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Yangonin inhibits ethanol-induced hepatocyte senescence via miR-194/FXR axis
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2020-10-15 , DOI: 10.1016/j.ejphar.2020.173653
Renchao Dong , Xiaohui Wang , Lu Wang , Changyuan Wang , Kai Huang , Ting Fu , Kexin Liu , Jingjing Wu , Huijun Sun , Qiang Meng

Chronic alcohol assumption has been recognized as a major cause of alcoholic liver disease (ALD), which ranges from alcoholic steatohepatitis to fibrosis and hepatocellular carcinoma. Alcoholic liver disease has become the leading cause of liver-related health problem in the world. Herewith, effective therapeutic strategy for alcoholic liver disease is necessary. Yangonin (Yan), a bioactive compound extract from Kava, has been reported to exert hepatoprotective effects via Farnesoid X receptor (FXR) activation. The present study aims to investigate whether Yan ameliorated the ethanol-stimulated liver injury and further to elucidate the mechanisms in vivo and in vitro. Yan improved cell viabilities via cell count kit-8 (CCK-8) methods and obviously reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG) levels. We detected miR-194 levels in ethanol-induced LO2 cells and male C57BL/6 mice by quantitative real-time PCR. Also, the effects of miR-194 on modulating cellular senescence via targeting FXR were further verified. The cellular senescence markers p16, p21, telomerase activity and senescence-related β-galactosidase (SA-β-gal) were evaluated by quantitative real-time PCR and Western blot. Also, LO2 cells or liver tissues were stained with special primary antibodies and 4′,6′-Diamidino-2-phenylindole (DAPI). The cell cycle was detected by flow cytometry. We observed that Yan significantly inhibited ethanol-induced cellular senescence via FXR activation (P < 0.05). Our results demonstrate that Yan significantly reduced the cellular markers p16, p21 and Hmga1 expression and inhibited the cell cycle arrest (P < 0.05). MiR-194 was upregulated in the alcoholic liver disease, which was significantly suppressed by Yan (P < 0.05). Moreover, miR-194 mimic inhibited FXR expression in vitro. In summary, these aggregated data demonstrate that Yan alleviates chronic ethanol-induced liver injury through inhibition of cellular senescence via regulating miR-194/FXR axis.



中文翻译:

仰光宁通过miR-194 / FXR轴抑制乙醇诱导的肝细胞衰老

慢性酒精假设已被认为是酒精性肝病(ALD)的主要原因,其范围从酒精性脂肪性肝炎到纤维化和肝细胞癌。酒精性肝病已成为世界上与肝脏相关的健康问题的主要原因。因此,对于酒精性肝病有效的治疗策略是必要的。仰光宁(Yan)是一种来自卡瓦(Kava)的生物活性化合物提取物,据报道可通过Farnesoid X受体(FXR)激活发挥肝保护作用。本研究旨在研究Yan是否能改善乙醇刺激的肝损伤,并进一步阐明体内体外的机制。Yan通过细胞计数试剂盒8(CCK-8)方法提高了细胞活力,并明显降低了天冬氨酸转氨酶(AST),丙氨酸转氨酶(ALT),总胆固醇(TC)和总甘油三酯(TG)的水平。我们通过定量实时PCR检测了乙醇诱导的LO 2细胞和雄性C57BL / 6小鼠中的miR-194水平。此外,进一步验证了miR-194通过靶向FXR调节细胞衰老的作用。通过实时荧光定量PCR和蛋白质印迹法评估细胞的衰老标记p16,p21,端粒酶活性和衰老相关的β-半乳糖苷酶(SA-β-gal)。另外,LO 2细胞或肝组织用特殊的一抗和4',6'-Diamidino-2-phenylindole(DAPI)染色。通过流式细胞术检测细胞周期。我们观察到,Yan通过FXR激活显着抑制乙醇诱导的细胞衰老(P  <0.05)。我们的结果表明,Yan显着降低了细胞标志物p16,p21和Hmga1的表达,并抑制了细胞周期停滞(P  <0.05)。在酒精性肝病中,MiR-194上调,而Yan显着抑制了MiR-194(P  <0.05)。此外,miR-194模拟物在体外抑制FXR表达。总之,这些汇总数据表明,Yan通过调节miR-194 / FXR轴来抑制细胞衰老,从而减轻了乙醇引起的慢性肝损伤。

更新日期:2020-10-16
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