenylalanine to mice caused a slight increase in the p-HPAA concentration in the corpus striatum after 2 h while a larger dose of L-phenylalanine (800 mg/kg) produced a greater increase.", "type": "CHEMICAL", "entities": [ "p-HPAA", "L-phenylalanine", "L-phenylalanine" ], "offsets": [ [ 78, 84 ], [ 155, 170 ], [ 22, 37 ] ] }, { "pmid": "6621777", "text": "Eight hours following L-phenylalanine injection, p-HPAA concentrations were still elevated.", "type": "CHEMICAL", "entities": [ "L-phenylalanine", "p-HPAA" ], "offsets": [ [ 22, 37 ], [ 49, 55 ] ] }, { "pmid": "6621777", "text": "With D-phenylalanine a significant increase was observed at eight hours after drug administration.", "type": "CHEMICAL", "entities": [ "D-phenylalanine" ], "offsets": [ [ 5, 20 ] ] }, { "pmid": "6621777", "text": "Two drugs which reduce dopamine synthesis, alpha-methyl-para-tyrosine and apomorphine, decreased m-HPAA striatal concentrations without affecting p-HPAA concentrations.", "type": "CHEMICAL", "entities": [ "dopamine", "alpha-methyl-para-tyrosine", "apomorphine", "m-HPAA", "p-HPAA" ], "offsets": [ [ 23, 31 ], [ 43, 69 ], [ 74, 85 ], [ 97, 103 ], [ 146, 152 ] ] }, { "pmid": "6621777", "text": "From these results, it is proposed that tyrosine hydroxylase activity determines p-HPAA concentrations by regulating p-tyrosine availability.", "type": "CHEMICAL", "entities": [ "tyrosine", "p-HPAA", "p-tyrosine" ], "offsets": [ [ 40, 48 ], [ 81, 87 ], [ 117, 127 ] ] }, { "pmid": "6621777", "text": "This enzyme may also synthesize m-tyrosine which is subsequently decarboxylated to form m-tyramine and then oxidatively deaminated to form m-HPAA.", "type": "CHEMICAL", "entities": [ "m-tyrosine", "m-tyramine", "m-HPAA" ], "offsets": [ [ 32, 42 ], [ 88, 98 ], [ 139, 145 ] ] }, { "pmid": "6701456", "text": "Demonstration of histamine receptors on human platelets by flow cytometry.\n", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "6701456", "text": "Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets.", "type": "CHEMICAL", "entities": [ "histamine", "histamine" ], "offsets": [ [ 105, 114 ], [ 46, 55 ] ] }, { "pmid": "6701456", "text": "The binding of FHA-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists diphenhydramine and clemastine.", "type": "CHEMICAL", "entities": [ "histamine", "diphenhydramine", "clemastine" ], "offsets": [ [ 71, 80 ], [ 105, 120 ], [ 125, 135 ] ] }, { "pmid": "6701456", "text": "The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets.", "type": "CHEMICAL", "entities": [ "histamine", "cimetidine" ], "offsets": [ [ 4, 13 ], [ 37, 47 ] ] }, { "pmid": "6701456", "text": "It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 21, 30 ] ] }, { "pmid": "6703688", "text": "The effect of vitamin B6 deficiency on alanine: glyoxylate aminotransferase isoenzymes in rat liver.\n", "type": "CHEMICAL", "entities": [ "vitamin B6", "alanine", "glyoxylate" ], "offsets": [ [ 14, 24 ], [ 39, 46 ], [ 48, 58 ] ] }, { "pmid": "6703688", "text": "Endogenous synthesis of oxalate has been reported to increase in vitamin B6 deficiency probably due to defective transamination of glyoxylate, the direct source of oxalate, to glycine.", "type": "CHEMICAL", "entities": [ "oxalate", "vitamin B6", "glyoxylate", "oxalate", "glycine" ], "offsets": [ [ 24, 31 ], [ 65, 75 ], [ 131, 141 ], [ 164, 171 ], [ 176, 183 ] ] }, { "pmid": "6703688", "text": "Alanine:glyoxylate aminotransferase (AGT) in the liver catalyzes most of the glyoxylate transamination in mammalian tissues (E. V. Rowsell, K. Snell, J. A. Carnie, and K. V. Rowsell (1972) Biochem.", "type": "CHEMICAL", "entities": [ "glyoxylate", "Alanine", "glyoxylate" ], "offsets": [ [ 77, 87 ], [ 0, 7 ], [ 8, 18 ] ] }, { "pmid": "6703688", "text": "The effects of vitamin B6 deficiency on hepatic AGT isoenzymes, designated AGT 1 and AGT 2, respectively, were examined with male rats; AGT 1 is located both in the peroxisomes and in the mitochondria, and AGT 2 only in the mitochondria.", "type": "CHEMICAL", "entities": [ "vitamin B6" ], "offsets": [ [ 15, 25 ] ] }, { "pmid": "6703688", "text": "The holo activity of combined peroxisomal and mitochondrial AGT 1 with a low Km for L-alanine rapidly decreased after a lag time of about 2 days during feeding of the vitamin B6-deficient diet (by 50% in 5 days, by 86% in 14 days).", "type": "CHEMICAL", "entities": [ "L-alanine", "vitamin B6" ], "offsets": [ [ 84, 93 ], [ 167, 177 ] ] }, { "pmid": "6703688", "text": "The holo activity of AGT 2 with a high Km for L-alanine decreased more slowly than AGT 1 (by 33% in 14 days, by 60% in 28 days).", "type": "CHEMICAL", "entities": [ "L-alanine" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "6703688", "text": "Urinary excretion of oxalate began to increase in 8-9 days, when AGT 2 remained intact but most of AGT 1 is depleted.", "type": "CHEMICAL", "entities": [ "oxalate" ], "offsets": [ [ 21, 28 ] ] }, { "pmid": "6703688", "text": "When the defect in the glyoxylate transamination in vivo in vitamin B6 deficiency is considered, these findings suggest that it is due to the deficiency of AGT 1.", "type": "CHEMICAL", "entities": [ "glyoxylate", "vitamin B6" ], "offsets": [ [ 23, 33 ], [ 60, 70 ] ] }, { "pmid": "6703688", "text": "The importance of peroxisomal AGT 1 is discussed, since peroxisomes have been described to be probably the major site of glyoxylate formation.", "type": "CHEMICAL", "entities": [ "glyoxylate" ], "offsets": [ [ 121, 131 ] ] }, { "pmid": "7499320", "text": "How do volatile anesthetics inhibit Ca(2+)-ATPases?\n", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 36, 42 ] ] }, { "pmid": "7499320", "text": "Volatile anesthetics at concentrations that are used in clinical practice to induce anesthesia selectively inhibit activity of the plasma membrane Ca(2+)-transport", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 147, 153 ] ] }, { "pmid": "7499320", "text": "We have investigated the mechanism of the inhibitory action of several anesthetics on the purified erythrocyte Ca(2+)-ATPase by employing fluorescence spectroscopy measurements that report changes in the environment of intrinsic tryptophans and of an extrinsic probe attached in the active site of the enzyme.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "tryptophans" ], "offsets": [ [ 111, 117 ], [ 229, 240 ] ] }, { "pmid": "7499320", "text": "We have shown that the observed inhibition of the Ca(2+)-dependent activation of the enzyme correlates well with the elimination of the Ca(2+)-induced conformation change that is important for the proper function of the enzyme.", "type": "CHEMICAL", "entities": [ "Ca(2+)", "Ca(2+)" ], "offsets": [ [ 50, 56 ], [ 136, 142 ] ] }, { "pmid": "7499320", "text": "Analysis of the anesthetics effects on the total tryptophan fluorescence indicates a significant effect on enzyme conformation.", "type": "CHEMICAL", "entities": [ "tryptophan" ], "offsets": [ [ 49, 59 ] ] }, { "pmid": "7499320", "text": "Similar changes have been observed in the sarcoplasmic reticulum Ca(2+)-ATPase.", "type": "CHEMICAL", "entities": [ "Ca(2+)" ], "offsets": [ [ 65, 71 ] ] }, { "pmid": "7499320", "text": "We propose that volatile anesthetics inhibit Ca(2+)-ATPase by interacting with nonpolar sites in protein interior, in analogy to the binding demonstrated for myoglobin, hemoglobin, and adenylate kinase (Schoenborn, B. P., and Featherstone, R. M. (1967)", "type": "CHEMICAL", "entities": [ "Ca(2+)", "adenylate" ], "offsets": [ [ 45, 51 ], [ 185, 194 ] ] }, { "pmid": "7560228", "text": "The effect of triclosan on mediators of gingival inflammation.\n", "type": "CHEMICAL", "entities": [ "triclosan" ], "offsets": [ [ 14, 23 ] ] }, { "pmid": "7560228", "text": "Triclosan (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses.", "type": "CHEMICAL", "entities": [ "Triclosan", "2,4,4',-trichloro-2'-hydroxydiphenylether" ], "offsets": [ [ 0, 9 ], [ 11, 52 ] ] }, { "pmid": "7560228", "text": "The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented.", "type": "CHEMICAL", "entities": [ "triclosan" ], "offsets": [ [ 16, 25 ] ] }, { "pmid": "7560228", "text": "It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues.", "type": "CHEMICAL", "entities": [ "triclosan" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "7560228", "text": "Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase.", "type": "CHEMICAL", "entities": [ "triclosan", "arachidonic acid" ], "offsets": [ [ 66, 75 ], [ 116, 132 ] ] }, { "pmid": "7560228", "text": "These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins.", "type": "CHEMICAL", "entities": [ "prostaglandins", "leukotrienes", "lipoxins" ], "offsets": [ [ 85, 99 ], [ 101, 113 ], [ 118, 126 ] ] }, { "pmid": "7560228", "text": "Triclosan inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively.", "type": "CHEMICAL", "entities": [ "Triclosan" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "7560228", "text": "Triclosan also inhibited 5-lipoxygenase with an IC-50 of 43 microM.", "type": "CHEMICAL", "entities": [ "Triclosan" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "7560228", "text": "The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM.", "type": "CHEMICAL", "entities": [ "triclosan" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "7560228", "text": "Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy.", "type": "CHEMICAL", "entities": [ "triclosan", "arachidonic acid" ], "offsets": [ [ 7, 16 ], [ 98, 114 ] ] }, { "pmid": "7560228", "text": "In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations.", "type": "CHEMICAL", "entities": [ "triclosan", "prostaglandin E2" ], "offsets": [ [ 47, 56 ], [ 85, 101 ] ] }, { "pmid": "7560228", "text": "These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)", "type": "CHEMICAL", "entities": [ "triclosan" ], "offsets": [ [ 42, 51 ] ] }, { "pmid": "7599160", "text": "The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism.\n", "type": "CHEMICAL", "entities": [ "cobalamin", "cobalamin" ], "offsets": [ [ 16, 25 ], [ 90, 99 ] ] }, { "pmid": "7599160", "text": "The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro.", "type": "CHEMICAL", "entities": [ "cobalamin", "Cbl" ], "offsets": [ [ 29, 38 ], [ 40, 43 ] ] }, { "pmid": "7599160", "text": "Extracellular Cbl (protein bound and free) and intracellular", "type": "CHEMICAL", "entities": [ "Cbl" ], "offsets": [ [ 14, 17 ] ] }, { "pmid": "7599160", "text": "Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC).", "type": "CHEMICAL", "entities": [ "CN-Cbl", "Cbl", "[57Co]cyanocobalamin" ], "offsets": [ [ 115, 121 ], [ 0, 3 ], [ 93, 113 ] ] }, { "pmid": "7599160", "text": "The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium.", "type": "CHEMICAL", "entities": [ "[57Co]Cbl" ], "offsets": [ [ 31, 40 ] ] }, { "pmid": "7599160", "text": "Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium.", "type": "CHEMICAL", "entities": [ "TC-[57Co]CN-Cbl", "Cbl", "Cbl" ], "offsets": [ [ 32, 47 ], [ 89, 92 ], [ 124, 127 ] ] }, { "pmid": "7599160", "text": "Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin.", "type": "CHEMICAL", "entities": [ "[57Co]CN-Cbl", "hydroxocobalamin", "OH-Cbl", "methylcobalamin", "Me-Cbl", "5'-deoxyadenosylcobalamin" ], "offsets": [ [ 13, 25 ], [ 43, 59 ], [ 61, 67 ], [ 70, 85 ], [ 87, 93 ], [ 99, 124 ] ] }, { "pmid": "7599160", "text": "These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions.", "type": "CHEMICAL", "entities": [ "Cbl" ], "offsets": [ [ 6, 9 ] ] }, { "pmid": "7599160", "text": "Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity.", "type": "CHEMICAL", "entities": [ "[57Co]Cbl", "methionine", "methylmalonyl-CoA" ], "offsets": [ [ 28, 37 ], [ 56, 66 ], [ 85, 102 ] ] }, { "pmid": "7599160", "text": "The major form of Cbl associated with the two enzymes was OH-Cbl.", "type": "CHEMICAL", "entities": [ "Cbl", "OH-Cbl" ], "offsets": [ [ 18, 21 ], [ 58, 64 ] ] }, { "pmid": "7599160", "text": "Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme.", "type": "CHEMICAL", "entities": [ "N5-methyltetrahydrofolate", "homocysteine", "Me-Cbl", "Cbl" ], "offsets": [ [ 38, 63 ], [ 68, 80 ], [ 194, 200 ], [ 209, 212 ] ] }, { "pmid": "7665369", "text": "Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells.\n", "type": "CHEMICAL", "entities": [ "Ergovaline", "dopamine" ], "offsets": [ [ 0, 10 ], [ 40, 48 ] ] }, { "pmid": "7665369", "text": "Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated.", "type": "CHEMICAL", "entities": [ "dopamine", "Ergovaline", "ergot alkaloid", "cyclic AMP", "dopamine" ], "offsets": [ [ 55, 63 ], [ 0, 10 ], [ 77, 91 ], [ 153, 163 ], [ 225, 233 ] ] }, { "pmid": "7665369", "text": "Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM).", "type": "CHEMICAL", "entities": [ "Ergovaline", "[3H]YM-09151-2", "dopamine" ], "offsets": [ [ 0, 10 ], [ 69, 83 ], [ 149, 157 ] ] }, { "pmid": "7665369", "text": "Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively.", "type": "CHEMICAL", "entities": [ "Ergot alkaloids", "cyclic AMP", "ergovaline", "ergonovine", "alpha-ergocryptine", "ergotamine", "dopamine" ], "offsets": [ [ 0, 15 ], [ 65, 75 ], [ 109, 119 ], [ 121, 131 ], [ 133, 151 ], [ 153, 163 ], [ 169, 177 ] ] }, { "pmid": "7665369", "text": "Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM).", "type": "CHEMICAL", "entities": [ "cyclic AMP", "ergovaline", "dopamine", "(-)-sulpiride" ], "offsets": [ [ 14, 24 ], [ 39, 49 ], [ 69, 77 ], [ 99, 112 ] ] }, { "pmid": "7665369", "text": "Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine.", "type": "CHEMICAL", "entities": [ "ergovaline", "dopamine", "dopamine" ], "offsets": [ [ 54, 64 ], [ 77, 85 ], [ 153, 161 ] ] }, { "pmid": "7665369", "text": "These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation.", "type": "CHEMICAL", "entities": [ "ergot alkaloids", "ergovaline", "dopamine" ], "offsets": [ [ 133, 148 ], [ 159, 169 ], [ 188, 196 ] ] }, { "pmid": "7691623", "text": "Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors.\n", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 72, 83 ] ] }, { "pmid": "7691623", "text": "The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor.", "type": "CHEMICAL", "entities": [ "clozapine", "haloperidol", "spiperone", "thioridazine", "YM-09151-2", "risperidone", "(+)-butaclamol" ], "offsets": [ [ 68, 77 ], [ 79, 90 ], [ 92, 101 ], [ 103, 115 ], [ 120, 130 ], [ 39, 50 ], [ 52, 66 ] ] }, { "pmid": "7691623", "text": "Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively).", "type": "CHEMICAL", "entities": [ "[3H]prazosin" ], "offsets": [ [ 35, 47 ] ] }, { "pmid": "7691623", "text": "Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus.", "type": "CHEMICAL", "entities": [ "phentolamine", "WB 4101", "Prazosin", "5-methyl-urapidil" ], "offsets": [ [ 120, 132 ], [ 137, 144 ], [ 0, 8 ], [ 101, 118 ] ] }, { "pmid": "7691623", "text": "With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes.", "type": "CHEMICAL", "entities": [ "risperidone" ], "offsets": [ [ 22, 33 ] ] }, { "pmid": "7691623", "text": "Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively).", "type": "CHEMICAL", "entities": [ "Risperidone" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "7773533", "text": "Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype.\n", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 13, 26 ] ] }, { "pmid": "7773533", "text": "The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies.", "type": "CHEMICAL", "entities": [ "noradrenaline", "NA" ], "offsets": [ [ 73, 86 ], [ 88, 90 ] ] }, { "pmid": "7773533", "text": "2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax).", "type": "CHEMICAL", "entities": [ "chloroethylclonidine", "CEC", "[3H]-prazosin" ], "offsets": [ [ 94, 114 ], [ 116, 119 ], [ 157, 170 ] ] }, { "pmid": "7773533", "text": "3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response.", "type": "CHEMICAL", "entities": [ "NA", "NA", "CEC" ], "offsets": [ [ 159, 161 ], [ 40, 42 ], [ 49, 52 ] ] }, { "pmid": "7773533", "text": "The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM).", "type": "CHEMICAL", "entities": [ "NA", "CEC", "prazosin" ], "offsets": [ [ 29, 31 ], [ 38, 41 ], [ 74, 82 ] ] }, { "pmid": "7773533", "text": "The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively.", "type": "CHEMICAL", "entities": [ "prazosin", "terazosin", "(R)-YM-12617", "phentolamine", "5-methylurapidil", "spiperone", "NA" ], "offsets": [ [ 28, 36 ], [ 38, 47 ], [ 49, 61 ], [ 63, 75 ], [ 77, 93 ], [ 98, 107 ], [ 134, 136 ] ] }, { "pmid": "7773533", "text": "The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively.", "type": "CHEMICAL", "entities": [ "CEC" ], "offsets": [ [ 157, 160 ] ] }, { "pmid": "7773533", "text": "5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective.", "type": "CHEMICAL", "entities": [ "5-Methylurapidil", "phentolamine", "spiperone" ], "offsets": [ [ 0, 16 ], [ 21, 33 ], [ 102, 111 ] ] }, { "pmid": "7816863", "text": "Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice.\n", "type": "CHEMICAL", "entities": [ "desipramine" ], "offsets": [ [ 53, 64 ] ] }, { "pmid": "7816863", "text": "The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined.", "type": "CHEMICAL", "entities": [ "desipramine" ], "offsets": [ [ 60, 71 ] ] }, { "pmid": "7816863", "text": "Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports.", "type": "CHEMICAL", "entities": [ "Desipramine HCl" ], "offsets": [ [ 0, 15 ] ] }, { "pmid": "7816863", "text": "Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses.", "type": "CHEMICAL", "entities": [ "(+/- )propranolol HCl", "desipramine" ], "offsets": [ [ 34, 55 ], [ 149, 160 ] ] }, { "pmid": "7816863", "text": "ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it.", "type": "CHEMICAL", "entities": [ "ICI118,551 HCl", "metoprolol tartrate" ], "offsets": [ [ 0, 14 ], [ 187, 206 ] ] }, { "pmid": "7816863", "text": "Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior.", "type": "CHEMICAL", "entities": [ "clenbuterol HCl" ], "offsets": [ [ 10, 25 ] ] }, { "pmid": "7816863", "text": "Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice.", "type": "CHEMICAL", "entities": [ "desipramine", "yohimbine" ], "offsets": [ [ 50, 61 ], [ 123, 132 ] ] }, { "pmid": "7875228", "text": "Alpha 1-adrenoceptor subtypes mediating the regulation and modulation of Ca2+ sensitization in rabbit thoracic aorta.\n", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 73, 77 ] ] }, { "pmid": "7875228", "text": "Norepinephrine (10 microM), methoxamine (100 microM) and clonidine (100 microM) with guanosine 5'-triphosphate (GTP, 50 microM) or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma-S, 10 microM) all significantly enhanced the contraction induced by 0.3 microM Ca2+ (pCa6.5) in beta-escin-skinned smooth muscle of rabbit thoracic aorta.", "type": "CHEMICAL", "entities": [ "GTP gamma-S", "Ca2+", "methoxamine", "Norepinephrine", "clonidine", "guanosine 5'-triphosphate", "guanosine 5'-O-(3-thiotriphosphate)" ], "offsets": [ [ 168, 179 ], [ 257, 261 ], [ 28, 39 ], [ 0, 14 ], [ 57, 66 ], [ 85, 110 ], [ 131, 166 ] ] }, { "pmid": "7875228", "text": "The enhancement of Ca2+ contraction produced by norepinephrine was greater than that produced by methoxamine or clonidine.", "type": "CHEMICAL", "entities": [ "Ca2+", "norepinephrine", "methoxamine", "clonidine" ], "offsets": [ [ 19, 23 ], [ 48, 62 ], [ 97, 108 ], [ 112, 121 ] ] }, { "pmid": "7875228", "text": "In beta-escin-skinned strips of chloroethylclonidine-pretreated smooth muscle, the enhancement of Ca2+ contraction produced by norepinephrine was significantly decreased, whereas the amplitude was the same as that produced by methoxamine or clonidine; this enhancement was inhibited by the selective alpha 1A-adrenoceptor antagonist WB 4101 (100 nM).", "type": "CHEMICAL", "entities": [ "chloroethylclonidine", "Ca2+", "norepinephrine", "methoxamine", "clonidine", "WB 4101" ], "offsets": [ [ 32, 52 ], [ 98, 102 ], [ 127, 141 ], [ 226, 237 ], [ 241, 250 ], [ 333, 340 ] ] }, { "pmid": "7875228", "text": "The enhancement of Ca2+ contraction produced by methoxamine and clonidine was not affected by chloroethylclonidine pretreatment.", "type": "CHEMICAL", "entities": [ "Ca2+", "methoxamine", "clonidine", "chloroethylclonidine" ], "offsets": [ [ 19, 23 ], [ 48, 59 ], [ 64, 73 ], [ 94, 114 ] ] }, { "pmid": "7875228", "text": "The effects of methoxamine, clonidine and norepinephrine in the chloroethylclonidine-pretreated tissue were all inhibited by guanosine 5'-O-(2-thiodiphosphate) (GDP beta-S, 1 mM) and 1-(5-isoquinolinylsulfonyl)-methylpiperazine (H-7, 20 microM).", "type": "CHEMICAL", "entities": [ "chloroethylclonidine", "methoxamine", "clonidine", "norepinephrine", "guanosine 5'-O-(2-thiodiphosphate)", "GDP beta-S", "1-(5-isoquinolinylsulfonyl)-methylpiperazine" ], "offsets": [ [ 64, 84 ], [ 15, 26 ], [ 28, 37 ], [ 42, 56 ], [ 125, 159 ], [ 161, 171 ], [ 183, 227 ] ] }, { "pmid": "7875228", "text": "Furthermore, the phosphorylation of myosin light chain produced by norepinephrine was greater than that produced by clonidine.", "type": "CHEMICAL", "entities": [ "norepinephrine", "clonidine" ], "offsets": [ [ 67, 81 ], [ 116, 125 ] ] }, { "pmid": "7875228", "text": "These results suggest that both alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) increase the Ca2+ sensitivity of contractile elements, and that the Ca2+ sensitization produced by alpha 1A-subtype receptors is mediated through G-protein and protein kinase C, and plays an important role in contraction of smooth muscle of rabbit thoracic aorta.", "type": "CHEMICAL", "entities": [ "Ca2+", "Ca2+" ], "offsets": [ [ 154, 158 ], [ 99, 103 ] ] }, { "pmid": "7926307", "text": "The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes beta-cell destruction is not well understood.", "type": "CHEMICAL", "entities": [ "streptozotocin", "STZ", "STZ", "glucose" ], "offsets": [ [ 19, 33 ], [ 216, 219 ], [ 35, 38 ], [ 4, 11 ] ] }, { "pmid": "7926307", "text": "In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GLUT2 or GLUT1 to investigate the role of glucose transporter isoforms in mediating STZ cytotoxicity.", "type": "CHEMICAL", "entities": [ "glucose", "STZ" ], "offsets": [ [ 152, 159 ], [ 194, 197 ] ] }, { "pmid": "7926307", "text": "The in vivo effects of STZ were evaluated by implantation of RIN cells expressing or lacking GLUT2 into athymic nude rats.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 23, 26 ] ] }, { "pmid": "7926307", "text": "The drug had a potent cytotoxic effect on RIN cells expressing GLUT2, but had no effect on cells lacking GLUT2 expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 190, 197 ] ] }, { "pmid": "7926307", "text": "The preferential cytotoxic effect of STZ on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 37, 40 ] ] }, { "pmid": "7926307", "text": "Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported STZ efficiently.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 85, 88 ] ] }, { "pmid": "7926307", "text": "We conclude that expression of GLUT2 is required for efficient killing of neuroendocrine cells by STZ, and this effect is related to specific recognition of the drug as a transported substrate by GLUT2 but not GLUT1.", "type": "CHEMICAL", "entities": [ "STZ" ], "offsets": [ [ 98, 101 ] ] }, { "pmid": "7981624", "text": "We found that the protein was secreted only in low Ca2+ medium (0.15 mM), this process required an active metabolism.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 51, 55 ] ] }, { "pmid": "8073394", "text": "Inhibitory effects of lysine analogues on t-PA induced whole blood clot lysis.\n", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 22, 28 ] ] }, { "pmid": "8073394", "text": "The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA).", "type": "CHEMICAL", "entities": [ "AMCA", "epsilon-aminocaproic acid", "lysine", "EACA", "trans-4-amino-methyl cyclohexane carboxylic acid" ], "offsets": [ [ 108, 112 ], [ 21, 46 ], [ 4, 10 ], [ 48, 52 ], [ 58, 106 ] ] }, { "pmid": "8073394", "text": "The present study utilized blood from normal volunteers and 125I-fibrinogen in a dilute whole blood clot assay to determine the relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous t-PA.", "type": "CHEMICAL", "entities": [ "125I", "lysine" ], "offsets": [ [ 60, 64 ], [ 155, 161 ] ] }, { "pmid": "8073394", "text": "AMCA (0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a lysine analogue and exogenous t-PA or if (2) whole blood clots were formed in the presence of exogenous t-PA and a lysine analogue.", "type": "CHEMICAL", "entities": [ "AMCA", "EACA", "lysine", "lysine" ], "offsets": [ [ 0, 4 ], [ 19, 23 ], [ 132, 138 ], [ 247, 253 ] ] }, { "pmid": "8073394", "text": "However, their inhibitory effect was markedly reduced if clots were formed in the presence of t-PA and then exposed to either of the lysine analogues.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 133, 139 ] ] }, { "pmid": "8073394", "text": "The data suggest that lysine analogues, even at low concentrations, reduce the rate of t-PA induced whole blood clot lysis by several mechanisms.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 22, 28 ] ] }, { "pmid": "8098142", "text": "Histamine enhances the depolarizing afterpotential of immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus via H1-receptor activation.\n", "type": "CHEMICAL", "entities": [ "Histamine", "vasopressin" ], "offsets": [ [ 0, 9 ], [ 87, 98 ] ] }, { "pmid": "8098142", "text": "Previous studies have demonstrated that histamine primarily excites unidentified neurons in the rat supraoptic nucleus.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 40, 49 ] ] }, { "pmid": "8098142", "text": "We investigated the neuromodulatory effects of histamine on immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus using intracellular recording techniques from the hypothalamo-neurohypophysial explant.", "type": "CHEMICAL", "entities": [ "histamine", "vasopressin" ], "offsets": [ [ 47, 56 ], [ 93, 104 ] ] }, { "pmid": "8098142", "text": "Exogenous application of histamine (0.1-100 microM) to vasopressinergic neurons produced a small membrane depolarization accompanied by an increase of up to 100% in the amplitude of the depolarizing afterpotential that follows current-evoked trains of action potentials.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 25, 34 ] ] }, { "pmid": "8098142", "text": "The enhancement of the depolarizing afterpotential by histamine did not depend upon the depolarization.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 54, 63 ] ] }, { "pmid": "8098142", "text": "Further, histamine enhanced the amplitude of the depolarizing afterpotential when blocking the afterhyperpolarizing potential with d-tubocurarine or apamin, and in the presence of tetrodotoxin and d-tubocurarine or apamin, indicating a postsynaptic action of histamine on the depolarizing afterpotential that is not simply a reflection of a decrease in the afterhyperpolarizing potential.", "type": "CHEMICAL", "entities": [ "histamine", "d-tubocurarine", "tetrodotoxin", "d-tubocurarine", "histamine" ], "offsets": [ [ 9, 18 ], [ 131, 145 ], [ 180, 192 ], [ 197, 211 ], [ 259, 268 ] ] }, { "pmid": "8098142", "text": "These toxins also had no effect on the histamine-induced depolarization.", "type": "CHEMICAL", "entities": [ "histamine" ], "offsets": [ [ 39, 48 ] ] }, { "pmid": "8098142", "text": "The enhancement of the depolarizing afterpotential by histamine was mimicked by the histamine H1-receptor agonist 2-thiazolylethylamine and was reduced or blocked by the H1-receptor antagonist promethazine, but was not blocked or reduced in the presence of the histamine H2-receptor antagonist, cimetidine.", "type": "CHEMICAL", "entities": [ "histamine", "histamine", "2-thiazolylethylamine", "promethazine", "histamine", "cimetidine" ], "offsets": [ [ 54, 63 ], [ 84, 93 ], [ 114, 135 ], [ 193, 205 ], [ 261, 270 ], [ 295, 305 ] ] }, { "pmid": "8098142", "text": "In summary, these results show that the excitatory effect of histamine on immunohistochemically identified vasopressin neurons in the supraoptic nucleus is due in part to the H1-receptor-mediated enhancement of the depolarizing afterpotential independent of any change in the afterhyperpolarizing potential or membrane potential.", "type": "CHEMICAL", "entities": [ "histamine", "vasopressin" ], "offsets": [ [ 61, 70 ], [ 107, 118 ] ] }, { "pmid": "8142113", "text": "Adapalene, a new chemical entity with retinoid activity.\n", "type": "CHEMICAL", "entities": [ "Adapalene", "retinoid" ], "offsets": [ [ 0, 9 ], [ 38, 46 ] ] }, { "pmid": "8142113", "text": "Adapalene is a novel chemical entity which, in terms of pharmacology, behaves similar to tretinoin, but is chemically and photochemically stable.", "type": "CHEMICAL", "entities": [ "tretinoin", "Adapalene" ], "offsets": [ [ 89, 98 ], [ 0, 9 ] ] }, { "pmid": "8142113", "text": "It has a particular selectivity profile for the known nuclear retinoic acid receptors with low affinity for RAR alpha and no transactivating potential for RXR alpha.", "type": "CHEMICAL", "entities": [ "retinoic acid" ], "offsets": [ [ 62, 75 ] ] }, { "pmid": "8142113", "text": "This receptor profile could imply that adapalene, in contrast to tretinoin, affects the terminal differentiation pathway of epidermal cells rather than their proliferation.", "type": "CHEMICAL", "entities": [ "adapalene", "tretinoin" ], "offsets": [ [ 39, 48 ], [ 65, 74 ] ] }, { "pmid": "8142113", "text": "Furthermore, adapalene does not bind to members of the cellular retinoic acid binding protein family.", "type": "CHEMICAL", "entities": [ "adapalene", "retinoic acid" ], "offsets": [ [ 13, 22 ], [ 64, 77 ] ] }, { "pmid": "8142113", "text": "Adapalene has comedolytic activity in the topical rhino mouse model.", "type": "CHEMICAL", "entities": [ "Adapalene" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "8142113", "text": "In comparative clinical studies involving 72 acne patients, the efficacy of adapalene was comparable, if not superior, to tretinoin, but adapalene was better tolerated.", "type": "CHEMICAL", "entities": [ "adapalene", "adapalene", "tretinoin" ], "offsets": [ [ 137, 146 ], [ 76, 85 ], [ 122, 131 ] ] }, { "pmid": "8142113", "text": "The data reviewed in this paper indicate that adapalene should be particularly beneficial in the treatment of acne.", "type": "CHEMICAL", "entities": [ "adapalene" ], "offsets": [ [ 46, 55 ] ] }, { "pmid": "8319997", "text": "The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys.", "type": "CHEMICAL", "entities": [ "remikiren", "CGP 38560A", "enalkiren", "sodium" ], "offsets": [ [ 101, 110 ], [ 112, 122 ], [ 128, 137 ], [ 142, 148 ] ] }, { "pmid": "8319997", "text": "In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals.", "type": "CHEMICAL", "entities": [ "CGP 38560A", "enalkiren" ], "offsets": [ [ 64, 74 ], [ 78, 87 ] ] }, { "pmid": "8319997", "text": "Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril.", "type": "CHEMICAL", "entities": [ "cilazapril" ], "offsets": [ [ 88, 98 ] ] }, { "pmid": "8319997", "text": "Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model.", "type": "CHEMICAL", "entities": [ "remikiren", "cilazapril", "CGP 38560A", "enalkiren" ], "offsets": [ [ 22, 31 ], [ 52, 62 ], [ 96, 106 ], [ 110, 119 ] ] }, { "pmid": "8319997", "text": "One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment.", "type": "CHEMICAL", "entities": [ "remikiren", "CGP 38560A", "enalkiren" ], "offsets": [ [ 48, 57 ], [ 73, 83 ], [ 88, 97 ] ] }, { "pmid": "8384226", "text": "Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium.\n", "type": "CHEMICAL", "entities": [ "nedocromil sodium" ], "offsets": [ [ 55, 72 ] ] }, { "pmid": "8384226", "text": "These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a).", "type": "CHEMICAL", "entities": [ "formyl-methionyl-leucyl-phenylalanine", "FMLP" ], "offsets": [ [ 118, 155 ], [ 158, 162 ] ] }, { "pmid": "8384226", "text": "Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated.", "type": "CHEMICAL", "entities": [ "nedocromil sodium" ], "offsets": [ [ 19, 36 ] ] }, { "pmid": "8384226", "text": "Nedocromil sodium inhibited the chemotactic response toward FMLP and NAF/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50%", "type": "CHEMICAL", "entities": [ "Nedocromil sodium", "FMLP" ], "offsets": [ [ 0, 17 ], [ 60, 64 ] ] }, { "pmid": "8384226", "text": "The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L).", "type": "CHEMICAL", "entities": [ "nedocromil sodium" ], "offsets": [ [ 55, 72 ] ] }, { "pmid": "8384226", "text": "Nedocromil sodium (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge.", "type": "CHEMICAL", "entities": [ "Nedocromil sodium", "FMLP" ], "offsets": [ [ 0, 17 ], [ 97, 101 ] ] }, { "pmid": "8384226", "text": "These findings might explain in part the antiinflammatory action of nedocromil sodium.", "type": "CHEMICAL", "entities": [ "nedocromil sodium" ], "offsets": [ [ 68, 85 ] ] }, { "pmid": "8415655", "text": "Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain.\n", "type": "CHEMICAL", "entities": [ "prostaglandin D" ], "offsets": [ [ 32, 47 ] ] }, { "pmid": "8415655", "text": "Glutathione-independent prostaglandin D synthase [prostaglandin-H2 D-isomerase; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, EC 5.3.99.2] is an enzyme responsible for biosynthesis of prostaglandin D2 in the central nervous system.", "type": "CHEMICAL", "entities": [ "Glutathione", "prostaglandin D2", "prostaglandin D", "prostaglandin-H2", "(5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate" ], "offsets": [ [ 0, 11 ], [ 223, 239 ], [ 24, 39 ], [ 50, 66 ], [ 80, 151 ] ] }, { "pmid": "8415655", "text": "It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein).", "type": "CHEMICAL", "entities": [ "prostaglandin D" ], "offsets": [ [ 29, 44 ] ] }, { "pmid": "8589992", "text": "cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration.\n", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 48, 57 ] ] }, { "pmid": "8589992", "text": "We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library.", "type": "CHEMICAL", "entities": [ "glutamate" ], "offsets": [ [ 43, 52 ] ] }, { "pmid": "8589992", "text": "This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions.", "type": "CHEMICAL", "entities": [ "nucleotide", "amino", "carboxy" ], "offsets": [ [ 48, 58 ], [ 170, 175 ], [ 180, 187 ] ] }, { "pmid": "8589992", "text": "Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA).", "type": "CHEMICAL", "entities": [ "kainate", "L-glutamate", "(RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate", "AMPA" ], "offsets": [ [ 142, 149 ], [ 151, 162 ], [ 167, 223 ], [ 225, 229 ] ] }, { "pmid": "8589992", "text": "Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione).", "type": "CHEMICAL", "entities": [ "Kainate", "cyclothiazide", "non-N-methyl-D-aspartate", "NMDA", "CNQX", "6-cyano-7-nitro-quinoxalinedione" ], "offsets": [ [ 0, 7 ], [ 121, 134 ], [ 162, 186 ], [ 188, 192 ], [ 214, 218 ], [ 220, 252 ] ] }, { "pmid": "8589992", "text": "Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone.", "type": "CHEMICAL", "entities": [ "Kainate", "AMPA" ], "offsets": [ [ 0, 7 ], [ 12, 16 ] ] }, { "pmid": "8589992", "text": "Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM).", "type": "CHEMICAL", "entities": [ "kainate" ], "offsets": [ [ 114, 121 ] ] }, { "pmid": "8589992", "text": "The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate >", "type": "CHEMICAL", "entities": [ "[3H]-kainate", "kainate", "L-glutamate", "quisqualate" ], "offsets": [ [ 48, 60 ], [ 102, 109 ], [ 112, 123 ], [ 126, 137 ] ] }, { "pmid": "8589992", "text": "6,7-dinitroquinoxaline-2,3-dione (DNQX)", "type": "CHEMICAL", "entities": [ "6,7-dinitroquinoxaline-2,3-dione", "DNQX" ], "offsets": [ [ 0, 32 ], [ 34, 38 ] ] }, { "pmid": "8589992", "text": "= CNQX >", "type": "CHEMICAL", "entities": [ "CNQX" ], "offsets": [ [ 2, 6 ] ] }, { "pmid": "8589992", "text": "AMPA > dihydrokainate > NMDA.", "type": "CHEMICAL", "entities": [ "dihydrokainate", "NMDA", "AMPA" ], "offsets": [ [ 7, 21 ], [ 24, 28 ], [ 0, 4 ] ] }, { "pmid": "8606397", "text": "Leukotrienes in the pathogenesis of pulmonary blast injury.\n", "type": "CHEMICAL", "entities": [ "Leukotrienes" ], "offsets": [ [ 0, 12 ] ] }, { "pmid": "8606397", "text": "Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast.", "type": "CHEMICAL", "entities": [ "leukotriene" ], "offsets": [ [ 74, 85 ] ] }, { "pmid": "8606397", "text": "The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure.", "type": "CHEMICAL", "entities": [ "leukotrienes" ], "offsets": [ [ 49, 61 ] ] }, { "pmid": "8606397", "text": "One group of experimental animals was treated with 5-lipoxygenase (5-LO) inhibitor, diethylcarbamazine (DEC, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast.", "type": "CHEMICAL", "entities": [ "diethylcarbamazine", "DEC" ], "offsets": [ [ 84, 102 ], [ 104, 107 ] ] }, { "pmid": "8606397", "text": "In this study, we demonstrated that treatment with DEC inhibits the increased systemic generation of conjugated dienes after blast injury.", "type": "CHEMICAL", "entities": [ "DEC" ], "offsets": [ [ 51, 54 ] ] }, { "pmid": "8606397", "text": "Although DEC exerts local antioxidant activity with beneficial effects on lung tissue, this 5-LO inhibitor intensifies the blast overpressure caused hemodynamic insufficiency.", "type": "CHEMICAL", "entities": [ "DEC" ], "offsets": [ [ 9, 12 ] ] }, { "pmid": "8647141", "text": "Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist.", "type": "CHEMICAL", "entities": [ "Tamsulosin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "8647141", "text": "European Tamsulosin Study Group.\n", "type": "CHEMICAL", "entities": [ "Tamsulosin" ], "offsets": [ [ 9, 19 ] ] }, { "pmid": "8647141", "text": "This meta-analysis of two European studies evaluated the efficacy and safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in patients with benign prostatic enlargement, lower urinary tract symptoms and prostatic obstruction (symptomatic BPH).", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 97, 107 ] ] }, { "pmid": "8647141", "text": "Patients entered a 2-week placebo run-in period, followed by randomization to treatment with tamsulosin (382 patients) or placebo (193 patients) once daily for 12 weeks.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 93, 103 ] ] }, { "pmid": "8647141", "text": "Maximum urinary flow rate improved to a greater extent in the tamsulosin group (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002).", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 62, 72 ] ] }, { "pmid": "8647141", "text": "Total Boyarsky symptom score also improved to a greater extent in the tamsulosin group (3.3 points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p = 0.002).", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 70, 80 ] ] }, { "pmid": "8647141", "text": "Significantly more tamsulosin patients (66%) than placebo patients (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001).", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "8647141", "text": "Twelve weeks of treatment with tamsulosin also produced significant improvements in average urinary flow rate (p = 0.005) and voiding or \"obstructive\" (p = 0.008) and storage or \"irritative' (p = 0.017) symptom scores.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 31, 41 ] ] }, { "pmid": "8647141", "text": "The incidence of drug-related adverse events was comparable for the tamsulosin and placebo groups (13 and 12% respectively, p = 0.802).", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 68, 78 ] ] }, { "pmid": "8647141", "text": "There were no clinically significant changes in blood pressure or pulse rate in tamsulosin patients compared with placebo patients both in hypertensive and normotensive BPH patients.", "type": "CHEMICAL", "entities": [ "tamsulosin" ], "offsets": [ [ 80, 90 ] ] }, { "pmid": "8647141", "text": "Tamsulosin 0.4 mg once daily is safe, well-tolerated and improves both the symptoms and urinary flow rate in patients with benign prostatic obstruction (symptomatic BPH).", "type": "CHEMICAL", "entities": [ "Tamsulosin" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "8666140", "text": "PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide.", "type": "CHEMICAL", "entities": [ "COOH", "C" ], "offsets": [ [ 154, 158 ], [ 234, 235 ] ] }, { "pmid": "8666140", "text": "Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing.", "type": "CHEMICAL", "entities": [ "glucose" ], "offsets": [ [ 75, 82 ] ] }, { "pmid": "8666140", "text": "Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 42, 52 ] ] }, { "pmid": "8730743", "text": "Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour.\n", "type": "CHEMICAL", "entities": [ "Desipramine" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "8730743", "text": "The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats.", "type": "CHEMICAL", "entities": [ "DMI", "tricyclic", "desipramine" ], "offsets": [ [ 90, 93 ], [ 46, 55 ], [ 77, 88 ] ] }, { "pmid": "8730743", "text": "The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 31, 34 ] ] }, { "pmid": "8730743", "text": "The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 19, 22 ] ] }, { "pmid": "8730743", "text": "After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 16, 19 ] ] }, { "pmid": "8730743", "text": "Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 18, 21 ] ] }, { "pmid": "8730743", "text": "The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 4, 7 ] ] }, { "pmid": "8730743", "text": "5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 3, 6 ] ] }, { "pmid": "8730743", "text": "The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 94, 97 ] ] }, { "pmid": "8730743", "text": "The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.", "type": "CHEMICAL", "entities": [ "DMI" ], "offsets": [ [ 47, 50 ] ] }, { "pmid": "8755512", "text": "Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production.\n", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 11, 22 ] ] }, { "pmid": "8755512", "text": "The immunomodulatory activity of thalidomide has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 33, 44 ] ] }, { "pmid": "8755512", "text": "The molecular mechanism for the immunomodulatory effect of thalidomide remains unknown.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 59, 70 ] ] }, { "pmid": "8755512", "text": "To elucidate this mechanism, we synthesized an active photoaffinity label of thalidomide as a probe to identify the molecular target of the drug.", "type": "CHEMICAL", "entities": [ "thalidomide" ], "offsets": [ [ 77, 88 ] ] }, { "pmid": "8755512", "text": "We show that the binding of thalidomide photoaffinity label to authentic human AGP is competed with both thalidomide and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of thalidomide.", "type": "CHEMICAL", "entities": [ "thalidomide", "thalidomide", "thalidomide" ], "offsets": [ [ 361, 372 ], [ 28, 39 ], [ 105, 116 ] ] }, { "pmid": "8793745", "text": "AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide.\n", "type": "CHEMICAL", "entities": [ "AMPA", "cyclothiazide" ], "offsets": [ [ 0, 4 ], [ 95, 108 ] ] }, { "pmid": "8793745", "text": "The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by cyclothiazide, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons.", "type": "CHEMICAL", "entities": [ "cyclothiazide", "alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid", "AMPA", "glutamate", "AMPA" ], "offsets": [ [ 194, 207 ], [ 25, 81 ], [ 83, 87 ], [ 117, 126 ], [ 161, 165 ] ] }, { "pmid": "8793745", "text": "Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by cyclothiazide than cultures prepared from the whole hippocampus.", "type": "CHEMICAL", "entities": [ "cyclothiazide" ], "offsets": [ [ 85, 98 ] ] }, { "pmid": "8793745", "text": "2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by cyclothiazide.", "type": "CHEMICAL", "entities": [ "glutamate", "cyclothiazide" ], "offsets": [ [ 55, 64 ], [ 243, 256 ] ] }, { "pmid": "8793745", "text": "The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell.", "type": "CHEMICAL", "entities": [ "AMPA" ], "offsets": [ [ 122, 126 ] ] }, { "pmid": "8793745", "text": "The complex patterns of sensitivity to cyclothiazide seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits.", "type": "CHEMICAL", "entities": [ "cyclothiazide", "AMPA" ], "offsets": [ [ 39, 52 ], [ 131, 135 ] ] }, { "pmid": "8793745", "text": "Recovery from modulation by cyclothiazide was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo.", "type": "CHEMICAL", "entities": [ "cyclothiazide" ], "offsets": [ [ 28, 41 ] ] }, { "pmid": "8793745", "text": "4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to cyclothiazide, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit.", "type": "CHEMICAL", "entities": [ "AMPA", "cyclothiazide" ], "offsets": [ [ 116, 120 ], [ 164, 177 ] ] }, { "pmid": "8793745", "text": "However, recovery from modulation by cyclothiazide was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to cyclothiazide.", "type": "CHEMICAL", "entities": [ "cyclothiazide", "cyclothiazide" ], "offsets": [ [ 37, 50 ], [ 221, 234 ] ] }, { "pmid": "8793745", "text": "These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission.", "type": "CHEMICAL", "entities": [ "AMPA" ], "offsets": [ [ 31, 35 ] ] }, { "pmid": "8797532", "text": "Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users.\n", "type": "CHEMICAL", "entities": [ "dopamine", "monoamine", "cocaine", "dopamine" ], "offsets": [ [ 19, 27 ], [ 55, 64 ], [ 88, 95 ], [ 9, 17 ] ] }, { "pmid": "8797532", "text": "Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders.", "type": "CHEMICAL", "entities": [ "cocaine", "dopamine", "DA" ], "offsets": [ [ 142, 149 ], [ 22, 30 ], [ 32, 34 ] ] }, { "pmid": "8797532", "text": "We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users.", "type": "CHEMICAL", "entities": [ "DA", "DA", "DA", "monoamine", "cocaine" ], "offsets": [ [ 22, 24 ], [ 41, 43 ], [ 80, 82 ], [ 119, 128 ], [ 182, 189 ] ] }, { "pmid": "8797532", "text": "Mean DA levels were normal in the putamen, the motor component of the striatum; however 4 of the 12 subjects had DA values below the lower limit of the control range.", "type": "CHEMICAL", "entities": [ "DA", "DA" ], "offsets": [ [ 113, 115 ], [ 5, 7 ] ] }, { "pmid": "8797532", "text": "DA concentrations were significantly reduced in the caudate head (head, -33%; tail, -39%) with a trend for reduction in nucleus accumbens (-27%).", "type": "CHEMICAL", "entities": [ "DA" ], "offsets": [ [ 0, 2 ] ] }, { "pmid": "8797532", "text": "Striatal DAT protein (-25 to -46%) and VMAT2 (-17 to -22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal.", "type": "CHEMICAL", "entities": [ "[3H]WIN 35,428" ], "offsets": [ [ 99, 113 ] ] }, { "pmid": "8797532", "text": "In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug.", "type": "CHEMICAL", "entities": [ "cocaine", "DA", "DA" ], "offsets": [ [ 45, 52 ], [ 112, 114 ], [ 123, 125 ] ] }, { "pmid": "8827452", "text": "Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator.\n", "type": "CHEMICAL", "entities": [ "serine" ], "offsets": [ [ 132, 138 ] ] }, { "pmid": "8827452", "text": "Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage.", "type": "CHEMICAL", "entities": [ "disulfide" ], "offsets": [ [ 82, 91 ] ] }, { "pmid": "8827452", "text": "Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma.", "type": "CHEMICAL", "entities": [ "N-terminal amino acid" ], "offsets": [ [ 24, 45 ] ] }, { "pmid": "8827452", "text": "The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA).", "type": "CHEMICAL", "entities": [ "amino acid", "nucleotide" ], "offsets": [ [ 4, 14 ], [ 41, 51 ] ] }, { "pmid": "8827452", "text": "The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus.", "type": "CHEMICAL", "entities": [ "serine", "N", "serine", "N" ], "offsets": [ [ 107, 113 ], [ 140, 141 ], [ 283, 289 ], [ 316, 317 ] ] }, { "pmid": "8863950", "text": "Hypoxemia associated with cimetidine therapy in a newborn infant.\n", "type": "CHEMICAL", "entities": [ "cimetidine" ], "offsets": [ [ 26, 36 ] ] }, { "pmid": "8863950", "text": "Cimetidine therapy used for the treatment of gastric bleeding due to tolazoline therapy in a newborn infant was temporally associated with episodes of severe hypoxemia.", "type": "CHEMICAL", "entities": [ "Cimetidine", "tolazoline" ], "offsets": [ [ 0, 10 ], [ 69, 79 ] ] }, { "pmid": "8863950", "text": "It appears likely that the histamine H2 receptor blocked by cimetidine obviated the pulmonary vasodilator effect of tolazoline therapy.", "type": "CHEMICAL", "entities": [ "histamine", "cimetidine", "tolazoline" ], "offsets": [ [ 27, 36 ], [ 60, 70 ], [ 116, 126 ] ] }, { "pmid": "8882618", "text": "Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices.\n", "type": "CHEMICAL", "entities": [ "2,3-benzodiazepines", "cyclothiazide", "AMPA" ], "offsets": [ [ 16, 35 ], [ 40, 53 ], [ 57, 61 ] ] }, { "pmid": "8882618", "text": "The 2,3-benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM).", "type": "CHEMICAL", "entities": [ "GYKI 52466", "GYKI 53405", "GYKI 53655", "GYKI 52466", "GYKI 53405", "GYKI 53655", "2,3-benzodiazepines", "AMPA" ], "offsets": [ [ 188, 198 ], [ 219, 229 ], [ 250, 260 ], [ 24, 34 ], [ 36, 46 ], [ 51, 61 ], [ 4, 23 ], [ 74, 78 ] ] }, { "pmid": "8882618", "text": "2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site.", "type": "CHEMICAL", "entities": [ "AMPA", "AMPA" ], "offsets": [ [ 113, 117 ], [ 184, 188 ] ] }, { "pmid": "8882618", "text": "3. Cyclothiazide (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents.", "type": "CHEMICAL", "entities": [ "Cyclothiazide", "AMPA" ], "offsets": [ [ 3, 16 ], [ 71, 75 ] ] }, { "pmid": "8882618", "text": "Both tau on and tau off were also increased by cyclothiazide in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM).", "type": "CHEMICAL", "entities": [ "cyclothiazide" ], "offsets": [ [ 47, 60 ] ] }, { "pmid": "8882618", "text": "4. Cyclothiazide (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right.", "type": "CHEMICAL", "entities": [ "Cyclothiazide", "2,3-benzodiazepines" ], "offsets": [ [ 3, 16 ], [ 82, 101 ] ] }, { "pmid": "8882618", "text": "For example, with 10 microM cyclothiazide the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively.", "type": "CHEMICAL", "entities": [ "cyclothiazide", "GYKI 52466", "GYKI 53405", "AMPA" ], "offsets": [ [ 28, 41 ], [ 55, 65 ], [ 70, 80 ], [ 97, 101 ] ] }, { "pmid": "8882618", "text": "5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of cyclothiazide (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM).", "type": "CHEMICAL", "entities": [ "GYKI 53405", "GYKI 52466", "cyclothiazide", "GYKI 53405" ], "offsets": [ [ 3, 13 ], [ 18, 28 ], [ 79, 92 ], [ 126, 136 ] ] }, { "pmid": "8882618", "text": "However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of cyclothiazide and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM).", "type": "CHEMICAL", "entities": [ "cyclothiazide", "AMPA", "GYKI 53405", "2,3-benzodiazepines" ], "offsets": [ [ 95, 108 ], [ 173, 177 ], [ 197, 207 ], [ 13, 32 ] ] }, { "pmid": "8882618", "text": "GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics.", "type": "CHEMICAL", "entities": [ "GYKI 52466", "AMPA" ], "offsets": [ [ 0, 10 ], [ 64, 68 ] ] }, { "pmid": "8882618", "text": "Cyclothiazide prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude.", "type": "CHEMICAL", "entities": [ "Cyclothiazide", "AMPA" ], "offsets": [ [ 0, 13 ], [ 51, 55 ] ] }, { "pmid": "8882618", "text": "7. Cyclothiazide (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM).", "type": "CHEMICAL", "entities": [ "Cyclothiazide", "GYKI 52466", "AMPA", "GYKI 52466" ], "offsets": [ [ 3, 16 ], [ 90, 100 ], [ 104, 108 ], [ 165, 175 ] ] }, { "pmid": "8882618", "text": "Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of cyclothiazide on AMPA receptor-mediated e.p.s.c. decay time constants to the right.", "type": "CHEMICAL", "entities": [ "GYKI 52466", "cyclothiazide", "AMPA" ], "offsets": [ [ 10, 20 ], [ 98, 111 ], [ 115, 119 ] ] }, { "pmid": "8882618", "text": "In conclusion, cyclothiazide and the 2,3-benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site.", "type": "CHEMICAL", "entities": [ "cyclothiazide", "2,3-benzodiazepines", "AMPA" ], "offsets": [ [ 15, 28 ], [ 37, 56 ], [ 92, 96 ] ] }, { "pmid": "8882618", "text": "The interactions of GYKI 52466 and cyclothiazide on AMPA receptor-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization.", "type": "CHEMICAL", "entities": [ "GYKI 52466", "cyclothiazide", "AMPA" ], "offsets": [ [ 20, 30 ], [ 35, 48 ], [ 52, 56 ] ] }, { "pmid": "8930173", "text": "Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes.\n", "type": "CHEMICAL", "entities": [ "imidazoline" ], "offsets": [ [ 52, 63 ] ] }, { "pmid": "8930173", "text": "To identify selective compounds for nonadrenergic I1-imidazoline receptors (I1), the affinities of 22 ligands for [125I]p-iodoclonidine binding have been compared at human platelet I1-imidazoline binding sites (analyzed under norepinephrine mask of alpha-2 AR) and at human alpha-2A, alpha-2B and alpha-2C adrenoceptors stably expressed on transfected Chinese hamster ovary cells.", "type": "CHEMICAL", "entities": [ "imidazoline", "[125I]p-iodoclonidine", "imidazoline", "norepinephrine" ], "offsets": [ [ 53, 64 ], [ 114, 135 ], [ 184, 195 ], [ 226, 240 ] ] }, { "pmid": "8930173", "text": "Competition curves at the platelet I1-imidazoline binding site were biphasic for most compounds.", "type": "CHEMICAL", "entities": [ "imidazoline" ], "offsets": [ [ 38, 49 ] ] }, { "pmid": "8930173", "text": "Only tizanidine and BDF,6143 displayed monophasic I1 competition curves.", "type": "CHEMICAL", "entities": [ "tizanidine", "BDF,6143" ], "offsets": [ [ 5, 15 ], [ 20, 28 ] ] }, { "pmid": "8930173", "text": "Agmatine, an endogenous neurotransmitter candidate for the I1-imidazoline receptor, was identified as the most selective agent for a subcomponent of platelet I1 sites.", "type": "CHEMICAL", "entities": [ "Agmatine", "imidazoline" ], "offsets": [ [ 0, 8 ], [ 62, 73 ] ] }, { "pmid": "8930173", "text": "The affinity of agmatine at the high affinity component of platelet I1 sites was 1400-fold selective over alpha-2A adrenoceptors, 5000-fold selective over alpha-2B adrenoceptors and 800-fold selective over alpha-2C adrenoceptors.", "type": "CHEMICAL", "entities": [ "agmatine" ], "offsets": [ [ 16, 24 ] ] }, { "pmid": "8930173", "text": "Moxonidine and tizanidine also displayed selectivities for a high affinity component of the platelet I1 binding sites over alpha-2 adrenoceptors.", "type": "CHEMICAL", "entities": [ "Moxonidine", "tizanidine" ], "offsets": [ [ 0, 10 ], [ 15, 25 ] ] }, { "pmid": "8930173", "text": "Naphazoline was the most selective compound for the high affinity state of the alpha-2A adrenoceptor, displaying 7-, 23- and 9-fold higher affinity than alpha-2B, alpha-2C and platelet I1-midazoline binding sites, respectively.", "type": "CHEMICAL", "entities": [ "Naphazoline", "midazoline" ], "offsets": [ [ 0, 11 ], [ 188, 198 ] ] }, { "pmid": "8930173", "text": "Norepinephrine displayed, respectively, 18- and 31-fold selectivity for the high affinity state of the alpha-2C adrenoceptor as compared to alpha-2A- or alpha-2B adrenoceptors, and was > 100,000- fold selective over platelet I1-imidazoline sites.", "type": "CHEMICAL", "entities": [ "Norepinephrine", "imidazoline" ], "offsets": [ [ 0, 14 ], [ 228, 239 ] ] }, { "pmid": "8930173", "text": "Thus, human alpha-2 adrenoceptors and the platelet I1-imidazoline binding site can be clearly discriminated based on their affinities for certain compounds.", "type": "CHEMICAL", "entities": [ "imidazoline" ], "offsets": [ [ 54, 65 ] ] }, { "pmid": "9008235", "text": "Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect.\n", "type": "CHEMICAL", "entities": [ "prostaglandin", "minoxidil" ], "offsets": [ [ 29, 42 ], [ 57, 66 ] ] }, { "pmid": "9008235", "text": "Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo.", "type": "CHEMICAL", "entities": [ "indomethacin", "naproxen", "piroxicam", "ibuprofen" ], "offsets": [ [ 94, 106 ], [ 108, 116 ], [ 118, 127 ], [ 132, 141 ] ] }, { "pmid": "9008235", "text": "These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2).", "type": "CHEMICAL", "entities": [ "prostaglandin" ], "offsets": [ [ 77, 90 ] ] }, { "pmid": "9008235", "text": "We thus speculated that activation of PGHS-1 might be a mechanism by which minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo.", "type": "CHEMICAL", "entities": [ "minoxidil", "2,4-diamino-6-piperidinopyrimidine-3-oxyde" ], "offsets": [ [ 75, 84 ], [ 86, 128 ] ] }, { "pmid": "9008235", "text": "We demonstrate here that minoxidil is a potent activator of purified PGHS-1 (AC50 = 80 microM), as assayed by oxygen consumption and PGE2 production.", "type": "CHEMICAL", "entities": [ "minoxidil", "oxygen" ], "offsets": [ [ 25, 34 ], [ 110, 116 ] ] }, { "pmid": "9008235", "text": "Our findings suggest that minoxidil and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism.", "type": "CHEMICAL", "entities": [ "minoxidil" ], "offsets": [ [ 26, 35 ] ] }, { "pmid": "9020367", "text": "Clonal T cells defined as a predominance of a single T cell receptor (TCR) V gene usage, in one case verified by TCR CDR3 fragment analysis and nucleotide sequencing, emerged within the CD52-/CD8+ cell population during Campath-1H therapy in 2 CLL patients, both achieving a long-lasting remission.", "type": "CHEMICAL", "entities": [ "nucleotide" ], "offsets": [ [ 144, 154 ] ] }, { "pmid": "9039330", "text": "Female precocious puberty may require hyperactivity of both gonadotrophin axes because of the \"two-cell' arrangement required for ovarian oestrogen production.", "type": "CHEMICAL", "entities": [ "oestrogen" ], "offsets": [ [ 138, 147 ] ] }, { "pmid": "9063462", "text": "Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila glutamyl-prolyl-tRNA synthetase gene.", "type": "CHEMICAL", "entities": [ "aminoacyl", "glutamyl" ], "offsets": [ [ 17, 26 ], [ 89, 97 ] ] }, { "pmid": "9063462", "text": "In Drosophila, glutamyl-prolyl-tRNA synthetase is a multifunctional synthetase encoded by a unique gene and composed of three domains: the amino- and carboxy-terminal domains catalyze the aminoacylation of glutamic acid and proline tRNA species, respectively, and the central domain is made of 75 amino acids repeated six times amongst which 46 are highly conserved and constitute the repeated motifs [Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M. & Semeriva, M. (1991) EMBO J. 10, 4267-4277].", "type": "CHEMICAL", "entities": [ "amino", "carboxy", "glutamyl", "glutamic acid", "amino acids" ], "offsets": [ [ 139, 144 ], [ 150, 157 ], [ 15, 23 ], [ 206, 219 ], [ 297, 308 ] ] }, { "pmid": "9063462", "text": "The intron/exon organization of the Drosophila gene reveals the presence of six exons among which four are in the 5'-end encoding glutamic acid activity.", "type": "CHEMICAL", "entities": [ "glutamic acid" ], "offsets": [ [ 130, 143 ] ] }, { "pmid": "9063462", "text": "The small mRNA promoter resides in the 4th intron and evidence is provided that the mRNA encodes only the domain corresponding to prolyl-tRNA synthetase and is functional in vivo.", "type": "CHEMICAL", "entities": [ "prolyl" ], "offsets": [ [ 130, 136 ] ] }, { "pmid": "9204085", "text": "Pharmacology and chemistry of adapalene.\n", "type": "CHEMICAL", "entities": [ "adapalene" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "9204085", "text": "BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones.", "type": "CHEMICAL", "entities": [ "tretinoin", "Retinoid", "isotretinoin", "retinoic acid", "vitamins" ], "offsets": [ [ 113, 122 ], [ 12, 20 ], [ 132, 144 ], [ 230, 243 ], [ 292, 300 ] ] }, { "pmid": "9204085", "text": "In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation.", "type": "CHEMICAL", "entities": [ "retinoids" ], "offsets": [ [ 71, 80 ] ] }, { "pmid": "9204085", "text": "Binding and transactivation assays were used to compare affinities and transcriptional activities of adapalene and tretinoin for the nuclear transcription factors, retinoic acid receptors (RARs).", "type": "CHEMICAL", "entities": [ "tretinoin", "retinoic acid", "adapalene" ], "offsets": [ [ 115, 124 ], [ 164, 177 ], [ 101, 110 ] ] }, { "pmid": "9204085", "text": "Adapalene is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation.", "type": "CHEMICAL", "entities": [ "Adapalene", "naphthoic acid", "retinoid" ], "offsets": [ [ 0, 9 ], [ 22, 36 ], [ 60, 68 ] ] }, { "pmid": "9204085", "text": "The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of adapalene.", "type": "CHEMICAL", "entities": [ "retinoid", "adapalene" ], "offsets": [ [ 74, 82 ], [ 95, 104 ] ] }, { "pmid": "9211565", "text": "Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds.\n", "type": "CHEMICAL", "entities": [ "Cinitapride", "prostaglandins", "sulfhydryl", "ethanol", "5-hydroxytryptamine" ], "offsets": [ [ 0, 11 ], [ 106, 120 ], [ 125, 135 ], [ 29, 36 ], [ 85, 104 ] ] }, { "pmid": "9211565", "text": "This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol.", "type": "CHEMICAL", "entities": [ "cinitapride", "benzamide", "CNT", "ethanol" ], "offsets": [ [ 72, 83 ], [ 110, 119 ], [ 85, 88 ], [ 230, 237 ] ] }, { "pmid": "9211565", "text": "Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1).", "type": "CHEMICAL", "entities": [ "5-hydroxytryptamine", "5-HT" ], "offsets": [ [ 37, 56 ], [ 58, 62 ] ] }, { "pmid": "9211565", "text": "The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined.", "type": "CHEMICAL", "entities": [ "sulfhydryl", "SH", "CNT", "prostaglandins", "PGs" ], "offsets": [ [ 90, 100 ], [ 112, 114 ], [ 146, 149 ], [ 65, 79 ], [ 81, 84 ] ] }, { "pmid": "9211565", "text": "Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus.", "type": "CHEMICAL", "entities": [ "CNT", "ethanol", "hexosamine" ], "offsets": [ [ 34, 37 ], [ 74, 81 ], [ 144, 154 ] ] }, { "pmid": "9211565", "text": "CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values.", "type": "CHEMICAL", "entities": [ "CNT", "PGE2", "SH" ], "offsets": [ [ 0, 3 ], [ 82, 86 ], [ 134, 136 ] ] }, { "pmid": "9211565", "text": "On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased.", "type": "CHEMICAL", "entities": [ "5-HT", "ethanol", "PGE2", "SH" ], "offsets": [ [ 35, 39 ], [ 49, 56 ], [ 148, 152 ], [ 186, 188 ] ] }, { "pmid": "9211565", "text": "The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism.", "type": "CHEMICAL", "entities": [ "CNT", "PG" ], "offsets": [ [ 69, 72 ], [ 112, 114 ] ] }, { "pmid": "9211565", "text": "We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved.", "type": "CHEMICAL", "entities": [ "5-HT" ], "offsets": [ [ 16, 20 ] ] }, { "pmid": "9231703", "text": "When the cloned guinea pig calcitonin receptor was transfected into COS 1 cells, salmon calcitonin stimulated intracellular cyclic AMP accumulation with an EC50 of 0.1 nM, whereas human calcitonin was >250-fold less potent (EC50 27.6 nM).", "type": "CHEMICAL", "entities": [ "cyclic AMP" ], "offsets": [ [ 124, 134 ] ] }, { "pmid": "9231703", "text": "Stimulation of the transfected guinea pig calcitonin receptor by salmon calcitonin also resulted in phosphatidylinositol hydrolysis with an EC50 of 2.5 nM. Expression of the calcitonin receptor was mapped by a combination of RT-PCR, northern analysis, and expression in Xenopus oocytes.", "type": "CHEMICAL", "entities": [ "phosphatidylinositol" ], "offsets": [ [ 100, 120 ] ] }, { "pmid": "9299436", "text": "Adenosine deaminase is a specific partner for the Grb2 isoform Grb3-3.\nGrb3-3 is an isoform of Grb2, thought to arise by alternative splicing, that lacks a functional SH2 domain but retains functional SH3 domains, which allow interaction with other proteins through binding to prolinerich sequences.", "type": "CHEMICAL", "entities": [ "Adenosine" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "9299436", "text": "We have identified adenosine deaminase, an enzyme involved in purine metabolism whose deficiency is associated with severe combined immunodeficiency, as a Grb3-3 binding protein that is not able to bind to Grb2.", "type": "CHEMICAL", "entities": [ "adenosine", "purine" ], "offsets": [ [ 19, 28 ], [ 62, 68 ] ] }, { "pmid": "9310349", "text": "Alendronate inhibition of protein-tyrosine-phosphatase-meg1.\n", "type": "CHEMICAL", "entities": [ "Alendronate", "tyrosine" ], "offsets": [ [ 0, 11 ], [ 34, 42 ] ] }, { "pmid": "9310349", "text": "Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis.", "type": "CHEMICAL", "entities": [ "bisphosphonate", "Alendronate", "4-amino-1-hydroxybutylidene-1,1-bisphosphonate" ], "offsets": [ [ 73, 87 ], [ 0, 11 ], [ 13, 59 ] ] }, { "pmid": "9310349", "text": "Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1).", "type": "CHEMICAL", "entities": [ "alendronate", "tyrosine" ], "offsets": [ [ 20, 31 ], [ 69, 77 ] ] }, { "pmid": "9310349", "text": "Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527.", "type": "CHEMICAL", "entities": [ "diphosphate" ], "offsets": [ [ 56, 67 ] ] }, { "pmid": "9310349", "text": "With either substrate, alendronate was a slow binding inhibitor of PTPmeg1.", "type": "CHEMICAL", "entities": [ "alendronate" ], "offsets": [ [ 23, 34 ] ] }, { "pmid": "9310349", "text": "Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1.", "type": "CHEMICAL", "entities": [ "bisphosphonates", "alendronate" ], "offsets": [ [ 16, 31 ], [ 41, 52 ] ] }, { "pmid": "9310349", "text": "The hydrolysis of fluorescein diphosphate by PTP epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate.", "type": "CHEMICAL", "entities": [ "diphosphate", "alendronate", "alendronate" ], "offsets": [ [ 30, 41 ], [ 86, 97 ], [ 227, 238 ] ] }, { "pmid": "9310349", "text": "Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent.", "type": "CHEMICAL", "entities": [ "alendronate" ], "offsets": [ [ 41, 52 ] ] }, { "pmid": "9310349", "text": "Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations", "type": "CHEMICAL", "entities": [ "Alendronate" ], "offsets": [ [ 0, 11 ] ] }, { "pmid": "9310349", "text": "up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor.", "type": "CHEMICAL", "entities": [ "alendronate" ], "offsets": [ [ 16, 27 ] ] }, { "pmid": "9310349", "text": "PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition.", "type": "CHEMICAL", "entities": [ "hisphosphonates", "vanadate", "EDTA", "dithiothreitol", "cysteine" ], "offsets": [ [ 18, 33 ], [ 37, 45 ], [ 90, 94 ], [ 121, 135 ], [ 188, 196 ] ] }, { "pmid": "9310349", "text": "These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action.", "type": "CHEMICAL", "entities": [ "alendronate", "alendronate" ], "offsets": [ [ 167, 178 ], [ 73, 84 ] ] }, { "pmid": "9313928", "text": "Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells.\n", "type": "CHEMICAL", "entities": [ "prostanoid" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "9313928", "text": "Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells.", "type": "CHEMICAL", "entities": [ "FP", "prostaglandin I", "IP", "prostaglandin F", "thromboxane A", "TP", "prostaglandin E", "prostanoid", "prostaglandin D", "DP" ], "offsets": [ [ 115, 117 ], [ 133, 148 ], [ 150, 152 ], [ 98, 113 ], [ 168, 181 ], [ 183, 185 ], [ 242, 257 ], [ 38, 48 ], [ 63, 78 ], [ 80, 82 ] ] }, { "pmid": "9313928", "text": "Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors.", "type": "CHEMICAL", "entities": [ "prostanoids" ], "offsets": [ [ 67, 78 ] ] }, { "pmid": "9313928", "text": "2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP.", "type": "CHEMICAL", "entities": [ "DP", "IP", "TP", "PGD2", "BW245C", "BW868C", "DP", "cicaprost", "iloprost", "isocabacyclin", "IP", "S-145", "I-BOP", "GR 32191", "TP" ], "offsets": [ [ 7, 9 ], [ 11, 13 ], [ 18, 20 ], [ 139, 143 ], [ 145, 151 ], [ 156, 162 ], [ 167, 169 ], [ 171, 180 ], [ 182, 190 ], [ 195, 208 ], [ 213, 215 ], [ 221, 226 ], [ 228, 233 ], [ 238, 246 ], [ 251, 253 ] ] }, { "pmid": "9313928", "text": "The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4.", "type": "CHEMICAL", "entities": [ "FP", "PGF2", "fluprostenol", "PGD2", "17-phenyl-PGE2", "STA2", "I-BOP", "PGE2", "M&B-28767" ], "offsets": [ [ 4, 6 ], [ 22, 26 ], [ 37, 49 ], [ 89, 93 ], [ 95, 109 ], [ 111, 115 ], [ 117, 122 ], [ 124, 128 ], [ 133, 142 ] ] }, { "pmid": "9313928", "text": "The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor.", "type": "CHEMICAL", "entities": [ "17-phenyl-PGE2", "sulprostone", "iloprost", "PGE2", "PGE1", "16,16-dimethyl-PGE2", "AH6809", "SC-19220" ], "offsets": [ [ 23, 37 ], [ 39, 50 ], [ 55, 63 ], [ 79, 83 ], [ 88, 92 ], [ 122, 141 ], [ 176, 182 ], [ 187, 195 ] ] }, { "pmid": "9313928", "text": "M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5.", "type": "CHEMICAL", "entities": [ "M&B-28767", "misoprostol" ], "offsets": [ [ 0, 9 ], [ 39, 50 ] ] }, { "pmid": "9313928", "text": "They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1.", "type": "CHEMICAL", "entities": [ "16,16-dimethyl PGE2", "11-deoxy-PGE1", "PGE2", "PGE1" ], "offsets": [ [ 11, 30 ], [ 35, 48 ], [ 64, 68 ], [ 73, 77 ] ] }, { "pmid": "9313928", "text": "The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor.", "type": "CHEMICAL", "entities": [ "butaprost", "AH-13205", "AH-6809", "1-OH-PGE1" ], "offsets": [ [ 40, 49 ], [ 51, 59 ], [ 64, 71 ], [ 139, 148 ] ] }, { "pmid": "9313928", "text": "The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively.", "type": "CHEMICAL", "entities": [ "sulprostone", "M&B-28767", "GR63799X", "11-deoxy-PGE1", "16,16-dimethyl-PGE2", "17-phenyl-PGE2", "PGE2", "PGE1", "IP", "iloprost", "carbacyclin", "isocarbacyclin", "TP", "STA2", "IP", "TP" ], "offsets": [ [ 64, 75 ], [ 77, 86 ], [ 88, 96 ], [ 98, 111 ], [ 113, 132 ], [ 137, 151 ], [ 168, 172 ], [ 177, 181 ], [ 232, 234 ], [ 244, 252 ], [ 254, 265 ], [ 270, 284 ], [ 294, 296 ], [ 305, 309 ], [ 404, 406 ], [ 411, 413 ] ] }, { "pmid": "9313928", "text": "7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration.", "type": "CHEMICAL", "entities": [ "7. 8-Epi-PGF2", "IP", "TP", "FP" ], "offsets": [ [ 0, 13 ], [ 52, 54 ], [ 56, 58 ], [ 60, 62 ] ] }, { "pmid": "9336833", "text": "The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue.\n", "type": "CHEMICAL", "entities": [ "thymidine" ], "offsets": [ [ 18, 27 ] ] }, { "pmid": "9336833", "text": "Thymidine kinase from Herpes simplex virus type 1 (TK) was crystallized in an N-terminally truncated but fully active form.", "type": "CHEMICAL", "entities": [ "Thymidine", "N" ], "offsets": [ [ 0, 9 ], [ 78, 79 ] ] }, { "pmid": "9336833", "text": "The structures of TK complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively.", "type": "CHEMICAL", "entities": [ "dT", "idoxuridine-5'-phosphate", "5-iodo-dUMP", "ADP", "ATP", "deoxythymidine-5'-monophosphate", "dTMP", "deoxythymidine" ], "offsets": [ [ 116, 118 ], [ 124, 148 ], [ 150, 161 ], [ 36, 39 ], [ 47, 50 ], [ 60, 91 ], [ 93, 97 ], [ 100, 114 ] ] }, { "pmid": "9336833", "text": "TK catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride.", "type": "CHEMICAL", "entities": [ "TK", "dT", "ester", "dTMP", "anhydride" ], "offsets": [ [ 0, 2 ], [ 36, 38 ], [ 55, 60 ], [ 89, 93 ], [ 112, 121 ] ] }, { "pmid": "9336833", "text": "The presented TK structures indicate that there are only small differences between these two modes of action.", "type": "CHEMICAL", "entities": [ "TK" ], "offsets": [ [ 14, 16 ] ] }, { "pmid": "9336833", "text": "Glu83 serves as a general base in the ester reaction.", "type": "CHEMICAL", "entities": [ "ester" ], "offsets": [ [ 38, 43 ] ] }, { "pmid": "9336833", "text": "Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation.", "type": "CHEMICAL", "entities": [ "aspartate", "ester", "alpha-phosphate", "dTMP", "anhydride" ], "offsets": [ [ 28, 37 ], [ 45, 50 ], [ 75, 90 ], [ 94, 98 ], [ 106, 115 ] ] }, { "pmid": "9336833", "text": "The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2.", "type": "CHEMICAL", "entities": [ "deoxythymidine" ], "offsets": [ [ 10, 24 ] ] }, { "pmid": "9336833", "text": "Cavity and water molecules reduce the substrate specificity to such an extent that TK can phosphorylate various substrate analogues useful in pharmaceutical applications.", "type": "CHEMICAL", "entities": [ "TK", "phosphorylate" ], "offsets": [ [ 83, 85 ], [ 90, 103 ] ] }, { "pmid": "9336833", "text": "TK is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments.", "type": "CHEMICAL", "entities": [ "TK", "nucleoside monophosphate" ], "offsets": [ [ 0, 2 ], [ 48, 72 ] ] }, { "pmid": "9374794", "text": "Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride.\n", "type": "CHEMICAL", "entities": [ "K+", "cisapride" ], "offsets": [ [ 35, 37 ], [ 87, 96 ] ] }, { "pmid": "9374794", "text": "Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias.", "type": "CHEMICAL", "entities": [ "Cisapride" ], "offsets": [ [ 0, 9 ] ] }, { "pmid": "9374794", "text": "The human ether-a-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisapride.", "type": "CHEMICAL", "entities": [ "K+", "cisapride" ], "offsets": [ [ 100, 102 ], [ 195, 204 ] ] }, { "pmid": "9374794", "text": "We tested the hypothesis that cisapride blocks HERG.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 30, 39 ] ] }, { "pmid": "9374794", "text": "Under voltage-clamp conditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells).", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 32, 41 ] ] }, { "pmid": "9374794", "text": "The onset of block by cisapride required channel activation indicative of open or inactivated state blockage.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 22, 31 ] ] }, { "pmid": "9374794", "text": "Block of HERG with cisapride after channel activation was voltage dependent.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 19, 28 ] ] }, { "pmid": "9374794", "text": "At -20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells).", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "9374794", "text": "and + 20 mV, 100 nM cisapride reduced tail-current amplitude by 66 and 90%, respectively.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 20, 29 ] ] }, { "pmid": "9374794", "text": "We conclude that cisapride is a potent blocker of HERG channels expressed in HEK293 cells.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 17, 26 ] ] }, { "pmid": "9374794", "text": "This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with cisapride.", "type": "CHEMICAL", "entities": [ "cisapride" ], "offsets": [ [ 114, 123 ] ] }, { "pmid": "9417820", "text": "Analysis of NMDA receptors in the human spinal cord.\n", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 12, 16 ] ] }, { "pmid": "9417820", "text": "NMDA receptors in postmortem human spinal cord were analyzed using [3H]MK-801 ligand binding and immunoblotting with NMDA receptor subunit-specific antibodies.", "type": "CHEMICAL", "entities": [ "NMDA", "NMDA", "[3H]MK-801" ], "offsets": [ [ 0, 4 ], [ 117, 121 ], [ 67, 77 ] ] }, { "pmid": "9417820", "text": "The average KD for [3H]MK-801 binding was 1.77 nM with a Bmax of 0.103 pmol/mg.", "type": "CHEMICAL", "entities": [ "[3H]MK-801" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "9417820", "text": "The EC50 for stimulation of -3H-MK-801 binding with L-glutamate was 0.34 microM.", "type": "CHEMICAL", "entities": [ "3H-MK-801", "L-glutamate" ], "offsets": [ [ 29, 38 ], [ 52, 63 ] ] }, { "pmid": "9417820", "text": "None of these parameters were affected by postmortem intervals up to 72 h. Immunoblotting of native NMDA receptors showed that NR1, NR2A, NR2C, and NR2D subunits could all be found in the human spinal cord of which NR1 was preferentially located to the dorsal half.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 100, 104 ] ] }, { "pmid": "9417820", "text": "Immunoprecipitation of solubilized receptors revealed that NR1, NR2C, and NR2D subunits coprecipitated with the NR2A subunit, indicating that native human spinal cord NMDA receptors are heteroligimeric receptors assembled by at least three different receptor subunits.", "type": "CHEMICAL", "entities": [ "NMDA", "heteroligimeric" ], "offsets": [ [ 167, 171 ], [ 186, 201 ] ] }, { "pmid": "9417820", "text": "These results provide a basis for the development of drugs selectively aimed at spinal cord NMDA receptors for the future treatment of spinal cord disorders.", "type": "CHEMICAL", "entities": [ "NMDA" ], "offsets": [ [ 92, 96 ] ] }, { "pmid": "9476974", "text": "Monoamine transporter and sodium channel mechanisms in the rapid pressor response to cocaine.\n", "type": "CHEMICAL", "entities": [ "Monoamine", "sodium", "cocaine" ], "offsets": [ [ 0, 9 ], [ 26, 32 ], [ 85, 92 ] ] }, { "pmid": "9476974", "text": "Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390.", "type": "CHEMICAL", "entities": [ "dopamine", "SCH 23390", "cocaine" ], "offsets": [ [ 155, 163 ], [ 185, 194 ], [ 19, 26 ] ] }, { "pmid": "9476974", "text": "Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response.", "type": "CHEMICAL", "entities": [ "Monoamine", "cocaine", "cocaethylene", "CFT", "betaCIT", "CPT", "(+)-cocaine", "norcocaine", "benztropine", "monoamine", "BTCP", "indatraline", "GBR 12935", "mazindol", "nomifensine", "zimeldine" ], "offsets": [ [ 0, 9 ], [ 54, 61 ], [ 63, 75 ], [ 77, 80 ], [ 82, 89 ], [ 91, 94 ], [ 96, 107 ], [ 109, 119 ], [ 125, 136 ], [ 243, 252 ], [ 280, 284 ], [ 286, 297 ], [ 299, 308 ], [ 310, 318 ], [ 320, 331 ], [ 337, 346 ] ] }, { "pmid": "9476974", "text": "At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP.", "type": "CHEMICAL", "entities": [ "sodium", "acetylprocainamide", "dibucaine", "dyclonine", "prilocaine", "proparacaine", "quinidine", "tetracaine" ], "offsets": [ [ 28, 34 ], [ 52, 70 ], [ 72, 81 ], [ 83, 92 ], [ 94, 104 ], [ 106, 118 ], [ 120, 129 ], [ 135, 145 ] ] }, { "pmid": "9476974", "text": "In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity.", "type": "CHEMICAL", "entities": [ "cocaine", "CFT" ], "offsets": [ [ 43, 50 ], [ 67, 70 ] ] }, { "pmid": "9476974", "text": "Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration.", "type": "CHEMICAL", "entities": [ "SCH 23390", "cocaine", "CFT" ], "offsets": [ [ 18, 27 ], [ 127, 134 ], [ 139, 142 ] ] }, { "pmid": "9476974", "text": "The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine.", "type": "CHEMICAL", "entities": [ "dopamine", "norepinephrine", "serotonin", "cocaine" ], "offsets": [ [ 48, 56 ], [ 58, 72 ], [ 77, 86 ], [ 189, 196 ] ] }, { "pmid": "9476974", "text": "The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine.", "type": "CHEMICAL", "entities": [ "cocaine", "sodium", "cocaine" ], "offsets": [ [ 117, 124 ], [ 4, 10 ], [ 38, 45 ] ] }, { "pmid": "9476974", "text": "Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine.", "type": "CHEMICAL", "entities": [ "cocaine" ], "offsets": [ [ 157, 164 ] ] }, { "pmid": "9480897", "text": "Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4.\n", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 55, 66 ] ] }, { "pmid": "9480897", "text": "The Expressed Sequence Tag database has been searched for examples of previously undescribed human Alpha class glutathione transferases.", "type": "CHEMICAL", "entities": [ "glutathione" ], "offsets": [ [ 111, 122 ] ] }, { "pmid": "9551716", "text": "Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain.\n", "type": "CHEMICAL", "entities": [ "neurotensin", "[3H]SR 142948A" ], "offsets": [ [ 43, 54 ], [ 76, 90 ] ] }, { "pmid": "9551716", "text": "The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A", "2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride", "neurotensin" ], "offsets": [ [ 166, 180 ], [ 182, 356 ], [ 143, 154 ] ] }, { "pmid": "9551716", "text": "The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A" ], "offsets": [ [ 15, 29 ] ] }, { "pmid": "9551716", "text": "[3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A", "[3H]neurotensin" ], "offsets": [ [ 0, 14 ], [ 206, 221 ] ] }, { "pmid": "9551716", "text": "[3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A", "SR 142948A", "SR 48692", "2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid", "neurotensin" ], "offsets": [ [ 0, 14 ], [ 40, 50 ], [ 96, 104 ], [ 106, 219 ], [ 225, 236 ] ] }, { "pmid": "9551716", "text": "Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively).", "type": "CHEMICAL", "entities": [ "histamine", "levocabastine", "[3H]SR 142948A", "levocabastine", "neurotensin", "levocabastine" ], "offsets": [ [ 69, 78 ], [ 103, 116 ], [ 132, 146 ], [ 189, 202 ], [ 215, 226 ], [ 303, 316 ] ] }, { "pmid": "9551716", "text": "The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A", "[125I]neurotensin" ], "offsets": [ [ 29, 43 ], [ 105, 122 ] ] }, { "pmid": "9551716", "text": "In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain.", "type": "CHEMICAL", "entities": [ "[3H]SR 142948A", "neurotensin", "neurotensin" ], "offsets": [ [ 44, 58 ], [ 139, 150 ], [ 220, 231 ] ] }, { "pmid": "9557255", "text": "Adapalene is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology.", "type": "CHEMICAL", "entities": [ "Adapalene", "naphthoic acid", "retinoid" ], "offsets": [ [ 0, 9 ], [ 22, 36 ], [ 71, 79 ] ] }, { "pmid": "9557255", "text": "The retinoid action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and RAR gamma.", "type": "CHEMICAL", "entities": [ "retinoid", "adapalene", "retinoic acid" ], "offsets": [ [ 4, 12 ], [ 23, 32 ], [ 97, 110 ] ] }, { "pmid": "9557255", "text": "We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne.", "type": "CHEMICAL", "entities": [ "adapalene" ], "offsets": [ [ 47, 56 ] ] }, { "pmid": "9584217", "text": "Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties.\n", "type": "CHEMICAL", "entities": [ "calcium", "dihydropyridines" ], "offsets": [ [ 38, 45 ], [ 58, 74 ] ] }, { "pmid": "9584217", "text": "Dihydropyridines (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state.", "type": "CHEMICAL", "entities": [ "Dihydropyridines", "DHPs", "Ca2+" ], "offsets": [ [ 0, 16 ], [ 18, 22 ], [ 37, 41 ] ] }, { "pmid": "9584217", "text": "Nisoldipine (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels.", "type": "CHEMICAL", "entities": [ "Nisoldipine", "DHP" ], "offsets": [ [ 0, 11 ], [ 15, 18 ] ] }, { "pmid": "9584217", "text": "We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion.", "type": "CHEMICAL", "entities": [ "Ca2+" ], "offsets": [ [ 155, 159 ] ] }, { "pmid": "9584217", "text": "Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state.", "type": "CHEMICAL", "entities": [ "nisoldipine" ], "offsets": [ [ 65, 76 ] ] }, { "pmid": "9584217", "text": "We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type Ca2+ channels is not attributable to differences in channel inactivation or activation.", "type": "CHEMICAL", "entities": [ "nisoldipine", "Ca2+" ], "offsets": [ [ 38, 49 ], [ 100, 104 ] ] }, { "pmid": "9584217", "text": "Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block.", "type": "CHEMICAL", "entities": [ "DHP", "DHP" ], "offsets": [ [ 30, 33 ], [ 139, 142 ] ] }, { "pmid": "9587031", "text": "The main remethylation defects include disorders which all have defective methionine synthesis in common.", "type": "CHEMICAL", "entities": [ "methionine" ], "offsets": [ [ 74, 84 ] ] }, { "pmid": "9587031", "text": "Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis.", "type": "CHEMICAL", "entities": [ "Methylenetetrahydrofolate", "methyltetrahydrofolate", "hydroxocobalamin", "methyl", "adenosyl cobalamin", "methionine", "methyl cobalamin" ], "offsets": [ [ 0, 25 ], [ 55, 77 ], [ 123, 139 ], [ 178, 184 ], [ 190, 208 ], [ 229, 239 ], [ 288, 304 ] ] }, { "pmid": "9587031", "text": "Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose).", "type": "CHEMICAL", "entities": [ "hydroxocobalamin", "Cobalamin" ], "offsets": [ [ 80, 96 ], [ 0, 9 ] ] }, { "pmid": "9587031", "text": "Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial.", "type": "CHEMICAL", "entities": [ "methylenetetrahydrofolate", "folate" ], "offsets": [ [ 5, 30 ], [ 49, 55 ] ] }, { "pmid": "9587031", "text": "In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration.", "type": "CHEMICAL", "entities": [ "betaine" ], "offsets": [ [ 18, 25 ] ] }, { "pmid": "9614060", "text": "Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines.\n", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 33, 43 ] ] }, { "pmid": "9614060", "text": "Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide.", "type": "CHEMICAL", "entities": [ "Arginine", "nitric oxide" ], "offsets": [ [ 0, 8 ], [ 146, 158 ] ] }, { "pmid": "9614060", "text": "The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined.", "type": "CHEMICAL", "entities": [ "L-Arg" ], "offsets": [ [ 16, 21 ] ] }, { "pmid": "9614060", "text": "System y+ cationic amino acid transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and Cat3.", "type": "CHEMICAL", "entities": [ "amino acid" ], "offsets": [ [ 19, 29 ] ] }, { "pmid": "9614060", "text": "High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1.", "type": "CHEMICAL", "entities": [ "L-arginine" ], "offsets": [ [ 14, 24 ] ] }, { "pmid": "9614060", "text": "Both wild type and knockout cells transport arginine with comparable Km and Vmax.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 44, 52 ] ] }, { "pmid": "9614060", "text": "However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport.", "type": "CHEMICAL", "entities": [ "lysine" ], "offsets": [ [ 35, 41 ] ] }, { "pmid": "9614060", "text": "These results suggest that Cat3 compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport.", "type": "CHEMICAL", "entities": [ "arginine" ], "offsets": [ [ 160, 168 ] ] }, { "pmid": "9712175", "text": "Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans.\n", "type": "CHEMICAL", "entities": [ "lintitript" ], "offsets": [ [ 10, 20 ] ] }, { "pmid": "9712175", "text": "We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript.", "type": "CHEMICAL", "entities": [ "lintitript" ], "offsets": [ [ 153, 163 ] ] }, { "pmid": "9712175", "text": "Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days.", "type": "CHEMICAL", "entities": [ "lintitript" ], "offsets": [ [ 134, 144 ] ] }, { "pmid": "9712175", "text": "After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi.", "type": "CHEMICAL", "entities": [ "99mTc-sulfur" ], "offsets": [ [ 69, 81 ] ] }, { "pmid": "9712175", "text": "111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera.", "type": "CHEMICAL", "entities": [ "111In-DTPA" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "9712175", "text": "Lintitript distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered.", "type": "CHEMICAL", "entities": [ "Lintitript" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "9712175", "text": "Lintitript markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo.", "type": "CHEMICAL", "entities": [ "Lintitript" ], "offsets": [ [ 0, 10 ] ] }, { "pmid": "9712175", "text": "The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans.", "type": "CHEMICAL", "entities": [ "lintitript" ], "offsets": [ [ 115, 125 ] ] }, { "pmid": "9730867", "text": "Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol.", "type": "CHEMICAL", "entities": [ "isoproterenol", "fenoterol" ], "offsets": [ [ 131, 144 ], [ 182, 191 ] ] }, { "pmid": "9730867", "text": "The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist.", "type": "CHEMICAL", "entities": [ "ICI 118,551", "timolol" ], "offsets": [ [ 108, 119 ], [ 138, 145 ] ] }, { "pmid": "9730867", "text": "The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect.", "type": "CHEMICAL", "entities": [ "atenolol" ], "offsets": [ [ 33, 41 ] ] }, { "pmid": "9730867", "text": "Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA.", "type": "CHEMICAL", "entities": [ "isoproterenol" ], "offsets": [ [ 76, 89 ] ] }, { "pmid": "9730867", "text": "In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels.", "type": "CHEMICAL", "entities": [ "cyclic adenosine monophosphate", "cAMP" ], "offsets": [ [ 172, 202 ], [ 204, 208 ] ] }, { "pmid": "9730867", "text": "Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels.", "type": "CHEMICAL", "entities": [ "BRL 37344", "cAMP" ], "offsets": [ [ 180, 189 ], [ 297, 301 ] ] }, { "pmid": "9760035", "text": "Oxytocin receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation.\n", "type": "CHEMICAL", "entities": [ "Oxytocin", "carbetocin" ], "offsets": [ [ 0, 8 ], [ 53, 63 ] ] }, { "pmid": "9760035", "text": "Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated.", "type": "CHEMICAL", "entities": [ "1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin", "carbetocin" ], "offsets": [ [ 28, 75 ], [ 77, 87 ] ] }, { "pmid": "9760035", "text": "Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II).", "type": "CHEMICAL", "entities": [ "desGlyNH2", "carbetocin", "carbetocin", "desLeuGlyNH2", "carbetocin", "carbetocin" ], "offsets": [ [ 70, 79 ], [ 80, 90 ], [ 92, 102 ], [ 121, 133 ], [ 134, 144 ], [ 146, 156 ] ] }, { "pmid": "9760035", "text": "Both carbetocin, carbetocin metabolite I and carbetocin metabolite II displayed binding affinities to the myometrial oxytocin receptor of a similar magnitude as oxytocin.", "type": "CHEMICAL", "entities": [ "carbetocin", "carbetocin", "carbetocin", "oxytocin", "oxytocin" ], "offsets": [ [ 5, 15 ], [ 17, 27 ], [ 45, 55 ], [ 117, 125 ], [ 161, 169 ] ] }, { "pmid": "9760035", "text": "Carbetocin was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for oxytocin.", "type": "CHEMICAL", "entities": [ "Carbetocin", "inositol phosphates", "oxytocin" ], "offsets": [ [ 0, 10 ], [ 140, 159 ], [ 180, 188 ] ] }, { "pmid": "9760035", "text": "However, maximal contractile effect of carbetocin was approximately 50% lower than that of oxytocin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM).", "type": "CHEMICAL", "entities": [ "carbetocin", "oxytocin" ], "offsets": [ [ 39, 49 ], [ 91, 99 ] ] }, { "pmid": "9760035", "text": "Neither carbetocin metabolite I nor carbetocin metabolite II were able to contract isolated myometrial tissue.", "type": "CHEMICAL", "entities": [ "carbetocin", "carbetocin" ], "offsets": [ [ 36, 46 ], [ 8, 18 ] ] }, { "pmid": "9760035", "text": "All three compounds displayed antagonistic properties against oxytocin in vitro, with carbetocin being the strongest inhibitor (pA2 = 8.21) and carbetocin metabolite II (pA2 = 8.01) being stronger than carbetocin metabolite I (pA2 = 7.81).", "type": "CHEMICAL", "entities": [ "oxytocin", "carbetocin", "carbetocin", "carbetocin" ], "offsets": [ [ 62, 70 ], [ 86, 96 ], [ 144, 154 ], [ 202, 212 ] ] }, { "pmid": "9760035", "text": "These results indicate that carbetocin is a partial agonist/antagonist to the oxytocin receptor while the two metabolites carbetocin metabolite I and carbetocin metabolite II are pure antagonists.", "type": "CHEMICAL", "entities": [ "carbetocin", "oxytocin", "carbetocin", "carbetocin" ], "offsets": [ [ 28, 38 ], [ 78, 86 ], [ 122, 132 ], [ 150, 160 ] ] }, { "pmid": "9760035", "text": "All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the oxytocin receptor.", "type": "CHEMICAL", "entities": [ "vasopressin", "oxytocin" ], "offsets": [ [ 44, 55 ], [ 115, 123 ] ] }, { "pmid": "9760035", "text": "Carbetocin metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for carbetocin and 9.89 + 2.80 nM for carbetocin metabolite I. Only carbetocin bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM).", "type": "CHEMICAL", "entities": [ "Carbetocin", "carbetocin", "carbetocin", "carbetocin", "vasopressin" ], "offsets": [ [ 0, 10 ], [ 114, 124 ], [ 148, 158 ], [ 178, 188 ], [ 208, 219 ] ] }, { "pmid": "9843368", "text": "Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution.\n", "type": "CHEMICAL", "entities": [ "phenylalanine", "catechol" ], "offsets": [ [ 39, 52 ], [ 93, 101 ] ] }, { "pmid": "9843368", "text": "The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives.", "type": "CHEMICAL", "entities": [ "aromatic amino acid", "catechol" ], "offsets": [ [ 4, 23 ], [ 173, 181 ] ] }, { "pmid": "9843368", "text": "Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex.", "type": "CHEMICAL", "entities": [ "catechols", "iron", "catechol hydroxyl", "phenylalanine", "catechol" ], "offsets": [ [ 246, 255 ], [ 295, 299 ], [ 342, 359 ], [ 98, 111 ], [ 184, 192 ] ] }, { "pmid": "9843368", "text": "In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC).", "type": "CHEMICAL", "entities": [ "catecholamine", "PheOH" ], "offsets": [ [ 107, 120 ], [ 132, 137 ] ] }, { "pmid": "9843368", "text": "The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms).", "type": "CHEMICAL", "entities": [ "catechol" ], "offsets": [ [ 29, 37 ] ] }, { "pmid": "9843368", "text": "Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups.", "type": "CHEMICAL", "entities": [ "catechol hydroxyl" ], "offsets": [ [ 72, 89 ] ] }, { "pmid": "9843368", "text": "This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy", "type": "CHEMICAL", "entities": [ "noradrenaline" ], "offsets": [ [ 172, 185 ] ] }, { "pmid": "9843368", "text": "Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4.", "type": "CHEMICAL", "entities": [ "tyrosine", "7,8-dihydrobiopterin", "catechols", "catechols" ], "offsets": [ [ 62, 70 ], [ 125, 145 ], [ 189, 198 ], [ 273, 282 ] ] }, { "pmid": "9891987", "text": "In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action.", "type": "CHEMICAL", "entities": [ "steroid" ], "offsets": [ [ 71, 78 ] ] }, { "pmid": "9891987", "text": "Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis.", "type": "CHEMICAL", "entities": [ "Betamethasone", "triamcinolone", "dexamethasone", "clobetasol" ], "offsets": [ [ 0, 13 ], [ 15, 28 ], [ 30, 43 ], [ 48, 58 ] ] }, { "pmid": "9891987", "text": "All GCs including the antagonistic compound RU486 efficiently reduced NF-kappaB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression.", "type": "CHEMICAL", "entities": [ "RU486" ], "offsets": [ [ 44, 49 ] ] }, { "pmid": "9990013", "text": "Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide.\n", "type": "CHEMICAL", "entities": [ "ATP", "MgADP", "sulfonylurea", "glibenclamide" ], "offsets": [ [ 23, 26 ], [ 31, 36 ], [ 44, 56 ], [ 82, 95 ] ] }, { "pmid": "9990013", "text": "The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion.", "type": "CHEMICAL", "entities": [ "potassium", "ATP", "glucose" ], "offsets": [ [ 18, 27 ], [ 4, 7 ], [ 103, 110 ] ] }, { "pmid": "9990013", "text": "Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear.", "type": "CHEMICAL", "entities": [ "ATP", "MgADP" ], "offsets": [ [ 95, 98 ], [ 100, 105 ] ] }, { "pmid": "9990013", "text": "The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits.", "type": "CHEMICAL", "entities": [ "ATP", "nucleotide" ], "offsets": [ [ 71, 74 ], [ 113, 123 ] ] }, { "pmid": "9990013", "text": "Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1.", "type": "CHEMICAL", "entities": [ "MgATP", "MgADP", "Mg", "gamma-thio-ATP", "8-azido-[alpha-32P]ATP" ], "offsets": [ [ 21, 26 ], [ 31, 36 ], [ 50, 52 ], [ 61, 75 ], [ 111, 133 ] ] }, { "pmid": "9990013", "text": "Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP.", "type": "CHEMICAL", "entities": [ "MgADP" ], "offsets": [ [ 91, 96 ] ] }, { "pmid": "9990013", "text": "These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1.", "type": "CHEMICAL", "entities": [ "8-azido-ATP", "MgADP", "MgATP", "8-azido-ATP" ], "offsets": [ [ 38, 49 ], [ 76, 81 ], [ 142, 147 ], [ 177, 188 ] ] }, { "pmid": "9990013", "text": "The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner.", "type": "CHEMICAL", "entities": [ "sulfonylurea glibenclamide", "8-azido-[alpha-32P]ATP", "MgADP", "MgATP" ], "offsets": [ [ 4, 30 ], [ 58, 80 ], [ 110, 115 ], [ 119, 124 ] ] }, { "pmid": "9990013", "text": "This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1.", "type": "CHEMICAL", "entities": [ "ATP", "nucleotide", "glibenclamide", "ATP", "MgADP", "MgADP" ], "offsets": [ [ 245, 248 ], [ 63, 73 ], [ 120, 133 ], [ 174, 177 ], [ 182, 187 ], [ 217, 222 ] ] } ]