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Venkatachalam
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aging_reg_dataset

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gene_name string	gene_id string	category string	cell_name string	tissue_type string	phenotype string	aging_type string	experiment string	description string	target_gene string	regulatory_type_of_target_gene string	target_gene_experiment string	target_gene_description string	regulatory_pathway string	regulatory_type_of_pathway string	pathway_experiment string	pathway_description string	species string	experimental_category string	aging_characteristic string	pmid int64	source string	Atomic_force_microscopy_imaging int64	CCK_8_assay int64	Cell_transfection int64	Cell_viability_assay int64	ChIP_qPCR int64	Clonal_expansion_assay int64	Cytokine_assay int64	DNA_FISH int64	ELISA int64	EdU_assay int64	FITC_Annexin_V/PI int64	Flow_cytometry int64	GO_analysis int64	IHC int64	Immunofluorescence int64	Immunohistochemical_staining int64	Immunohistochemistry int64	Immunostainings int64	MTT_assay int64	RNA_seq int64	RT_PCR int64	RT_qPCR int64	SA__gal_activity int64	SA__gal_activity_assay int64	SA__gal_staining int64	Safranin_O int64	WST_1_assay int64	Western_blot int64	qRT_PCR int64	¦ÃH2AX_staining int64
FOXO1	2308	protein coding	CD8+T	--	Aging	Prevent	Cytokine assay//Flow cytometry	In Foxo1-KO T cells, CD28 was uniformly reduced in naive T cells, and it was even more reduced in P14 Foxo1-KO KLRG1low day 30 post-infection T cells, compared with WT. A further indication of senescence is the inability of T cells to produce effector cytokines upon stimulation: TNF, IFN-¦Ã, and interleukin-2 (IL-2). This was measured as the proportion of cytokine-expressing T cells (positive for TNF, IFN-¦Ã, or both), and was found to be diminished in T cells from Foxo1-KO mice compared with WT. Furthermore, the ability to simultaneously produce multiple cytokines, especially TNF, IFN-¦Ã, and IL-2, is a property of functional memory T cells, and as depicted in Figure 5G, Foxo1-KO mice possessed proportionately fewer double- and triple-cytokine-producing T cells.	BACH2//AP-1	Upregulation//Downregulation	CHIP-Seq//ATAC-seq//qRT-PCR	We found that FOXO1 exhibited genomic binding within and proximal to the Bach2 gene locus at multiple sites in naive and day 12 p.i. cells. We observed that Bach2 becomes FOXO1 dependent only post-activation. Whereas naive WT and Foxo1-KO cells had similar, abundant Bach2 mRNA expression, 7 and 12 days post-activation WT cells exhibited a ~4-fold increase versus Foxo1-KO cells, in both KLRG1low and KLRG1high subsets. The T cells were pre-sorted for KLRG1high and KLRG1low cells to segregate effector and memory-precursor populations. In both naive and post-infection (p.i.) T cells, among the prominent FOXO1-bound genomic sites were regulatory sequences of multiple AP-1 family members, including Fos, JunB, FosB, and JunD. FOXO1 bound to open chromatin proximal to the transcription start site (TSS) of each of these genes, or to nearby presumed enhancers (e.g., upstream of Fos). Found for both naive and day 12 P14 T cells, these data are consistent with FOXO1 acting as a direct or indirect co-repressor for genes that mediate T cell activation and differentiation.	--	--	--	--	Human	HL	cellular senescence	33,503,413	Gene	0	0	0	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
YAP1	10413	protein coding	SW 1353,Hs 819.T,Chondrocyte	knee	Chondrosarcoma	Prevent	Atomic force microscopy imaging//EdU assay//SA--gal activity assay	YAP1 knockdown significantly increased the percentage of senescence-associated ¦Â-galactosidase (SA-¦Â-gal)-positive cells in the two different CHS cell strains, including SW 1353 and Hs 819.T. AFM confirmed that knockdown of YAP1 increased the chondrocyte¡¯s elastic modulus, a characteristic of senescent cells, at the single-cell level. In addition, we demonstrated that YAP1 was essential for CHS cell proliferation, as evidenced by that loss of YAP1 reduced the percentage of EdU-incorporated cells, along with the suppression of c-Myc.	p21	Downregulation	Western blot//SA-¦Â-gal activity assay	Notably, loss of YAP1 dramatically upregulated the expression of p21 in the SW 1353 cells, regardless of cell density. As expected, overexpression of HA-YAP1-5SA upregulated the expression of its target gene Cyr61 and, reduced p21 expression and p21-induced cellular senescence in cells expressing shYAP1#4 but not SC.	YAP-p21	Downregulation	Western blot//Immunofluorescence	A lower concentration of VP significantly upregulated p21 expression and increased the percentage of senescent cells, while a higher concentration of VP suppressed the p21 expression, accompanied by pronounced cell apoptosis. Indeed, knockdown of p21 by sip21#3 and sip21#4 remarkably abolished the cell senescence induced by the shYAP1#3 or shYAP1#4. We also found a marked increase in DNA damage upon p21 knockdown, as seen from the representative images of the DNA tails and the calculation of the olive tail moment (OTM). In addition, we also noted that knockdown of p21 increased ¦Ã-H2AX expression, accompanied by the activation of caspase-3-dependent apoptosis.	Human	HL	cellular senescence	33,495,462	Gene	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
RPPH1	85495	ncRNA	WI-38,IDH4	--	Aging	Accelerate	Flow cytometry//SA--gal activity assay	Seven days after transfection, senescence associated ¦Â-galactosidase staining revealed that RPPH1 RNA overexpression promotes activation of acidic ¦Â-galactosidase as a marker of cellular senescence. Measurement of cell division cycle by Propidium Iodide (PI) and Flow Cytometry uncover that RPPH1 RNA overexpression arrested proliferating fibroblasts (WI-38, PDL 15) in G1 stage whereas RMRP RNA overexpression did not affect it.	MLC1 mRNA//CCR7 mRNA	Upregulation	qRT-PCR//RNA-seq	Prediction of partial complementarity was tested in MS2-tagged RNA affinity purification assay, confirming that MLC1 and CCR7 mRNAs are biochemically associated with RPPH1 RNA in proliferating fibroblasts but not senescent ones. In addition, we observed that MLC1 and CCR7 mRNAs are destabilized in senescent fibroblasts where RPPH1 RNA is less abundant in cytoplasm. We also analyzed the published RNA-seq datasets from the diverse models of senescence, and found that the levels of MLC1 and CCR7 mRNA are declined during replicative and irradiation-mediated senescence in IMR90 cells in conjunction with modestly decreased AUF1 mRNA level and increased p16 and p21 mRNA (senescent markers). Similarly, mRNAs targeted by RPPH1 RNA are unstable after AUF1 depletion in the condition when RPPH1 RNA accumulates in mitochondria.	--	--	--	--	Human	HL	cellular senescence	33,466,722	Gene	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
CLIC1	1192	protein coding	HUVECs	--	Aging	Accelerate	qRT-PCR	Upregulating CLIC1 in HUVECs promoted cell senescence, evidenced by the mRNA levels of p16, PAI-1, and Sirt1. However, CLIC1 silencing decreased H2O2 induced cellular senescence.	Nrf2	Downregulation	Western blot//Immunofluorescence	The findings revealed that even though H2O2 slightly induced nuclear translocation of Nrf2, IAA94 treatment or CLIC1 knockdown significantly increased Nrf2 translocation in H2O2-treated HUVECs. Nuclear levels of the Nrf2 protein were determined by Western blot analysis. H2O2 increased the nuclear protein expression levels of Nrf2 while IAA94 treatment increased the Nrf2 protein levels in the nuclear fraction. Nrf2 protein expression in the nuclear fraction demonstrated that overexpression of CLIC1 inhibited Nrf2 translocation.	Nrf2-HO1//AMPK-AKT-GSK3¦Â	Downregulation	Western blot	Overexpression of CLIC1 inhibited the activation of the Nrf2/HO-1 pathway and promoted oxidative stress injury in HUVECs. IAA-94 treatment activated the AMPK/AKT/GSK3¦Â pathway while CLIC1 knockdown enhanced the expresson of p-AMPK/total AMPK. However, CLIC1 overexpression significantly decreased the ratio of p-AMPK Thr172 to total-AMPK.	Human	L	cellular senescence	33,432,550	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
SMAD4	4089	protein coding	Fibroblast	--	Aging	Prevent	qRT-PCR	Next, we assessed expression of cellular senescence and proliferative markers, including p16, p21, and Ki67. The mRNA levels of p16 and p21 were increased > 4-fold and > 5-fold, respectively, in mutant compared to control or SMAD4-WT cells. Consistent with this, expression of the proliferative marker Ki67 was substantially reduced in SMAD4-R496C mutant compared to control cells. Quantitative analysis of the cell cycle regulators, CDK2 and CDC25A, indicated reduced expression in SMAD4-R496C compared to controls, providing further evidence for repressed or halted cell cycle progression and enforcement of cellular senescence.	--	--	--	--	TGF-¦Â/SMAD-IFN¦Ã	Activation	qRT-PCR//SA-¦Â-gal activity assay	Consistent with this, the growth curve of Werner cells displayed an increased doubling time with passage compared to control normal fibroblasts. At passage 14, the population doubling time of Werner cells was markedly increased compared to corresponding controls, suggesting proliferative arrest and accelerated senescence of Werner cells, as described previously. Increased senescence of Werner cells was further supported by increased numbers of SA-beta positive cells and expression of IL-6, STAT1, and IFN¦Ã.	Human	L	cellular senescence	33,428,109	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
MT-CO2	4513	protein coding	HMSCs	--	Aging	Prevent	SA--gal activity assay//WST-1 assay	The results of WST-1 assay revealed that the COX2 transfectants grew at a faster rate than the normal HMSCs. SA-¦Â-Gal staining revealed that the overexpression of COX2 significantly delayed the aging process of HMSCs.	--	--	--	--	--	--	--	--	Human	L	cellular senescence	33,416,107	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0
MIR217	406999	ncRNA	HUVECs	--	Aging	Accelerate	SA--gal activity assay	The data showed that overexpression of miR-217 significantly increased the proportion of SA-¦Â-gal positive cells in PDL12, PDL16 and PDL20 cells	SIRT1	Downregulation	qRT-PCR//Western blot	Western blot and RT-qPCR results showed that up-regulation of miR-217 in PDL8 cells significantly inhibited SIRT1 expression, whereas miR-217 inhibitor significantly inhibited SIRT1 expression in PDL44 cells.	SIRT1-p53	Activation	qRT-PCR//Western blot	SIRT1 protein levels and mRNA levels were significantly lower in senescent PDL44 HUVECs than in young PDL8 HUVECs, while p53 protein levels and mRNA levels were significantly higher in senescent PDL44 HUVECs than in young PDL8 HUVECs	Human	L	cellular senescence	33,392,891	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
TWIST1	7291	protein coding	NP Cells	Nucleus pulposus	Disc degeneration	Prevent	CCK-8 assay//SA--gal activity assay//Western blot//qRT-PCR	Of note, in the TWIST overexpression group, the p53 and p21 protein were effectively suppressed compared to the TNF-¦Á group. In addition, the collagen II and ¦Â-gal protein expression were determined by IF staining. However, TWIST1/2 overexpressed NP cells were partly efficient in inhibiting the MMP-13 and IL-1¦Â upregulation. The cell proliferation was determined by CCK-8 assay, and the result indicated the TWIST1/2 overexpressed NP presented a higher proliferative ability than the non-transfected cells under the treatment of TNF-¦Á.	--	--	--	--	p53-p21	Downregulation	Western blot	Of note, in the TWIST overexpression group, the p53 and p21 protein were effectively suppressed compared to the TNF-¦Á group. Besides, the p53 and p21 levels were inhibited due to the supplement of TWIST protein.	Human	L	cellular senescence	33,378,011	Gene	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	1	0
TWIST2	117581	protein coding	NP Cells	Nucleus pulposus	Disc degeneration	Prevent	CCK-8 assay//SA--gal activity assay//Western blot//qRT-PCR	Of note, in the TWIST overexpression group, the p53 and p21 protein were effectively suppressed compared to the TNF-¦Á group. In addition, the collagen II and ¦Â-gal protein expression were determined by IF staining. However, TWIST1/2 overexpressed NP cells were partly efficient in inhibiting the MMP-13 and IL-1¦Â upregulation. The cell proliferation was determined by CCK-8 assay, and the result indicated the TWIST1/2 overexpressed NP presented a higher proliferative ability than the non-transfected cells under the treatment of TNF-¦Á.	--	--	--	--	p53-p21	Downregulation	Western blot	Of note, in the TWIST overexpression group, the p53 and p21 protein were effectively suppressed compared to the TNF-¦Á group. Besides, the p53 and p21 levels were inhibited due to the supplement of TWIST protein.	Human	L	cellular senescence	33,378,011	Gene	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	1	0
CDK2	1017	protein coding	Phoenix-Eco	--	Leukemia	Prevent	Immunofluorescence//Immunohistochemistry//SA--gal activity assay//Western blot	Although samples from both CVT2584- and vehicle-treated mice showed a certain degree of positivity, the SA-¦Â-gal staining was significantly increased in spleens from CVT2584-treated mice, as quantitated in Figure 5. We also examined the presence of senescence-associated heterochromatin foci (SAHF), using an antibody directed against H3K9me3. Immunofluorescence staining of spleen tissue from CVT2584-treated mice showed a strong increase in SAHF formation compared to the vehicle-treated mice. Nuclear p19ARF-positive cells were readily detected in sections of CVT2584-treated animals but found virtually absent in the analyzed specimens from vehicle-treated animals. Nuclear p19ARF-positive cells were readily detected in sections of CVT2584-treated animals but found virtually absent in the analyzed specimens from vehicle-treated animals.	MYC	Upregulation	Western blot	In agreement with our previous report, reduced MYC Ser-62 phosphorylation was observed in CVT2584-treated compared with vehicle-treated animals, both at lower and higher doses of CVT2584, supporting the notion that CDK2 regulates MYC phosphorylation in vivo.	--	--	--	--	Human	L	cellular senescence	33,356,836	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	1	0	0	0	1	0	0
CFL1	1072	protein coding	WI-38	--	Aging	Accelerate	Immunofluorescence//SA--gal activity assay//Western blot	Subsequently, we assessed the expression of the cell cycle inhibitors involved in senescence©\associated growth arrest. We found that the over©\expression of cofilin©\1 in young cells could induce p53, p21Cip1, p27Kip1, p16INK4, and p©\cofilin©\1, but the silencing of cofilin©\1 in senescent cells suppressed these molecules. Subsequently, we assessed the expression of the cell cycle inhibitors involved in senescence©\associated growth arrest. We found that the over©\expression of cofilin©\1 in young cells could induce p53, p21Cip1, p27Kip1, p16INK4, and p©\cofilin©\1, but the silencing of cofilin©\1 in senescent cells suppressed these molecules. We then found that the levels of SA©\¦Â©\gal stained cells were increased by the over©\expression of cofilin©\1 in young cells and were decreased by the knockdown of cofilin©\1 in senescent cells.	TEAD1	Downregulation	qRT-PCR	To investigate whether the down©\regulation of TEAD1 mRNA is associated with up©\regulated cofilin©\1 in senescent cells, we silenced cofilin©\1 and found that the TEAD1 mRNA levels were restored in senescent cells. Additionally, the over©\expression of cofilin©\1 could suppress the expression of TEAD1 transcripts and protein in H1299/tet©\on©\cofilin©\1 cells.	--	--	--	--	Human	L	cellular senescence	33,336,885	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
GATA6	2627	protein coding	iPSC-MSC	--	Aging	Accelerate	SA--gal activity assay//qRT-PCR	GATA6 knockdown in cells at the late passage significantly reduced the ratio of senescent to total cells whereas that in cells at the early passage did not. Similarly, GATA6 knockdown markedly decreased the expression of p53 and p21CIP1 and significantly increased the expression of CDK1 in late-passage cells but did not affect early-passage cells. Other than the effect on cell cycle regulators, GATA6 knockdown significantly downregulated mRNA levels of senescence-associated secretory phenotype (SASP) marker IL6 and IL1B in late-passage as well as early-passage iPSC-MSCs.	--	--	--	--	SHH-FOXP1	Downregulation	SA-¦Â-gal activity assay//Western blot	Knockdown of GATA6 resulted in an increase in the expression of the SHH signaling molecule SHH, SMO, and GLI1 as well as FOXP1, suggesting that GATA6 is an upstream inhibitory regulator of both SHH signaling and FOXP1. When the expression of SMO, a key molecule in the SHH pathway, was repressed, the expression of its downstream molecule GLI1 was decreased as well as that of FOXP1. There was a significantly lower ratio of cells stained positive for SA-¦Â-gal in the culture of GATA6-knockdown cells compared to that in the culture of control cells whereas the opposite trend was shown between the culture of FOXP1-knockdown and control cells, suggesting that repressing the expression of GATA6 or FOXP1 leads to attenuation or increase of cellular senescence, respectively. Results of DNA content analysis showed that repressing the expression of GATA6 in iPSC-MSCs promoted cell proliferation whereas that of FOXP1 significantly inhibited cell proliferation. In terms of the activity of senescence- and cell cycle-associated markers, GATA6 knockdown resulted in a significant decrease in the expression of p53 and p21CIP1 and a significant increase in the expression of CDK1. Conversely, FOXP1 knockdown significantly increased the p53 and p21CIP1 expression and significantly decreased the CDK1 expression.	Human	HL	cellular senescence	33,252,174	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
PDK1	5163	protein coding	NHDF	--	Aging	Accelerate	EdU assay//SA--gal activity assay//qRT-PCR	Either PDK1 inhibition or dual inhibition of mTOR and NF-¦ÊB reduced the SA-¦Â-gal¨Cpositive cell population from >80% to <40%, whereas mTOR inhibition alone did not significantly alter the percent of SA-¦Â-gal¨Cpositive cells. We found that the percent of proliferating cells increased after either PDK1 inhibition or dual inhibition of mTOR and NF-¦ÊB, but not after only mTOR inhibition. Senescent cells showed a significantly increased expression of these SASP-associated genes. Either exposure to the NF-¦ÊB inhibitor JSH23 or the PDK1 inhibitor BX795 reduced the expression of these genes.	mTOR//NF-¦ÊB	Upregulation	qRT-PCR//EdU assay	We found that the percent of proliferating cells increased after either PDK1 inhibition or dual inhibition of mTOR and NF-¦ÊB, but not after only mTOR inhibition. Senescent cells showed a significantly increased expression of these SASP-associated genes. Either exposure to the NF-¦ÊB inhibitor JSH23 or the PDK1 inhibitor BX795 reduced the expression of these genes.	--	--	--	--	Human	HL	cellular senescence	33,229,519	Gene	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
SLX4IP	128710	protein coding	DU145,PC-3	--	CRPC	Prevent	SA--gal activity assay//Western blot	As expected, a considerable increase in the proportion of senescence-associated ¦Â-galactosidase (SA ¦Â-gal) staining was observed in late-passage cells with SLX4IP knockdown compared with late-passage controls. Elevations in relative p21 protein expression, a senescence-associated marker, further corroborated the senescent phenotype. Moreover, SLX4IP knockdown led to a prominent increase in both ¦Â-gal positively stained cells and relative p21 protein expression in late-passage DU145-derived cell lines that were not present in early-passage cells.	--	--	--	--	--	--	--	--	Human	L	telomere attrition	33,188,147	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
MEG3	55384	ncRNA	A549,MCF-7	--	Aging	Accelerate	SA--gal activity assay//Western blot//qRT-PCR	The degree of senescence of A549 and MCF-7 cells was detected by SA-¦Â-gal staining after depletion of lncRNA MEG3, showing a significant decrease compared with that of the control group. Next, we induced senescence by etoposide after overexpression of lncRNA MEG3 in A549 and MCF-7 cells, and increased expression of p21 and p16 was observed in senescent models.The mRNA and protein expression levels of senescence-related markers were attenuated to some extent after depletion of lncRNA MEG3 in senescent models of A549 and MCF-7 cells, indicating that lncRNA MEG3 might play an important role in the regulation of senescence induced by etoposide.	miR-16-5p	Binding	Dual-Luciferase reporter assay	The results showed that the luciferase activity decreased significantly in Hek293T cells co-transfected with wild type lncRNA MEG3 and miR-16-5p mimics, whereas luciferase activity was restored in cells co-transfected with mutant lncRNA MEG3 and miR-16-5p mimics, indicating that miR-16-5p is indeed a direct target gene of lncRNA MEG3 and lncRNA MEG3 plays a vital role in the senescent process by acting as a ceRNA.	miR-16-5p-VGLL4	Activation	qRT-PCR//SA-¦Â-gal activity assay	Moreover, silencing lncRNA MEG3 or VGLL4 significantly alleviated low dose etoposide induced senescence, as demonstrated by decreased p21 and p16 expression and SA-¦Â-gal staining positive cells. Interestingly, the effect of the inhibition of lncRNA MEG3 on the senescence of tumor cells was prominently abolished by the miR-16-5p inhibitor, as suggested by increased p21 and p16 expression and SA-¦Â-gal staining positive cells.	Human	HL	cellular senescence	33,141,998	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	1	0
NEAT1	283131	ncRNA	BM-MSC	--	Aging	Prevent	SA--gal activity assay//qRT-PCR	QRT-PCR results suggested that exosomeMIF transferred LncRNA¨CNEAT1 to cardiomyocytes, while silencing LncRNA¨CNEAT1 in MSCs blocked the transfer process. In the subsequent experiments, exosomeMIF significantly reduced the percentage of cells in the G0/G1 phase, expression of p27 and p16, and number of SA-¦Â-gal-positive cells. However, it elevated the telomere length and activity.	miR-221-3p	Binding	Dual-Luciferase reporter assay//qRT-PCR//SA-¦Â-gal activity assay	LncRNA¨CNEAT1 contains the binding site for miR-221-3p, suggesting that lncRNA as a ceRNA sponged miR-221-3p to limit its function, which was confirmed by dual-luciferase gene reporter assay. As illustrated in Fig. 6b, the co-transfection of miR-221-3p significantly inhibited the luciferase activities elicited by LncRNA¨CNEAT1. Further, a biotin¨Cavidin pulldown system was employed to test whether miR-221-3p could pull down NEAT1. Cardiomyocytes were transfected with biotinylated miR-221-3p, then collected for biotin based pulldown assay. NEAT1 was pulled down as analyzed by qRT-PCR. Further, a biotin¨Cavidin pulldown system was employed to test whether miR-221-3p could pull down NEAT1. Cardiomyocytes were transfected with biotinylated miR-221-3p, then collected for biotin based pulldown assay. NEAT1 was pulled down as analyzed by qRT-PCR. Importantly, miR-221-3p overexpression markedly increased the number of cells in the G0/G1 phase, expression of p27 and p16, and number of SA-¦Â-gal-positive cells, but inhibited the telomere and telomerase activity, even when exosomeMIF were added to Dox-treated cardiomyocytes.	--	--	--	--	Human	HL	cellular senescence	33,129,330	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
HEIH	100859930	ncRNA	OVCA429,OVCA433,OVCAR3	--	Ovarian cancer	Prevent	SA--gal activity assay	As shown in Fig. 2H, the percentage of SA-b-Gal-positive cells was increased by HEIH knockdown in OVCA429 (sh-HEIH#1: 5.2-fold higher than sh-NC group; sh-HEIH#2: 4.6-fold higher than sh-NC group) and OVCA433 cells (sh-HEIH#1: 4.8-fold higher than sh-NC group; shHEIH#2: 4.7-fold higher than sh-NC group).	miR-3619-5p	Binding	Dual-Luciferase reporter assay//qRT-PCR//RIP	From Figure 3D, the transfection of miR-3619-5p mimics showed no difference on the luciferase activity of pmirGLO-HEIH-Mut vectors, but significantly decreased the luciferase reporter activity of pmirGLO-HEIHWt vectors in OVCA429 (0.33-fold decreased) and OVCA433 cells (0.41-fold decreased) (n ? 3, P < 0.05). In addition, RIP assay indicated that HEIH-Wt and miR-3619-5p were apparently enriched in the Ago2 pellet but not the IgG control pellet in both OVCA429 (HEIH: 4.93-fold increased; miR-3619-5p: 3.21-fold increased) and OVCA433 cells (HEIH: 5.24-fold increased; miR-3619-5p: 3.07-fold increased). RT-qPCR analysis was carried out and the results indicated that HEIH expression was significantly decreased by miR-3619-5p mimics (OVCA429: 0.14-fold decreased; OVCA433: 0.26fold decreased), whereas HEIH knockdown markedly increased miR-3619-5p expression (OVCA429: 3.24-fold increased; OVCA433: 2.87-fold increased).	miR-3619-5p-CTTNBP2	Downregulation	Dual-Luciferase reporter assay//qRT-PCR//RIP	As presented in Figure 5C, the luciferase reporter activity of pmirGLO-CTTNBP2-Wt vectors was significantly reduced by miR-3619-5p mimics transfection (OVCA433: 0.38-fold decreased; OVCA429: 0.44-fold decreased). RIP assay indicated that miR-3619-5p (OVCA429: 785-fold increased; OVCA433: 833-fold increased) and CTTNBP2 expression (OVCA429: 1370-fold increased; OVCA433: 1260-fold increased) was significantly enriched in the Ago2 pellet rather than in the IgG control pellet. RT-qPCR and western blot analyses displayed that the mRNA and protein levels of CTTNBP2 were markedly decreased by miR-3619-5p overexpression (OVCA429: 0.15-fold decreased; OVCA433: 0.34-fold decreased) or HEIH knockdown (OVCA429: 0.22-fold decreased; OVCA433: 0.37-fold decreased). Additionally, the percentage of SA-b-Gal-positive cells was increased by HEIH knockdown, whereas these effects were abrogated by CTTNBP2 overexpression in OVCA429 (5.2-fold higher than sh-NC group; 0.2-fold lower than sh-HEIH#1 group) and OVCA433 cells (4.8-fold higher than sh-NC group; 0.2-fold lower than sh-HEIH#1 group).	Human	L	cellular senescence	33,110,047	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
SNHG29	125144	ncRNA	HTR8/SVneo	--	Preterm birth	Accelerate	SA--gal activity assay//qRT-PCR	SA-¦Â-Gal increased in the SNHG29 + H2O2 cells as compared to the NC + H2O2 cells (7.8%, 15.9% and 23% respectively). We measured the levels of pro-inflammatory cytokines, such as IL-8 and TNF- ¦Á. The mRNA levels of IL-8 and TNF-¦Á decreased in cells depleted of SNHG29 compared with NC-Si and NC-Si + H2O2 cells. However, there was an increase in the expression of IL-8 and TNF-¦Á in cells transfected with AAV-SNHG29 compared to NC and NC + H2O2 cells.	--	--	--	--	p53-p21	Activation	Western blot//SA-¦Â-gal activity assay//qRT-PCR	Treated cells depleted of SNHG29 (si-SNHG29 + H2O2) showed a reduction in the levels of mRNA of p53 and p21, and the protein levels of p53, phospho-p53,p21and phospho-p21, as compared to treated cells with wild-type SNHG29. Overexpression of SNHG29 in H 2O2-treated cells (SNHG29 + H2O2) showed increases in the level of mRNA of p53 and p21, and protein levels of p53, phospho-p53, p21and phospho-p21 as compared to treated cells with wild-type SNHG29.	Human	L	cellular senescence	33,080,448	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
METTL3	56339	protein coding	hMSCs	--	Progeroid syndromes	Prevent	Clonal expansion assay//SA--gal activity assay	Furthermore, METTL3-deficient hMSCs acquired premature aging phenotypes, as evidenced by decreased proliferative capacity and increased percentage of SA-¦Â-Gal-positive cells. Moreover, enhanced cell proliferative capacity and reduced SA-¦Â-Gal-positive cells were observed in HGPS and WS hMSCs upon METTL3 overexpression.	MIS12	Downregulation	qRT-PCR//Western blot	Among these transcripts, we noticed that m6A modifications in MIS12, a key regulator of cell proliferation, were markedly reduced in both prematurely senescent and METTL3-deficient hMSCs, as validated by MeRIP-qPCR analysis. We also detected a significant decrease in MIS12 expression at both the mRNA and protein levels in HGPS and WS hMSCs as well as in METTL3-deficient hMSCs. Among these transcripts, we noticed that m6A modifications in MIS12, a key regulator of cell proliferation, were markedly reduced in both prematurely senescent and METTL3-deficient hMSCs, as validated by MeRIP-qPCR analysis. We also detected a significant decrease in MIS12 expression at both the mRNA and protein levels in HGPS and WS hMSCs as well as in METTL3-deficient hMSCs.	--	--	--	--	Human	HL	cellular senescence	33,035,345	Gene	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
HES1	3280	protein coding	Dermal fibroblasts	Skin	Aging	Prevent	Clonal expansion assay//SA--gal activity assay	Ectopic overexpression or CRISPR-dCas9-mediated endogenous activation of HES1 protected human fibroblasts against aging phenotypes, evidenced by increased cell proliferation and attenuated cell senescence	--	--	--	--	--	--	--	--	Human	HL	cellular senescence	33,238,152	Gene	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
KLF6	1316	protein coding	Dermal fibroblasts	Skin	Aging	Prevent	Clonal expansion assay//ELISA//SA--gal activity assay//qRT-PCR	Senescence-associated ¦Â-galactosidase (SA-¦Â-gal) staining showed that knockdown of KLF6 promoted senescence of human primary epidermal keratinocytes In addition, the downregulation of KLF6 in human primary keratinocytes led to decreased proliferation ability and increased expression and secretion of pro-inflammatory cytokine IL6, in line with the decreased self-renewal and upregulated cytokine signaling in aged epithelial cells.	--	--	--	--	--	--	--	--	Human	HL	cellular senescence	33,238,152	Gene	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
PPARA	5465	protein coding	EA.hy926,HUVEC	--	Atherosclerosis	Prevent	Immunostainings//SA--gal activity assay	¦Â-gal staining showed that the number of senescent cells decreased after administration of the PPAR¦Á agonist.Immunofluorescence double labeling staining showed that there were a large number of aging endothelial cells in the atherosclerotic plaque of Apoe-/- mice, and the PPAR¦Á agonist inhibited the denudation and maintained the integrity of aging endothelial cells in Apoe-/- model mice.	GDF11	Binding	EMSA//Dual-Luciferase reporter assay	The EMSA results showed that PPAR¦Á bound to the labeled target probe, and partially to the mutant probe, indicating that PPAR¦Á could bind to the GDF11 target sequence and participate in the regulation of downstream gene transcription. Double-luciferase reporter gene experiment results indicated that PPAR¦Á could bind to the GDF11-specific sequence.	--	--	--	--	Human	L	cellular senescence	33,728,018	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0
SGK1	6446	protein coding	Glial cell	--	Parkinson disease	Accelerate	CCK-8 assay//ELISA//RNA-seq//SA--gal activity assay	Second, our RNA©\seq data show that treating glia with an SGK1 inhibitor downregulated the pro©\oxidant Cyba, Ncf2, Recql4, Bax, and Fdxr and senescence©\associated secretory phenotype (SASP) genes. We further observed that senescence©\associated ¦Â©\galactosidase (SA©\¦Â©\gal) activity, the hallmark senescence biomarker, was promoted in glia exposed to H2O2 and significantly rescued in the presence of the SGK1 inhibitor.In addition, in a paraquat©\induced glial senescence model, a WB analysis showed that the herbicide©\induced LMNB1 (Lamin B1) loss, a senescence©\associated biomarker, was alleviated in glial cultures treated with the SGK1 inhibitor, and levels of the pro©\senescence proteins IL6, MMP3, and p16 (CDKN2A) also decreased. Reduced secretion of IL6, a cytokine of SASP, from cultured glia treated with the SGK1 inhibitor was further demonstrated using ELISA.	--	--	--	--	--	--	--	--	Human	HL	delay aging	33,646,633	Gene	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0
LINC00858	170425	ncRNA	HCT116	Colon cancer tissues	Colorectal cancer	Prevent	SA--gal activity assay	The results of ¦Â-gal staining, immunofluorescence staining, and Western blot analysis demonstrated that the senescence and autophagy of cells treated with sh-NC + sh-WNK2 were reduced in parallel with diminished expression of Beclin-1 and LC3II/I, in contrast to findings in cells treated with sh-NC + sh-NC (p < 0.05). However, opposite effects were observed in cells treated with sh-LINC00858 + sh-WNK2 when compared with sh-NC + sh-WNK2 (p <0.05).	WNK2	Upregulation	Western blot	The results from Western blot analysis showed that, compared with cells treated with sh-NC (of WNK2) + sh-NC (of LINC00858), WNK2 expression was reduced in cells treated with sh-NC + sh-WNK2, while its expression was elevated in cells treated with sh-LINC00858 + sh-WNK2 when compared with cells treated with sh-NC + sh-WNK2 (p < 0.05).	--	--	--	--	Human	HL	apoptosis	32,768,499	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
CD70	970	protein coding	T cell	--	Aging	Accelerate	Flow cytometry	To investigate the potential role of CD70 signaling in T-cell aging, we examined the expression of CD70 on T cells from 217 healthy adults using flow cytometry. The results showed that CD70-expressing CD4+ and CD8+T cells accumulated with aging.The TCM, TEM, and TEMRA subsets of both CD4+ and CD8+ T cells, known as antigen-experienced T cells, expressed higher levels of CD70 than TN cells regardless of age. Also, CD70 expression was substantially increased in each T cell subset of CD4+ and CD8+ cells from older subjects as compared to young and middle-aged subjects. Thus, an elevated proportion of CD70+ fractions among CD4+ and CD8+ cells in elderly individuals was not only a result of the higher number of antigen-encountered T cells, but also the age-related increase of CD70 expression.	--	--	--	--	--	--	--	--	Human	L	delay aging	32,559,178	Gene	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
SETMAR	6419	protein coding	U87MG,SF268	--	Glioblastoma	Prevent	Cell transfection//SA--gal activity assay//Western blot	According to experiments, shRNA (sh1) or siRNA (mixture of 3 siRNAs) mediated knockdown of SETMAR initially induced cell death of RR cells; however, eventually (12 days post induction of shRNA and 10-day post siRNA treatment) the cells ceased to grow and became senescent. Importantly, SETMAR knockdown did not alter the growth pattern of parent cells but specifically halted the proliferation of RR cells, highlighting the dependency of RR cells on SETMAR to escape from senescence.	--	--	--	--	--	--	--	--	Human	HL	delay aging	32,458,986	Gene	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
CD9	928	protein coding	HUVEC	--	Aging	Accelerate	Cell transfection//Flow cytometry//SA--gal activity assay//Western blot	To examine the roles of CD9 in endothelial cell senescence, we measured the effects of CD9 knockdown in senescent HUVECs (PD>50). Knockdown of CD9 in senescent cells with siRNA reduced the p53 and p21 levels, representative senescence markers, and the pAKT and pS6K levels, decreased SA¦ÂG staining, and caused morphological changes similar to those observed in young cells. CD9 downregulation increased cell proliferation, BrdU incorporation, and Ki67 immunoreactivity, which are all well-known cell proliferation markers. CD9 knockdown decreased the G0/G1 cell population and increased the S and G2/M cell population, suggesting a release of G1 arrest, which is a typical phenotype in cellular senescence Young cells transduced with CD9 adenovirus were enlarged and flattened. Moreover, CD9 upregulation increased SA¦ÂG staining, but decreased BrdU incorporation, Ki67 immunoreactivity, the proportion of cells in the S phase, and endothelial tube formation.	--	--	--	--	PI3K-AKT-mTOR-p53	Activation	Cell transfection//SA-¦Â-gal activity assay//Flow cytometry//Western blot	Therefore, we tested whether the PI3K/AKT-mTOR pathway plays a role in CD9-induced senescence. Pretreatment with LY294002, a specific inhibitor of PI3K, or rapamycin, an inhibitor of mTOR, reduced the levels of p53 and p21 and SA-¦Â-gal staining induced by CD9 overexpression. We next tested whether PIK3CA 110¦Â or PIK3CB 110¦Â, two PI3K catalytic subunits, plays a role in CD9-induced senescence. Knockdown of PIK3CA, but not that of PIK3CB, significantly decreased the levels of pAKT, p53, p-p53, pS6K, and p21 proteins, as well as SA-¦Â-gal staining, suggesting that PIK3CA might be involved in CD9-induced cellular senescence. These results indicate that the PI3K-AKT-mTOR-p53 pathway might regulate CD9-mediated cellular senescence.	Human	L	cellular senescence	32,346,137	Gene	0	0	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
FBP1	2203	protein coding	HSC	--	Aging	Accelerate	Flow cytometry//SA--gal activity assay//¦ÃH2AX staining	Importantly, SA-¦Â-Gal+ cells colocalized with those positive for ¦Á-SMA (an activated HSC maker), and IL6 (prominent SASP component), and significant percentage of ¦Á-SMA+?HSCs also expressed the DNA damage marker ¦Ã-H2AX, collectively supporting the presence of senescent HSCs. As DEN is not usually fibrogenic in mice22,24, we surmised that FBP1 deficiency in and of itself promotes HSC activation and senescence. Indeed, liver fibrosis was also detected in?non-DEN treated Cre livers, together with a population of ¦Á-SMA+and Ki67+/¦Á-SMA+HSCs.	HMGB1	Upregulation	IF//Immunoblotting	We therefore treated DEN/GFP or DEN/Cre animals with inflachromene (ICM), a small molecule shown to block HMGB1 release45. ICM treatment greatly reduced not only surface tumours, but also microscopic lesions in DEN/Cre mice. ICM did not affect hepatic steatosis, based on comparable TG levels. As expected, cytosolic HMGB1 levels decreased while nuclear HMGB1 levels increased in ICM-treated livers. ICM also substantially reduced numbers of HSCs expressing SASP components.	--	--	--	--	Human	HL	cellular senescence	32,367,049	Gene	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
WISP1	8840	protein coding	Chondrocyte	Cartilage tissues	Osteoarthritis	Prevent	FITC-Annexin V/PI//IHC//SA--gal staining	Normal cartilage specimen ?showed very low expression levels of WISP1. The ?protein levels of WISP1 were significantly increased within ?the middle and deep regions of all detected pathological ?cartilage sections.The optical density analyses showed that OA pa?tients appeared to exhibit a higher WISP1 expression in joint ?cartilage than that in control groups ( p < 0.05); the WISP1 ?expression was higher ( p < 0.05) within moderate OA com?pared with that within mild OA; and WISP1 expression in ?severe OA was shown to be remarkably elevated than mod?erate OA ( p < 0.05).The senescence cell percentage and apoptotic cell percentage were ?remarkably downregulated in OA chondrocytes treated with ?rhWISP1 compared with the controls.	--	--	--	--	--	--	--	--	Human	L	apoptosis	33,646,053	Gene	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
PPAR	5465	protein coding	--	Great saphenous vein wall	Chronic venous disorder	Prevent	Immunohistochemical staining//RT-qPCR	We studied the gene and protein expression of ¦Á, ¦Â/¦Ä and ¦Ã PPAR isoforms in venous wall from CVeD patients and HV controls. We observed a significant decrease in PPAR-¦Á gene expression by RT-qPCR in CVeD patients with respect to HV controls (HV=5.224 [3.659-8.039] RQ vs CVeD=4.632 [2.365-6.387] RQ, *p=0.0004). We also studied PPAR-¦Á protein expression by immunohistochemistry (IHC). We observed a significant decrease in the score, with a mean of 1.500 [0.500-2.750] in the HV group and 0.000 [0.500-2.750] in the CVeD group, p=0, 0001. Furthermore, The percentage of positive samples was 100% (n=27) in the HV group and 74.286% (n=26) in the CVeD group.	PPAR-¦Á//PPAR-¦Â/¦Ä//TFEB	Downregulation//Downregulation//Downregulation	Immunohistochemical staining//qPCR	We observed a significant ?decrease in PPAR-¦Á gene expression by RT-qPCR in ?CVeD patients with respect to HV controls.//The score for ?PPAR-¦Â/¦Ä was significantly lower for patients with ?CVeD.//Our results showed that the gene expression of ?TFEB was significantly decreased in CVeD patients ?compared with the HV group.	--	--	--	--	Human	HL	cellular senescence	33,645,625	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0	0	0
RECQL4	9401	protein coding	KYSE30,KYSE450,KYSE410,KYSE150,TE-1	ESCC tissues	Esophageal cancer	Accelerate	SA--gal activity assay//Western blot	Approximately 45% of KYSE30 RECQL4-depleted cells and 30% of TE-1 RECQL4-depleted cells showed positive SA-¦Â-gal staining. The expression of p21, an effector molecule of G1 arrest and cellular senescence, was also increased significantly, which is consistent with previous studies.	c-myc//cyclinD//CDK6//cyclinE	Downregulation//Downregulation//Upregulation//Upregulation	Western blot	To further investigate how RECQL4 regulates G1/S phase ?transition and cellular senescence, we determined the expres?sion of other related proteins. Depletion of RECQL4 led to decreased expression of c-myc, cyclin D, ?CDK6, and cyclin E.	--	--	--	--	Human	HL	cellular senescence	33,628,589	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
ATM	472	protein coding	HFMs	Human haired scalp	Aging	Prevent	Cell viability assay//IHC//Western blot	The intensity and the distribution level of the staining of TRP-1 and GP100 was higher in the hair ?follicle melanocytes of fully pigmented follicles, sporadic in melanocytes with reduced pigmentation and lack?ing in weakly pigmented/white hair follicles.Results showed increased total ATM levels in HFMs afer H2O2 treatment, and this increase was blocked by pre?incubation of HFMs with antioxidants VitE/Q for 1h.Both Menadione and H2O2 treatment ?signifcantly reduced cell viability versus vehicle controls.As seen in Fig. 5, results showed that in the absence of ATM kinase activity, sustained H2O2 treatment for 24 h significantly reduced cell viability compared to controls.	--	--	--	--	--	--	--	--	Human	L	apoptosis	33,128,003	Gene	0	0	0	1	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
SENEX	93663	protein coding	OCI©\LY8	--	r/r DLBCL	Accelerate	SA--gal activity assay	Interestingly, compared with the control group (C group) and scramble negative control (NC group), the senescence rate and proliferation rate were significantly decreased (Figure 5C¨CG), but the apoptosis rate was significantly increased in SENEX silenced group (SS group).	--	--	--	--	p16-Rb	Activation	Western blot	We found that p16 ?and pRB expression levels were both significantly increased after the induction of doxorubicin, while RB ?expression level was decreased.	Human	L	apoptosis	33,015,970	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
HBP1	26959	protein coding	NP Cells	--	Intervertebral disc degeneration	Accelerate	RT-qPCR	The upregulation of HBP1 also af?fected collagen II expression and contributed to ?the rise of p16 expression.The ?HPB1 also triggered the IL-6, TNF, and MMP-3 ?expressions compared to the control. However, the silencing of HBP1 restrained the p16 expression and protected the collagen II level secreted by NP cells.	--	--	--	--	--	--	--	--	Human	L	apoptosis	32,964,956	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
BRD4	23476	protein coding	KYSE450	--	Oesophageal cancer	Prevent	SA--gal activity assay//Western blot	Treated with 125nM JQ1 for 6 days, the SA-¦Â-gal?positive cells significantly rose and increased subsequently in a ?dose-dependent manner.Immunoblotting also demonstrated that ?JQ1 increased p21 protein level within 6 days in KYSE450 cells.	AURKA//AURKB	Upregulation	Western blot//ChIP-Qpcr	Western blot analysis also showed that AURKA and AURKB protein were time- and ?dose-dependently decreased following JQ1 treatment. Data of ChIP-qPCR ?revealed that JQ1 suppressed BRD4 binding on the promoters of ?AURKA and AURKB genes in KYSE450 cells.	--	--	--	--	Human	L	apoptosis	32,954,665	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
MDM2	4193	protein coding	MCF-7	--	Breast ?cancer	Accelerate	SA--gal activity assay	We observed a significant increase in ¦Â- ?galactosidase staining in cells treated with the combination of 1¦ÌM NVP-CGM097 and 100 nM fulvestrant for ?72 h compared to vehicle treatment or treatment with ?either single agent alone (p < 0.01 vs NVP-CGM097; p < ?0.001 vs fulvestrant).	--	--	--	--	--	--	--	--	Human	HL	apoptosis	32,787,886	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
ASIC1	41	protein coding	NP-MSCs	--	Aging	Accelerate	CCK-8 assay//ELISA//Flow cytometry//SA--gal activity assay//Western blot	ASIC1 and ASIC3 were progressively upregulated in NP-MSCs derived from mild,moderate through to severely degenerated IVDs. CCK-8 showed that Pfirrmann grade II and grade IV isolates failed to grow at pH 6.6 in contrast to normal culture conditions.proliferative cells (S+G2/M phases) substantially declined from 25.72 to 7.12%.Acidic culture resulted in a time dependent increase in the percentage of senescence cells,reaching a striking ~80% of cells after 5 days.NP-MSC increased levels of secreted IL-6 and IL-8 by NP-MSCs under pH 6.6 culture conditions.	p53//p21//p27//Rb1//p16//MMP3//MMP9	Upregulation//Upregulation//Upregulation//Upregulation//Upregulation//Upregulation//Upregulation	Western blot	Exposure of isolated NP-MSCs to acidic growth conditions resulted in relatively increased levels of p53,p21,p27,Rb1 and p16 proteins.MMP3 and MMP9 levels also increased whereas aggrecan.	--	--	--	--	Human	L	cellular senescence	33,824,228	Gene	0	1	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
ASIC3	9311	protein coding	NP-MSCs	--	Aging	Accelerate	CCK-8 assay//ELISA//Flow cytometry//SA--gal activity assay//Western blot	ASIC1 and ASIC3 were progressively upregulated in NP-MSCs derived from mild,moderate through to severely degenerated IVDs. CCK-8 showed that Pfirrmann grade II and grade IV isolates failed to grow at pH 6.6 in contrast to normal culture conditions.proliferative cells (S+G2/M phases) substantially declined from 25.72 to 7.12%.Acidic culture resulted in a time dependent increase in the percentage of senescence cells,reaching a striking ~80% of cells after 5 days.NP-MSC increased levels of secreted IL-6 and IL-8 by NP-MSCs under pH 6.6 culture conditions.	p53//p21//p27//Rb1//p16//MMP3//MMP9	Upregulation//Upregulation//Upregulation//Upregulation//Upregulation//Upregulation//Upregulation	Western blot	Exposure of isolated NP-MSCs to acidic growth conditions resulted in relatively increased levels of p53,p21,p27,Rb1 and p16 proteins.MMP3 and MMP9 levels also increased whereas aggrecan.	--	--	--	--	Human	L	cellular senescence	33,824,228	Gene	0	1	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
LINC-PINT	378805	ncRNA	HCC,SPHC,SMMC-7721,MHCC-97H	--	Hepatocellular carcinoma	Accelerate	DNA FISH//Flow cytometry//IHC//SA--gal activity//Western blot	Our results confirmed that Ki67 was remarkably lower in the PINT87aa overexpression group.CircPINT less expressed in proliferating than senescent SMMC-7721 and MHCC-97H cells.CircPINT expression in proliferating and senescent SMMC-7721 and MHCC-97H cells.The proportion of G1 phase cells was increased in PINT87aa-overexpressing cells.SA-¦Â-gal staining showed a higher proportion of cellular senescence in HCC tissues with increased PINT87aa expression.	FOXM1//PHB2	Downregulation//Downregulation	Co-IP//immunfluorescence experiments	PINT87aa could bind to the DNA-binding domain of FOXM.We observed co-localization of PINT87aa and FOXM1.	--	--	--	--	Human	L	cellular senescence	33,754,036	Gene	0	0	0	0	0	0	0	1	0	0	0	1	0	1	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0	0
STING1	340061	protein coding	Chondrocytes	--	Osteoarthritis	Accelerate	SA--gal activity assay//Western blot	The results showed higher p16INK4a and p21 protein mea- sures in the STING-overexpressed and IL-1¦Â-treated chondrocytes. Although STING knockdown significantly reduced the IL-1¦Â-simulated upregulation of p16INK4a and p21 proteins, the knockdown of STING alone did not affect these proteins expression levels. We established that si-P65 remarkably reduced the expression of STING-induced senescence-associated (p16INK4a and p21), and apoptosis-associated (BAX, Cyto-c, as well as cleaved- caspase-3) proteins and increased the expression of BCL-2. The SA-¦Â-gal and TUNEL staining confirmed that STING regulates senescence and apopto- sis via the NF-¦ÊB-signaling axis activation.	--	--	--	--	NF-¦ÊB	Activation	Western blot//Immunofluorescence//SA-¦Â-gal activity assay//TUNEL assay	The results showed that higher phosphorylation of P65 and i¦Êb protein levels were seen in STING overexpressing and IL-1¦Â treated chondrocytes.The analysis of the immunofluorescence of nuclear P65 confirmed that STING activates NF-¦ÊB signaling.STING mediates the degradation of the ECM degradation through the NF-¦ÊBsignaling cascade.STING regulates senescence and apoptosis via the NF-¦ÊB-signaling axis activation.Si-P65 remarkably reduced the expression of STING-induced senescence-associated (p16INK4a and p21),and apoptosis-associated (BAX,Cyto-c,as well as cleavedcaspase-3) proteins and increased the expression of BCL-2. The SA-¦Â-gal and TUNEL staining confirmed that STING regulates senescence and apoptosis via the NF-¦ÊB-signaling axis activation.	Human	L	apoptosis	33,414,452	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0
EZH2	2146	protein coding	Chondrocytes	Human cartilage explants	Osteoarthritis	Accelerate	ELISA//RT-PCR//Safranin-O	We show that EPZ-6438 attenuated IL-1¦Â-induced expression and release of MMP-1, -3 and -13 in chondrocytes, suggesting that this inhibitor could reduce chondrocyte catabolism. We confirmed this hypothesis using human cartilage explants. Safranin-O staining in explants treated with IL-1¦Â for 48 h was less intense compared to untreated explants, showing that IL-1¦Â induced a proteoglycan loss in cartilage. In the explants with the co-treatments of IL-1¦Â with EPZ-6438, the safranin-O staining stayed intensively red, demonstrating that EPZ-6438 was able to preserve the proteoglycan content in the cartilage matrix, and consequently reduced cartilage degradation.	NGF	Upregulation	RT-PCR	We showed that EZH2 overexpression increases IL-1¦Â-mediated NGF expression. We showed that EZH2 overexpression increases IL-1¦Â-mediated NGF expression, while EPZ-6438 had the opposite effect and reduced IL-1¦Â-induced expression of NGF.	--	--	--	--	Human	L	loss of proteostasis	33,177,650	Gene	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0	0	0	0
MIR126	406913	ncRNA	DPSCs	--	Aging	Accelerate	MTT assay	For control group, data displayed that there was no any influence, while miR©\126 caused a reduced cell proliferative rate.For DPSCs at PD54, miR©\126 inhibition significantly increased the cell replication of DPSCs during 72 hours post©\transfection.	PTEN	Downregulation	qRT-PCR//Western blot	Here, the downregulation of PTEN was found in DPSC at PD54, compared with the DPSCs at PD16. Moreover, PTEN mRNA and protein level were also increased in senescent DPSCs transfected with miR©\126 inhibitor.	Akt	Activation	Western blot	The downstream Akt phosphorylation was remarkably upregulated in DPSCs at PD54, while transfection with miR©\126 inhibitor caused an impaired Akt phosphorylation in DPSCs.	Human	HL	apoptosis	33,150,661	Gene	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
NFKBIA	4792	protein coding	HDFs	--	Aging	Prevent	GO analysis//RNA-seq	The transcriptome of non©\irradiated NFKBIA©\depleted cells shared a strong overlap and the same GO terms with the senescent cells of the second phase.I¦ÊB¦Á rescue through ectopic overexpression of an NFKBIA mutant encoding the proteasome©\insensitive I¦ÊB¦ÁS32AS36A blocked the induction of the bona fide SASP factors.	--	--	--	--	--	--	--	--	Human	HL	apoptosis	33,459,422	Gene	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
EZH2	2146	protein coding	HSCs,JS1,LX-2	--	Aging	Prevent	Flow cytometry//GO analysis//RT-qPCR//SA--gal activity assay//Western blot	Treatment of primary HSCs with DZNep, or transient transfection with potent siRNAs for Ezh2 silencing, resulted in more quiescent HSCs-phenotype and pronounced growth retardation, remarkably weakened H3K27me2/3, and significantly downregulated ¦Á-SMA and COL1A.EZH2 inhibition by DZNep in mouse JS1 cells resulted in cell cycle arrest in S and G2 phases, lowered cell viability, increased cell senescence (in dose dependent mode), and higher percent of early apoptotic cells.DZNep treatment in rat primary HSCs, JS1 and LX-2 cells significantly lowered the transcriptional expression of cell proliferation marker protein Ki-67 coding gene MKI67 (marker of proliferation Ki-67).Key signaling pathways involved in cell cycle, DNA replication, mitotic cell cycle and spindle organization, and cytoplasmic ribosomal proteins were significantly inactivated. Some positive regulators of cell cycle including cyclins, cyclin-dependent kinases and E2F transcription factors, and of mitosis were pervasively downregulated; while the key negative regulators of cell cycle, Cdkn1a (cyclin dependent kinase inhibitor 1A), Gadd45a (growth arrest and DNA damage inducible alpha) and Gadd45b, the target genes of p53 and primary inhibitors of G2/M transition) were upregulated.(²»ÖªµÀÓÃÁËÊ²Ã´ÊµÑé)	--	--	--	--	TGF-¦Â-SMAD	Downregulation	RNA-seq	154 out of the 351 associated DEGs in knowledgebase have measurement direction consistent with Tgf¦Â1 inhibition (P = 9.96E-30, Z-score = -2.087), the majority (127) of which are downregulated activator or effector genes, while a few (27) are upregulated inhibitor genes.	Human	HL	apoptosis	33,391,480	Gene	0	0	0	0	0	0	0	0	0	0	0	1	1	0	0	0	0	0	0	0	0	1	0	1	0	0	0	1	0	0
KDM6B	23135	protein coding	HSCs,JS1	--	Aging	Accelerate	ChIP-qPCR//RT-qPCR//Western blot	Treatment of primary HSCs with GSK-J4, an jumonji H3K27me3 demethylase inhibitor of JMJD3 30, resulted in enhanced cell growth, morphological transition from quiescent HSCs to myofibroblast, reinforced H3K27me3, and upregulated fibrotic markers.DZNep-mediated EZH2 inhibition and adenovirus-mediated Jmjd3 overexpression in rat primary HSCs both consistently decreased H3K27me3 enrichment at promoters and gene bodies of Bambi, Cdkn1a, Gadd45a and Gadd45b, increased their transcriptional expression both at early (3 days) and late (6 days) stage of HSCs activation.We also observed substantial increase in protein expression for BAMBI, CDKN1A and GADD45B in HSCs with DZNep treatment or with overexpression of wild-type but not mutant Jmjd3.	--	--	--	--	--	--	--	--	Human	HL	apoptosis	33,391,480	Gene	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1	0	0

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