基于网络药理学探讨桂枝茯苓丸治疗糖尿病肾病的作用机制

A study on the mechanism of Guizhi Fuling Wan in treating diabetic nephropathy based on network pharmacology

目的:通过网络药理学的方法探讨桂枝茯苓丸治疗糖尿病肾病(Diabetic Nephropathy,DN)的信号通路及其可能的作用机制。方法:通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)检索桂枝茯苓丸中桂枝、茯苓、牡丹、赤芍、桃仁5味中药的有效活性成分,并用Perl软件得出药物作用靶基因,应用Uniprot数据库将药物靶点规范为相应的基因名称;在Genecards数据库、人类孟德尔遗传数据库中输入“diabetic nephropathy”,获取DN的疾病靶点基因。通过R软件获取药物-疾病的交集作用靶点,采用Cytoscape 3.2.1软件绘制成分-靶点-疾病可视化网络图,利用STRING数据库及Cytoscape 3.2.1软件得到靶点蛋白质-蛋白质相互作用(Protein-protein Interaction,PPI)网络图,并进一步对关键靶点进行基因本体论(Gene Ontology,GO)功能富集分析、京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。结果:桂枝茯苓丸药物组成中活性成分有85个,药物靶点有100个,DN疾病靶点有3496个,通过R软件得到交集靶点68个,PPI网络图核心靶点为白细胞介素-6(Interleukin-6,IL-6)、血管内皮生长因子(Vascular Endothelial Growth Factor A,VEGF)A、丝裂原激活蛋白激酶8(Mitogen-Activated Protein Kinase 8,MAPK8)等。GO功能富集分析主要涉及DNA结合转录因子、RNA聚合酶Ⅱ、血红素结合、泛素样蛋白连接酶结合、转录因子结合、核受体活性等。KEGG通路富集分析显示主要涉及流体剪应力与动脉粥样硬化、晚期糖基化终末产物(Advanced Glycation End Products,AGE)-晚期糖基化终末产物受体(Receptor For Advanced Glycation End Products,RAGE)、细胞凋亡、肿瘤坏死因子(Tumor Necrosis Factor,TNF)、缺氧诱导因子(Hypoxia Inducible Factor,HIF)-1信号通路等。结论:桂枝茯苓丸可能通过多成分、多靶点、多通路实现治疗DN的作用。

Objective:To explore the signal pathway and possible mechanism of Guizhi Fuling Wan(桂枝茯苓丸)in treating diabetic nephropathy by means of network pharmacology.Methods:The active components of Guizhi(cassia twig),Fuling(poria cocos),Mudan(peony),Chishao(red peony root)and Taoren(peach kernel)in Guizhi Fuling Wan were retrieved by systematic pharmacology analysis platform of Traditional Chinese Medicine(TCMSP).The target genes of drug action were obtained by Perl software,and the drug targets were normalized into the corresponding gene names by Uniprot database.The disease target genes of diabetic nephropathy were obtained by entering“diabetic nephropathy”into Genecards database and OMIM database.The target of drug-disease interaction was obtained by R software.The composition-target-disease visualization network diagram was drawn using Cytoscape 3.2.1 software,and the target protein-protein interaction(PPI)network diagram was obtained by STRING database and Cytoscape 3.2.1 software.Furthermore,GO function enrichment analysis and KEGG pathway enrichment analysis were conducted for key targets.Results:There were 85 active ingredients,100 drug targets,3496 diabetic nephropathy targets,and 68 intersecting targets obtained by R software.The core targets of PPI network diagram were interleukin-6(IL-6),vascular endothelial growth factor A(VEGFA),mitogen-activated protein kinase 8(MAPK8),etc.GO functional enrichment analysis mainly involved DNA binding transcription factor,RNA polymerase II,heme binding,transcription factor binding,nuclear receptor activity,etc.Enrichment analysis of KEGG pathway showed that it mainly involved fluid shear stress and atherosclerosis,AGE-RAGE,apoptosis,TNF,HIF-1signal pathway and so on.Conclusion:Guizhi Fuling Wan may be effective in treating diabetic nephropathy through multi-components,multi-targets and multi-channels.