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  • Title: [Hydroxynitone suppresses hepatic stellate cell activation by inhibiting TGF-β1 phosphorylation to alleviate CCl4-induced liver fibrosis in rats].
    Author: Zhao Z, Dong H, Li B, Shen B, Guo Y, Gu T, Qu Y, Cai X, Lu L.
    Journal: Nan Fang Yi Ke Da Xue Xue Bao; 2022 Oct 20; 42(10):1511-1516. PubMed ID: 36329585.
    Abstract:
    OBJECTIVE: To investigate the effect of hydronidone on CCl4-induced liver fibrosis in rats and explore the possible mechanism. METHODS: Sixty-six male SD rats were randomized into 5 groups, including a control group (n=10), a liver fibrosis model group (n=20), 2 hydronidone dose groups (100 and 250 mg/kg; n=12), and a pirfenidone (250 mg/kg) treatment group (n= 12). Rat models of liver fibrosis were established by subcutaneous injection of CCl4 in all but the control group. Hydronidone and pirfenidone were given daily at the indicated doses by intragastric administration for 6 weeks. After the treatments, serum samples were collected from the rats for detecting liver function parameters, and hydroxyproline content in the liver tissue was determined. Inflammation and fibrosis in the liver tissue were observed using HE staining and Sirius Red staining. In the cell experiment, human hepatic stellate cell line LX-2 was stimulated with TGF-β1 and treated with hydronidone or pirfenidone, and the expression levels of α-SMA, collagen type I and phosphorylated Smad3, phosphorylated p38, phosphorylated ERK1/2 and phosphorylated Akt were detected with Western blotting. RESULTS: In the rat models of liver fibrosis, treatment with hydronidone obviously improved the liver functions, reduced the content of hydroxyproline in the liver tissue, and significantly alleviated liver fibrosis (P < 0.05). In LX-2 cells, hydronidone dose-dependently decreased the expression levels of α-SMA and collagen type I. In TGF- β1-stimulated cells, the phosphorylation levels of Smad3, P38, ERK, and Akt increased progressively with the extension of the treatment time, but this effect was significantly attenuated by treatment with hydronidone (P < 0.05). CONCLUSION: Hydronidone can inhibit the phosphorylation of the proteins in the TGF-β signaling pathway, thereby preventing TGF-β1-mediated activation of hepatic stellate cells, which may be a possible mechanism by which hydronidone alleviates CCl4-induced liver fibrosis in rats. 目的: 探讨羟尼酮对CCl4诱导的大鼠肝纤维化的作用及相关机制。 方法: 66只雄性SD大鼠按随机数字法分为对照组10只、模型组20只、羟尼酮（100 mg/kg）组12只、羟尼酮（250 mg/kg）组12只、吡非尼酮（250 mg/kg）组12只，采用CCl4皮下注射进行肝纤维化造模，羟尼酮、吡非尼酮予以灌胃给药，处死大鼠后，留取血清检测肝功能，利用肝脏组织检测羟脯氨酸的含量，肝组织进行HE染色和Sirius Red染色，对炎症和纤维化程度进行评分。将人肝星状细胞系LX-2分组：对照组、TGF-β1组、羟尼酮组、吡非尼酮组，经过TGF-β1刺激和羟尼酮、吡非尼酮处理后，Western blot分别检测α-SMA、I型胶原蛋白和磷酸化Smad3、磷酸化p38、磷酸化Erk1/2、磷酸化Akt等磷酸化蛋白。 结果: 动物实验显示羟尼酮组大鼠肝功能值有改善，肝组织羟脯氨酸含量明显减少，肝组织纤维化程度显著降低，且均具有统计学意义（P < 0.05）。细胞实验发现随羟尼酮浓度的增高，ɑ-SMA和I型collagen蛋白表达水平降低；TGF-β1刺激细胞后，TGF-β信号转导通路中Smad3、P38、ERK、Akt等蛋白的磷酸化水平随着作用时间的延长而增加，但在相同作用时间下，羟尼酮组细胞TGF-β信号转导通路蛋白磷酸化的表达水平低于TGF-β1组细胞（P < 0.05）。 结论: 羟尼酮可抑制TGF-β信号转导通路蛋白的磷酸化，从而阻止TGF-β1介导的肝星状细胞活化，可能是其缓解CCl4诱导的大鼠肝纤维化机制之一。
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