Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine

Jin, Huanhuan; Lian, Naqi; Zhang, Feng; Bian, Mianli; Chen, Xingran; Zhang, Chenxi; Jia, Yan; Lu, Chunfeng; Meng, Hao; Yao, Shunyu; Wu, Li; Chen, Anping; Zheng, Shizhong

doi:10.1016/j.ejps.2016.10.002

Cited by 38 publications

(37 citation statements)

References 35 publications

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“…Pyrazines contain a heterocyclic motif that interacts with a diverse set of targets such as p53, the estrogen receptor, and the vascular endothelial growth factor (VEGF) making them an attractive target in the treatment of multiple diseases such as various cancers (Browne et al, 1991;Kamal et al, 2011;Lalitha et al, 2016). In hepatic stellate cells, tetramethylpyrazine induced senescence through a p53 dependent mechanism (Jin et al, 2017). Vanillin was associated with higher cytotoxicity in high throughput screening assays (Sassano et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

E-Liquid Containing a Mixture of Coconut, Vanilla, and Cookie Flavors Causes Cellular Senescence and Dysregulated Repair in Pulmonary Fibroblasts: Implications on Premature Aging

et al. 2020

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Electronic cigarette (e-cig) usage has risen dramatically worldwide over the past decade. While they are touted as a safe alternative to cigarettes, recent studies indicate that high levels of nicotine and flavoring chemicals present in e-cigs may still cause adverse health effects. We hypothesized that an e-liquid containing a mixture of tobacco, coconut, vanilla, and cookie flavors would induce senescence and disrupt wound healing processes in pulmonary fibroblasts. To test this hypothesis, we exposed pulmonary fibroblasts (HFL-1) to e-liquid at varying doses and assessed cytotoxicity, inflammation, senescence, and myofibroblast differentiation. We found that e-liquid exposure caused cytotoxicity, which was accompanied by an increase in IL-8 release in the conditioned media. E-liquid exposure resulted in elevated senescence-associated beta-galactosidase (SA-β-gal) activity. Transforming growth factor-β1 (TGF-β1) induced myofibroblast differentiation was inhibited by e-liquid exposure, resulting in decreased α-smooth muscle actin and fibronectin protein levels. Together, our data suggest that an e-liquid containing a mixture of flavors induces inflammation, senescence and dysregulated wound healing responses.

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Section: Discussionmentioning

confidence: 99%

E-Liquid Containing a Mixture of Coconut, Vanilla, and Cookie Flavors Causes Cellular Senescence and Dysregulated Repair in Pulmonary Fibroblasts: Implications on Premature Aging

et al. 2020

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“…Senescence is also important in stem cells because it affects regeneration in tissue engineering. Xie's study found that silencing YAP inhibits cell proliferation and induces premature senescence 41 , and Jin and his colleagues proved that inhibition of YAP contributes to the senescence of hepatic stellate cells induced by tetramethylpyrazine 42 . In the present research, the senescence of h-PDLSCs was delayed when YAP was overexpressed, suggesting that YAP partly regulates senescence in h-PDLSCs.…”

Section: Discussionmentioning

confidence: 99%

Activated Yes-Associated Protein Accelerates Cell Cycle, Inhibits Apoptosis, and Delays Senescence in Human Periodontal Ligament Stem Cells

Jia¹,

Gu²,

Zhang³

et al. 2018

Int. J. Med. Sci.

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Objectives: To provide insight into the biological effects of activated Yes-associated protein (YAP) on the proliferation, apoptosis, and senescence of human periodontal ligament stem cells (h-PDLSCs).Methods: h-PDLSCs were isolated by the limiting dilution method, and their surface markers were quantified by flow cytometry. Enhanced green fluorescence protein (EGFP)-labeled lentiviral vector was used to activate YAP in h-PDLSCs, then qRT-PCR and Western blotting were used to evaluate the expression level of YAP. Immunofluorescence was used to detect the location of YAP in h-PDLSCs. The proliferation activity was detected by cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU), and the cell cycle was determined by flow cytometry. Apoptosis was analyzed by Annexin V-APC staining. Cell senescence was detected by β-galactosidase staining. Proteins in ERK, Bcl-2, and p53 signaling pathways were detected by Western blotting.Results: h-PDLSCs were isolated successfully and were positive for human mesenchymal stem cell surface markers. After YAP was activated by lentiviral vector, the mRNA and protein of YAP were highly expressed, and more YAP translocated into the nucleus. When YAP was overexpressed in h-PDLSCs, proliferation activity was improved; early and late apoptosis rates decreased (P<0.05); the proportion of cells in G2/M phases increased (P<0.05), while that in G0/G1 phase decreased (P<0.05); cellular senescence was delayed (P<0.01); the expression of P-MEK, P-ERK, P-P90RSK and P-Msk increased, while the expression of Bcl-2 family members (Bak, Bid and Bik) decreased.Conclusions: Activated YAP promotes proliferation, inhibits apoptosis, and delays senescence of h-PDLSCs. The Hippo-YAP signaling pathway can influence ERK and Bcl-2 signaling pathways.

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“…The inhibition and removal of activated HSCs is a key strategy in the treatment of liver fibrosis ( 18 ). A previous study suggested that activated HSC senescence limits the extent of fibrosis following hepatic injury and that senescent HSCs lose the ability to produce collagen and proliferate ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…p53 promotes senescence by transactivating genes including p21, microRNA-34 and B cell lymphoma-2 associated X, apoptosis regulator which result in cell cycle progression and viability inhibition ( 21 ). Previous studies have demonstrated that p53-p21 signaling pathway activation may induce HSC senescence and inhibit HSC viability ( 18 , 20 , 22 ). p53 knockout mice exhibit severe hepatic fibrosis due to the inhibition of HSC senescence ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin‑10 promotes primary rat hepatic stellate cell senescence by upregulating the expression levels of p53 and p21

et al. 2018

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Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) components, and activated hepatic stellate cells (HSCs) are a primary source of ECM. Several studies have revealed that the induction of HSC senescence may reduce liver fibrosis. The effect of interleukin-10 (IL-10) on the senescence of activated HSCs is not fully understood. Therefore, the present study examined its effects and potential mechanisms in activated primary rat HSCs. Collagenase perfusion and density gradient centrifugation methods were used to isolate rat HSCs. HSCs were identified by autofluorescence, Oil Red O staining and immunocytochemical analysis. Activated HSCs were treated with 0, 10, 20 or 40 ng/ml IL-10 for 24 h. Senescence-associated β-galactosidase (SA-β-Gal) staining, flow cytometry analysis and a cell counting kit-8 assay were performed to detect the senescence, apoptosis and viability of rat HSCs, respectively. Reverse transcription-quantitative polymerase chain reaction, western blot analysis and enzyme linked immunosorbent assays were used to detect the expression of senescence-associated proteins and cytokines. Freshly isolated rat HSCs exhibited a striking blue-green autofluorescence and HSC retinoid droplets were stained bright red by Oil Red O. Immunocytochemical analysis demonstrated the cytoplasmic expression of HSC markers desmin and α-smooth muscle actin. The number of SA-β-Gal positive HSCs, the apoptotic rate and the expression levels of p53, p21 and tumor necrosis factor-α were significantly increased following IL-10 treatment. HSC viability and IL-6 and IL-8 expression levels were significantly decreased compared with the control group. In summary, primary rat HSCs were successfully isolated and IL-10 was demonstrated to promote the senescence of activated primary rat HSCs through the upregulation of p53 and p21 expression.

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Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine

Cited by 38 publications

References 35 publications

E-Liquid Containing a Mixture of Coconut, Vanilla, and Cookie Flavors Causes Cellular Senescence and Dysregulated Repair in Pulmonary Fibroblasts: Implications on Premature Aging

E-Liquid Containing a Mixture of Coconut, Vanilla, and Cookie Flavors Causes Cellular Senescence and Dysregulated Repair in Pulmonary Fibroblasts: Implications on Premature Aging

Activated Yes-Associated Protein Accelerates Cell Cycle, Inhibits Apoptosis, and Delays Senescence in Human Periodontal Ligament Stem Cells

Interleukin‑10 promotes primary rat hepatic stellate cell senescence by upregulating the expression levels of p53 and p21

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