川芎改善非酒精性脂肪性肝炎的作用机制  

The mechanism of Chuanxiong in improving nonalcoholic steatohepatitis

作　　者：王玉平 龚瑾[2] 李沙沙[1] 章正[1] 杨倩之 单璐琛 WANG Yuping;GONG Jin;LI Shasha;ZHANG Zheng;YANG Qianzhi;SHAN Luchen(Department of Pharmacy,the First Affiliated Hospital of Jinan University,Guangzhou 510630,Guangdong,China;Department of General Surgery,the First Affiliated Hospital of Jinan University,Guangzhou 510630,Guangdong,China;College of Pharmacy,Jinan University,Guangzhou 510000,Guangdong,China)

机构地区：[1]暨南大学附属第一医院药学部,广东广州510630 [2]暨南大学附属第一医院胃肠外科,广东广州510630 [3]暨南大学药学院,广东广州510000

出　　处：《暨南大学学报（自然科学与医学版）》2022年第4期382-392,共11页Journal of Jinan University(Natural Science & Medicine Edition)

基　　金：广东省中医药局基金资助项目(20222041)。

摘　　要：目的:通过网络药理学与分子对接技术探讨川芎改善非酒精性脂肪肝炎(NASH)的作用机制,并通过动物模型进一步检测其改善作用。方法:通过中药系统药理数据库及分析平台(TCMSP)收集川芎的候选化合物,利用Swiss Target Prediction数据库预测成分靶点,DisGenet数据库预测疾病靶点,挑选共有靶点并利用STRING数据库对川芎改善NASH的核心靶点进行PPI蛋白互作分析。此外,利用Metascape分析系统对川芎改善NASH的核心靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析,用Cytoscape软件构建可视化网络,使用AutoDock软件进行分子对接验证。通过小鼠NASH模型进行药效学确证。结果:共获得5个有效化合物和39个潜在的核心治疗靶点。网络分析结果5个有效化合物谷甾醇、杨梅酮、亚油酸乙酯、川芎萘呋内酯、阿魏酸是川芎改善NASH的有效成分,核心基因包括EGFR、ESR1、PPARG、MAPK14、PPARA等。GO富集分析结果发现炎症反应与脂质代谢、核受体和蛋白酶激活、脂肪酸绑定、脂质转运活性等相关。KEGG通路富集结果显示,川芎治疗NASH与众多通路有关,可能通过调节PPAR信号通路、AMPK信号通路、cAMP信号通路、Wnt信号通路等发挥作用。分子对接研究显示,谷甾醇、杨梅酮、川芎萘呋内酯是起主要作用的成分,PPARA和PPARG可能是川芎作用最紧密的靶点。动物实验结果表明,川芎提取物治疗组较NASH模型组血清ALT、AST及肝脏组织TG均有明显改善作用(P<0.05),并明显减轻小鼠肝小叶脂肪变程度。结论:川芎可能通过作用于PPARA和PPARG等核心基因、PPAR等信号通路发挥改善NASH的作用,并通过动物实验验证,川芎可以改善高脂饮食所致的非酒精性脂肪性肝病小鼠的肝功能异常,并减轻小鼠肝小叶脂肪变程度。Objective:To explore the potential targets and related signaling pathways of Chuanxiong in treating nonalcoholic steatohepatitis(NASH) using network pharmacology and molecular docking techniques, and further to verify its improvement by high-fat diet-induced non-alcoholic steatohepatitis in mice. Methods: Traditional Chinese Medicine Systematic Pharmacology(TCMSP) Database and Analysis Platform were applied to collect the candidate compounds from Chuanxiong. Swiss Target Prediction database and DisGenet database were chosen to predict the components and disease targets respectively. The core targets of Chuanxiong were obtained. The protein-protein interaction(PPI) analysis was performed by STRING database, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were carried out by Metascape. Cytoscape software was used to build the visual networks, and AutoDock was used to verify themolecular docking. The improvement of Chuanxiong on non-alcoholic steatohepatitis was investigated in mice.Results: Network analysis results revealed 5 active compounds of Chuanxiong and 39 potential targets of its action. They are sitosterol, myricanone, mandenol, wallichilide, and ferulic acid. EGFR, ESR1, PPARG, MAPK14, PPARA are the core genes. GO and KEGG analysis showed that these core genes are focused on the following biological process, such as inflammatory response, lipid metabolism, nuclear receptor and protease activation, fatty acid binding, and lipid transport activity, and the signaling pathway of PPAR, AMPK, cAMP, Wnt. Molecular docking studies proved that sitosterol, myricanone, and wallichilide were the main active components, PPARA and PPARG were the most targets. Animal experimental results showed that Chuanxiong extracts significantly reduced the level of ALT and AST in serum, and TG in liver tissue(P<0.05), and alleviated the hepatic lobular steatosis.Conclusion:Chuanxiong may be a potential drug used for treating nonalcoholic steatohepatitis by regulating PPARA and PPARG core

关 键 词：川芎 非酒精性脂肪性肝炎 网络药理学 分子对接 

分 类 号：R714.255[医药卫生—妇产科学]