Astragaloside prevents BDL-induced liver fibrosis through inhibition of notch signaling activation
Astragaloside prevents BDL-induced liver fibrosis through inhibition of notch signaling activation
复制标题
黄芪甲苷通过抑制 Notch 信号激活来预防 BDL 诱导的肝纤维化
DOI：
10.1016/j.jep.2015.04.015
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发表时间：
2015-07-01
影响因子：
5.4
通讯作者：
Liu, Ping
中科院分区：
文献类型：
--
作者：
Mu, Yongping;Zhang, Xiao;Liu, Ping
民族药理学相关性：黄芪汤最早见于《宋代太平福利药局方剂》（公元1078年）。它由黄芪（黄芪）组成。知母。黄芪根和甘草(glycyrhiza uralensis Fisch。甘草，根和根茎)，是一种有效的处方，通常用于治疗消耗性疾病和慢性肝病。黄芪甲苷（Astragaloside， AS）是黄芪的主要成分，其抗肝纤维化作用与黄芪汤相似。研究目的：胆汁淤积与许多慢性肝脏疾病有关，Notch信号已被证明参与导管反应。既往研究表明，AS可阻止胆汁淤积性肝纤维化的进展，但AS是否影响Notch信号通路尚不清楚。材料与方法：采用胆总管结扎法建立大鼠胆汁淤积性肝纤维化。第一个周末将大鼠随机分为模型组（BDL）、AS组和索拉非尼阳性对照组（Sorafenib阳性对照组），治疗3周。组织染色观察胆管增生及肝纤维化情况。通过分析Notch-1、-2、-3、-4、Jagged 1 （JAG1）、Delta-like (DLL)-1、-3、-4、Hesl、Numb和RBP-J kappa的表达来评估Notch信号通路的激活情况。通过分析Wnt-4、-5a、-5b、frizzed (Fzd)-2、-3、-6和β -catenin的表达来评估Wnt信号通路的激活。结果：(1)与BDL组相比，AS显著降低肝组织胶原沉积和Hyp含量，抑制hsc活化。此外，AS显著降低了tgf - β 1和α - sma蛋白和mRNA的表达。相反，AS显著增强了Smad 7蛋白的表达。AS还能抑制胆道上皮细胞的增殖，降低CK7、CK8、CK18、CK19、OV6、Sox9和EpCAM mRNA和蛋白的表达。(2)与BDL组相比，AS中Notch-2、-3、-4和JAG1 mRNA和蛋白表达均显著降低。相比之下，AS处理后Numb的mRNA和蛋白水平明显升高。结论：AS可能通过抑制Notch信号通路预防胆道肝纤维化，从而抑制胆道上皮细胞的异常增殖。结果表明，AS可能是一种潜在的治疗胆汁淤积性肝病的药物。2015爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in the Song Dynasty (AD1078). It consists of Radix Astragali (Astragalus membranceus (Fisch.) Bge. Root, Huangqi) and Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch., root and rhizome, Gancao), and it is an effective recipe that is usually used to treat consumptive disease and chronic liver diseases. Astragaloside (AS) is a main component of Radix Astragali had an effect similar to the Huangqi decoction on hepatic fibrosis.Aim of the study: Cholestasis is associated with a number of chronic liver diseases and Notch signaling has been demonstrated to be involved in ductular reaction. Previous studies have shown that AS can prevent the progression of cholestatic liver fibrosis, however, whether AS affects the Notch signaling pathway is unclear.Materials and methods: Cholestatic liver fibrosis was established by common bile duct ligation (BDL) in rats. At first weekend, the rats were randomly divided into a model group (BDL), an AS group, and a Sorafenib positive control group (SORA) and treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, -4, Jagged 1 (JAG1), Delta-like (DLL)-1, -3, -4, Hesl, Numb and RBP-J kappa. Activation of the Wnt signaling pathway was evaluated by analyzing expressions of Wnt-4, -5a, -5b, Frizzled (Fzd)-2, -3, -6 and beta-catenin.Results: (1) Compared with the BDL group, AS significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs. In addition, AS significantly decreased the protein and mRNA expressions of TGF-beta 1 and alpha-SMA. In contrast, AS significantly enhanced expression of the Smad 7 protein. AS also reduced biliary epithelial cell proliferation, and reduced the mRNA and protein expressions of CK7, CK8, CK18, CK19, OV6, Sox9 and EpCAM. (2) The mRNA and protein expressions of Notch-2, -3, -4 and JAG1 were significantly reduced in the AS compared to the BDL group. In contrast, the mRNA and protein level of Numb was clearly enhanced after AS treatment.Conclusion: AS may prevent biliary liver fibrosis via inhibition of the Notch signaling pathway, thereby inhibiting the abnormal proliferation of biliary epithelial cells. Results indicate that AS may be a potential therapeutic drug for cholestatic liver disease. (C) 2015 Elsevier Ireland Ltd. All rights reserved.