基于网络药理学和分子对接技术探究川芎抗肝纤维化的作用机制

Investigating the Mechanism of Chuanxiong Against Liver Fibrosis Based on Network Pharmacology and Molecular Docking Techniques

为探究川芎抗肝纤维化的活性成分及作用机制。本研究采用网络药理学方法,采用GEO数据库及DisGeNET数据库检索获取肝纤维化靶点;利用TCMSP数据库及文献检索获取川芎化学成分及作用靶点;将川芎药物靶点与疾病靶点取交集,并进行蛋白互作网络构建及拓扑分析;采用DAVID数据库进行GO和KEGG富集分析,利用微生信进行做图;通过Cytoscape软件构建“成分-靶点-信号通路”调控网络。采用分子对接技术针对川芎活性成分和关键靶点进行对接模拟。结果表明,TCMSP数据库检索结合文献研究,筛选得到川芎中8个活性成分及对应的88个作用靶点;GEO数据库筛选及DisGeNET数据库检索获取疾病靶点2038个,交集得到32个川芎治疗肝纤维化的共同靶点,并筛选出转录激活因子3(Signal transducer and activator of transcription 3,STAT3)、前列腺素内过氧化物合成酶2(Recombinant prostaglandin endoperoxide synthase 2,PTGS2)和表皮生长因子受体(Epidermal growth factor receptor,EGFR)等关键靶点。富集分析表明,川芎治疗肝纤维化的靶点主要参与肝癌信号通路、脂质代谢和动脉粥样硬化、白介素17信号通路和内分泌抵抗等信号通路,涉及RNA聚合酶Ⅱ启动子转录的正向调节过程和信号转导过程等生物学过程。“成分-靶点-信号通路”分析表明,川芎抗肝纤维化活性成分6个,分别为阿魏酸(Ferulic acid,FA)、川芎哚(Perlolyrine)、叶酸(Folic acid)、川芎萘呋内酯(Wallichilide)、亚麻油酸乙酯(Mandenol)和肉豆蔻酮(Myricanone),其中阿魏酸的节点度值最大。分子对接结果表明,川芎抗肝纤维化关键成分阿魏酸和关键靶点PTSG2、MMP9和EGFR分子均具有较好的结合能力,结合能分别为-23.04kJ/mol、-22.17kJ/mol和-25.14kJ/mol。川芎可通过靶向STAT3、PTGS2和EGFR等靶点,调控肝癌和脂质代谢等信号通路,改善肝纤维化病变,发挥保护肝脏的作用。

In order to investigate the active components and mechanism of Chuanxiong against liver fibrosis.In this study,the liver fibrosis targets were obtained from GEO database and DisGeNET database.The chemical components and their action targets were obtained from TCMSP database and literature.The drug targets and disease targets were intersected.Protein interaction network construction and topology analysis was performed and GO and KEGG enrichment analysis was performed using DAVID database.Then,the "component-target-signaling pathway" network was built via using Cytoscape software.Molecular docking technique was used to analysis the combining capabilities of main active component and targets of Chuanxiong against liver fibers.8 active ingredients of Chuanxiong and 88 corresponding targets were selected,and 2 038 disease targets were collected.32 targets of Chuanxiong for the treatment of liver fibrosis were obtained,and PPI analysis revealed the core targets including signal transducer and activator of transcription 3(STAT3),recombinant prostaglandin endoperoxide synthase 2(PTGS2) and epidermal growth factor receptor(EGFR).The enrichment analysis showed that the targets of Chuanxiong for liver fibro sis were mainly involved in the signaling pathways of hepatocellular carcinoma,lipid metabolism and atherosclerosis,interleukin 17 signaling pathway and endocrine resistance,as well as participating in process of the positive regulation of RNA polymerase Ⅱ promoter transcription and signal transduction.The "component-target-pathway" analysis showed that there were six active components of Chuanxiong against liver fibrosis,namely ferulic acid,perlolyrine,folic acid,wallichilide,mandenol and myricanone.In vitro target molecular docking showed that ferulic acid,a key component of Chuanxiong's anti-hepatic fibrosis,had good binding ability to and key targets PTSG2,MMP9 and EGFR molecules,with binding energies of 23.04 kJ/mol、-22.17 kJ/mol and-25.14 kJ/mol,respectively.Chuanxiong can improve hepatic fibrotic lesions and exert hepatoprotective effects through targeting STAT3,PTGS2 and EGFR,as well as regulating signaling pathways related to liver cancer and lipid metabolism.