基于网络药理学探讨舒肝颗粒治疗肝损伤的作用机制

Mechanism of Shugan Granules in Treatment of Drug-induced Liver Injury Based on Network Pharmacology

目的基于网络药理学探讨舒肝颗粒治疗肝损伤的作用机制,以期为临床应用提供参考。方法通过中药系统药理学数据库及分析平台数据库和文献检索收集舒肝颗粒化学成分及其靶点。借助人类基因数据库寻找导致肝损伤的相关靶点。利用在线韦恩图(Veney 2.1)筛选出成分和与肝损伤相关的作用靶点的交集,进而运用Cytoscape 3.9.0软件构建中药-活性成分-靶点网络进行可视化,通过DAVID数据库进行GO功能富集分析和KEGG通路富集分析,预测交集靶点作用机制,并绘制柱状图及气泡图进行可视化。结合String数据库和Cytoscape的NetworkAnalyzer分析蛋白相互作用关系并用分子对接进行验证。结果中药-活性成分-靶点网络包含了4种中药,126个活性成分和相应靶点203个,关键靶点涉及PTGS2、ESR1、PPARG、AR等。GO功能富集分析得到条目2084个(P<0.05),KEGG通路富集分析筛选得到162条信号通路,富集分析表明舒肝颗粒主要涉及对脂多糖、细菌来源分子、对外界刺激的反应等生物过程。针对潜在靶点得到的String蛋白质相互作用图筛选出前10个度值最高的靶点是AKT1、IL-6、JUN、VEGFA、CASP3、IL1B、PTGS2、EGFR、HIF1A、MYC。结论舒肝颗粒中的化合物通过作用于AKT1、IL-6、VEGF、CASP3、PTGS2等靶点基因,影响细胞凋亡和增殖、自由基生成、抗炎症、抗脂肪积累等方面,通过减少氧化应激、炎症、细胞凋亡及谷胱甘肽的消耗,起到保护肝脏的作用。本研究初步揭示了舒肝颗粒治疗肝损伤的作用机制是多成分、多靶点的,可为后续研究提供参考。

Objective To explore the mechanism by which Shugan granules protect against liver injury based on network pharmacology so as to provide reference for clinical applications.Methods The chemical constituents and targets of Shugan granules were retrieved from the Traditional Chinese Medicine Systematic Pharmacology(TCMSP)Database and Analysis Platform.The related targets that caused liver injury were searched for in the Human Gene Database.The online Venn diagram(Veney 2.1)was used to screen the intersections of components and targets related to liver injury.Cytoscape 3.9.0 software was used to construct the traditional Chinese medicine(TCM)-active ingredient-target network for visualization.GO functional enrichment analysis and KEGG pathway enrichment analysis were conducted via the DAVID database to predict the mechanism of intersection targets,and bar charts and bubble charts were drawn for visualization.The interactions between proteins were analyzed via the String database and Cytoscape Network Analyzer and verified by molecular docking.Results The TCM-active ingredient-target network included 4 types of TCM,126 active ingredients and 203 corresponding targets,and the key targets involved PTGS2,ESR1,PPARG and AR.There were 2084 items obtained by GO functional enrichment analysis(P<0.05),and 162 signal pathways were screened by KEGG pathway enrichment analysis.Enrichment analysis showed that Shugan granules were mostly involved in such biological processes as response to lipopolysaccharides,bacterial-derived molecules,and external stimuli.According to the String protein interaction map obtained from potential targets,the top 10 targets with the highest degree were AKT1,IL-6,JUN,VEGFA,CASP3,IL1B,PTGS2,EGFR,HIF1A and MYC.Conclusion Compounds in Shugan granules affect cell apoptosis and proliferation,free radical generation,anti-inflammation and anti-fat accumulation by acting on such target genes as AKT1,IL-6,VEGF,CASP3 and PTGS2.They can also help protect the liver by reducing oxidative stress,inflammation,apoptosis and glutathione consumption.