Oroxylin A inhibits ethanol‐induced hepatocyte senescence <i>via</i> <scp>YAP</scp> pathway

Jin, Huanhuan; Lian, Naqi; Bian, Mianli; Zhang, Chenxi; Chen, Xingran; Shao, Jiangjuan; Wu, Li; Chen, Anping; Guo, Qing; Zhang, Feng; Zheng, Shizhong

doi:10.1111/cpr.12431

Cited by 38 publications

(15 citation statements)

References 48 publications

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“…Finally, metformin, a potential anti-aging agent, activated the YAP-CDK6 pathway and suppressed D-gal-induced senescence of C6 cells. Our implication of the YAP-CDK6 pathway in senescence is in line with recent observations that have demonstrated that YAP controls senescence of IMR90 cells [ 24 ], human mesenchymal stem cells [ 44 ], hepatocytes [ 45 ], and YAP-1 deficiency promotes health ageing of Caenorhabditis elegans [ 46 ]. Moreover, some other YAP-targeted genes, such as CYR61 (Cysteine Rich Angiogenic Inducer 61) and CTGF (Connective Tissue Growth Factor), are also reported to be involved in cellular senescence [ 47 , 48 ].…”

Section: Discussionsupporting

confidence: 89%

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

Shen

Feng

et al. 2020

Aging

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Treatment of glioblastoma using radiotherapy and chemotherapy has various outcomes, key among them being cellular senescence. However, the molecular mechanisms of this process remain unclear. In the present study, we tested the ability of D-galactose (D-gal), a reducing sugar, to induce senescence in glioblastoma cells. Following pretreatment with D-gal, glioblastoma cell lines (C6 and U87MG) showed typical characteristics of senescence. These included the reduced cell proliferation, hypertrophic morphology, increased senescence-associated β-galactosidase activity, downregulation of Lamin B1, and upregulation of several senescence-associated genes such as p16, p53, and NF-κB. Furthermore, our results showed that D-gal was more suitable than etoposide (a DNA-damage drug) in inducing senescence of glioblastoma cells. Mechanistically, D-gal inactivated the YAP-CDK6 signaling pathway, while overexpression of YAP or CDK6 could restore D-gal-induced senescence of C6 cells. Finally, metformin, an anti-aging agent, activated the YAP-CDK6 pathway and suppressed D-gal-induced senescence of C6 cells. Taken together, these findings established a new model for analyzing senescence in glioblastoma cells, which occurred through the YAP-CDK6 pathway. This is expected to provide a basis for development of novel therapies for the treatment of glioblastoma.

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Section: Discussionsupporting

confidence: 89%

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

Shen

Feng

et al. 2020

Aging

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“…Accordingly, restriction of HSC contraction represents a novel intervention strategy for liver fibrosis or cirrhosis, as well as portal hypertension. We recently reported that oroxylin A had significant antifibrotic and hepatoprotective effects in vitro and in vivo [17, 31, 32], and observed that oroxylin A could improve sinusoidal vascular remodeling [27]. These observations directed us to investigate whether modulation of HSC contractile phenotype was involved in oroxylin A’s effects.…”

Section: Discussionmentioning

confidence: 99%

Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells

Wang

Jia

et al. 2019

Cell Commun Signal

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BackgroundContraction of hepatic stellate cells (HSCs) plays an important role in the pathogenesis of liver fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Here, we investigated how HSC contraction was affected by the natural compound oroxylin A, and elucidated the underlying mechanism.MethodsCell contraction and glycolysis were examined in cultured human HSCs and mouse liver fibrosis model upon oroxylin A intervention using diversified cellular and molecular assays, as well as genetic approaches.ResultsOroxylin A limited HSC contraction associated with inhibiting myosin light chain 2 phosphorylation. Oroxylin A blocked aerobic glycolysis in HSCs evidenced by reduction in glucose uptake and consumption and lactate production. Oroxylin A also decreased extracellular acidification rate and inhibited the expression and activity of glycolysis rate-limiting enzymes (hexose kinase 2, phosphofructokinase 1 and pyruvate kinas type M2) in HSCs. Then, we identified that oroxylin A blockade of aerobic glycolysis contributed to inhibition of HSC contraction. Furthermore, oroxylin A inhibited the expression and activity of lactate dehydrogenase-A (LDH-A) in HSCs, which was required for oroxylin A blockade of glycolysis and suppression of contraction. Oral administration of oroxylin A at 40 mg/kg reduced liver injury and fibrosis, and inhibited HSC glycolysis and contraction in mice with carbon tetrachloride-induced hepatic fibrosis. However, adenovirus-mediated overexpression of LDH-A significantly counteracted the oroxylin A’s effects in fibrotic mice.ConclusionsBlockade of aerobic glycolysis by oroxylin A via inhibition of LDH-A reduced HSC contraction and attenuated liver fibrosis, suggesting LDH-A as a promising target for intervention of hepatic fibrosis.Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0324-8) contains supplementary material, which is available to authorized users.

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“…Oroxylin A can restore the deceased cell viability and increased expression of senescence makers in ethanol‐treated hepatocytes. And this protective role of oroxylin A is associated with activation of the YAP pathway, because YAP inhibitor or YAP knockdown significantly disturbed its function (Jin et al, ). In addition, oroxylin A prevents ethanol‐induced lipid accumulation by regulating genes implicated in lipid metabolism (Jin et al, ).…”

Section: Natural Compounds Beneficial For Ald Treatmentmentioning

confidence: 99%

Natural compounds in the chemoprevention of alcoholic liver disease

Zhu

Wang

et al. 2019

Phytotherapy Research

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Alcoholic liver disease (ALD), caused by excessive consumption of alcohol, is a major cause of chronic liver disease worldwide. Much effort has been expended to explore the pathogenesis of ALD. Hepatic cell injury, oxidative stress, inflammation, regeneration, and bacterial translocation are all involved in the pathogenesis of ALD. Immediate abstinence is the most important therapeutic treatment for affected individuals. However, the medical treatment for ALD had not advanced in a long period. Intriguingly, an increasing body of research indicates the potential of natural compounds in the targeted therapy of ALD. A plethora of dietary natural products such as flavonoids, resveratrol, saponins, and β‐carotene are found to exert protective effects on ALD. This occurs through various mechanisms composed of antioxidative, anti‐inflammatory, iron chelation, pro‐apoptosis, and/or antiproliferation of hepatic stellate cells and hepatocellular carcinoma cells. In this review, we will summarize current knowledge about the pathogenesis and treatments of ALD and focus on the potential of natural compounds in ALD therapies and underlying mechanisms.

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Oroxylin A inhibits ethanol‐induced hepatocyte senescence via YAP pathway

Abstract: Therefore, these aggregated data suggested that oroxylin A relieved alcoholic liver injury possibly by inhibiting the senescence of hepatocyte, which was dependent on its activation of YAP in hepatocytes.

Cited by 38 publications

References 48 publications

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells

Natural compounds in the chemoprevention of alcoholic liver disease

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