基于网络药理学探讨巴元明治疗慢性肾功能衰竭核心药物的作用机制

Study on the Mechanism of Action of Ba Yuanming′s Core Drugs for Chronic Renal Failure Based on Network Pharmacology

目的:基于网络药理学方法探讨巴元明治疗慢性肾功能衰竭(chronic renal failure,CRF)核心药物的作用机制。方法:通过中医药整合药理学研究平台(integrative pharmacology-based research platform of traditional Chinese medicine,TCMIP)V2.0数据库检索巴元明治疗CRF核心药物(黄芪、党参、生地黄、山药、山茱萸、茯苓、白茅根、茜草、金樱子、芡实、黄柏、穿山龙)的化学成分,进而筛选核心药物的作用靶点。从TCMIP V2.0数据库获取CRF疾病靶点,将核心药物作用靶点与CRF疾病靶点进行匹配,所得靶点即为核心靶点。通过TCMIP V2.0数据库构建核心药物作用靶点与CRF疾病靶点的蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络,计算网络拓扑特征值从而筛选关键靶点。构建“核心药物-活性成分-关键靶点”的多维关系网络,采用David v 6.7数据库进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析。结果:12个核心药物含有356个活性成分,CRF相关疾病靶点13个;将核心药物作用靶点与CRF疾病靶点进行匹配,得到136个核心靶点;经过拓扑分析筛选得到62个关键靶点,包括腺苷酸环化酶1、多巴胺D2受体、蛋白激酶B1等;GO分析共获得170个功能(P<0.01),包括信号转导、凋亡过程负调控、细胞色素C氧化酶活性等;KEGG分析共获得105条通路(P<0.05),包括神经活性配体-受体相互作用、近端小管对钠离子的重吸收、代谢通路、Ras信号通路等。结论:巴元明治疗CRF的核心药物具有多成分、多靶点、多途径的作用特点,其可作用于腺苷酸环化酶1、多巴胺D2受体、热休克蛋白αA1等靶点,调控近端小管对钠离子的重吸收、代谢通路、Ras信号通路等通路。

Objective:To explore the mechanism of action of Professor Ba Yuanming′s core drugs for chronic renal failure(CRF)based on network pharmacology.Methods:The chemical compositions of Ba Yuanming′s core drugs for CRF,such as Huangqi(Radix Scutel-lariae),Dangshen(Radix Salviae Miltiorrhizae),Shengdihuang(Radix Rehmanniae),Shanyao(Rhizoma Dioscoreae),Shanzhuyu(Fructus Corni),Fuling(Poria),Baimaogen(Rhizoma Imperatae),Qiancao(Radix et Rhizoma Rubiae),Jinyingzi(Fructus Rosae Laevigatae),Qianshi(Semen Euryales),Huangbai(Cortex Phellodendri Chinensis),Chuanshanlong(Rhizoma Dioscoreae Nipponicae),were retrieved from the integrative pharmacology-based research platform of traditional Chinese medicine(TCMIP)V2.0 database,and the targets of the core drugs were screened.The CRF disease targets were obtained from the TCMIP V2.0 database,and the targets of the core drugs were matched with the CRF disease targets,and the obtained targets were the core targets.The protein-protein interaction(PPI)network of the core drug targets and the CRF disease targets was constructed by the TCMIP V2.0 platform,and the network to-pological characteristic value was calculated to screen the core targets.A multi-dimensional relationship network of"core drug-active component-key target"was constructed,and gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis was performed by using David v 6.7 database.Results:The 12 core drugs contained 356 active ingredients and 13 CRF-related disease targets.A total of 136 core targets were obtained by matching the targets of the core drugs and the targets of CRF;62 key targets were screened by topological analysis,including adenosine cyclase 1,dopamine D2 receptor,protein kinase B1,etc;170 functions were obtained by GO analysis(P<0.01),including signal transduction,negative regulation of apoptosis process,cytochrome C oxidase activ-ity,etc.;105 pathways were obtained by KEGG analysis(P<0.05),including neuroactive ligand-receptor interaction,proximal tubular sodium ion resorption,metabolic pathway,Ras signaling pathway,etc.Conclusion:Professor Ba Yuanming′s core drugs for the treatment of CRF have the characteristics of multi-component,multi-target and multi-pathway.They can act on adenosine cyclase 1,dopamine D2 receptor,heat shock proteinαA1 and other targets,and regulate the reabsorption of sodium ions by proximal tubular,metabolic pathway,Ras signaling pathway and other pathways.