基于网络药理学、微阵列数据分析和分子对接探究四君子汤治疗缺血性心力衰竭的作用机制

Effect of Sijunzi Decoction on Ischemic Heart Failure: an Analysis Based on Network Pharmacology, Microarray Data Analysis,and Molecular Docking

目的:通过网络药理学、微阵列数据分析和分子对接探讨四君子汤治疗缺血性心力衰竭的作用机制。方法:采用R软件对GEO数据库中下载的缺血性心力衰竭(HF)的微阵列数据进行分析;借助中药系统药理学数据库及分析平台(TCMSP)数据库获取四君子汤中4味中药的化学成分和作用靶点,利用网络药理学的方法获取四君子汤有效成分与心力衰竭的匹配靶点;通过Cytoscape(v 3.2.1)软件和STRING数据库构建蛋白-蛋白相互作用(PPI)网络;在R软件上使用clusterProfiler(v3.8)和DOSE(v3.6)软件包进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。最后,借助AutoDockTool、PyMOL软件进行预处理及分子对接。结果:通过对微阵列数据的分析,获得关于心力衰竭的371个差异表达基因(DEGs)。共筛选出四君子汤有效成分136种,活性成分所涉及的相关靶点4 134个,对9个匹配靶点和5个重要化学成分进行后续分析,构建了“四君子汤-心力衰竭”PPI网络。通过GO生物过程、KEGG富集分析,得到细胞对酸性化学物质的反应、有机羟基化合物转运、轴突再生、神经元投影再生、内质网腔、胶原三聚体、蛋白结合和局灶性黏附途径等重要生物学过程。分子对接显示核心成分柚皮素与核心靶点载脂蛋白B(APOB)、补体C1q结合蛋白(C1QB)对接良好。结论:四君子汤治疗缺血性心力衰竭的机制可能是多靶点、多途径的直接或间接作用,为后续的四君子汤药理机制研究提供了生物学依据。

Objective:To investigate the mechanism of Sijunzi Decoction(SJZD)in the treatment of ischemic heart failure through network pharmacology,microarray data analysis,and molecular docking.Methods:R software was used to analyze the microarray data of ischemic heart failure(HF)from the GEO database.The active components of 4 herbs in SJZD and targets corresponding to each component were scanned out from Traditional Chinese Medicines Systems Pharmacology Platform(TCMSP).The matching target of active components between SJZD and heart failure was obtained through network pharmacology.The protein-protein interaction(PPI)network was constructed by the Cytoscape software(v 3.2.1)and the STRING database.Gene ontology(GO)enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were executed by clusterProfiler(v 3.8)and DOSE(v 3.6)package on R platform.Finally,AutoDockTool and PyMOL software were used for preprocessing and molecular docking.Results:A total of 371 differentially expressed genes(DEGs)related to heart failure were obtained through the analysis of microarray data.A total of 136 active ingredients and 4134 targets of SJZD were picked out.Nine matching target genes and 5 relative active compounds were selected for subsequent analyses and the"SJZD-HF"PPI network was constructed.Through GO biological process and KEGG enrichment analysis,important biological processes such as cell response to acidic chemicals,transport of organic hydroxyl compounds,axon regeneration,neuronal projection regeneration,endoplasmic reticulum lumen,collagen trimer formation,protein binding and focal adhesion pathway were obtained.The results of molecular docking showed that naringin exhibited strong binding affinity with apolipoprotein B(APOB)and complement C1q binding protein(C1QB).Conclusion:The mechanism of SJZD for treating ischemic heart failure may be the direct or indirect action of multi-target and multi-pathway,which provides biological basis for the subsequent study of pharmacological mechanism of SJZD.