基于网络药理学探讨补肾和脉方核心药物治疗高血压的作用机制

The Mechanism of Bushen Hemai Formula in the Treatment of Hypertension Based on Network Pharmacology

目的:运用网络药理学技术探讨补肾和脉方核心中药治疗高血压的作用机制。方法:分别在中药系统药理学数据库与分析平台(TCMSP)、中国知网(CNKI)数据库、SwissTargetPrediction数据库、SEA数据库检索并整合得到补肾和脉方中5味核心药物杜仲、泽泻、黄芪、怀牛膝、地龙活性成分及其作用靶点;在OMIM数据库和GeneCards数据库中检索获得高血压相关靶点,并通过Venny 2.1映射得到核心药物治疗高血压潜在靶点;利用Cytoscape 3.9.0软件构建成分-靶点关系网络并使用STRING 11.5数据库建立蛋白质互作网络,筛选核心治疗靶点;最后对核心药物治疗高血压的潜在靶点进行基因本体(GO)富集分析、京都基因与基因组百科全书(KEGG)通路富集分析。结果:在补肾和脉方核心药物中共筛选获得70种活性成分以及432个作用靶点,主要核心靶点包括信号转导和转录激活因子3(STAT3)、类固醇受体辅助激活因子(SRC)、磷脂酰肌醇-3激酶调节亚基1(PIK3R1)、非受体型蛋白酪氨酸磷酸酶11(PTPN11)、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α(PIK3CA)、表皮生长因子受体(EGFR)、蛋白酪氨酸激酶2(PTK2)、丝裂原活化蛋白激酶3(MAPK3)、血管内皮生长因子A(VEGFA)、雌激素受体1(ESR1)等。GO分析主要途径为含氧化合物反应、外源性刺激、对有机物质反应等生物学过程有关;KEGG通路主要包括癌症通路、糖尿病并发症中的糖基化终末产物及其受体(AGE-RAGE)信号通路、血流剪切应力与动脉粥样硬化、表皮生长因子受体(EGFR)激酶抑制剂拮抗、丝裂原活化蛋白激酶(MAPK)信号通路等。结论:初步阐明补肾和脉方核心中药可通过多成分、多靶点、多途径协同治疗高血压。

Objective:To explore the mechanism of Bushen Hemai Formula(BHF)in the treatment of hypertension based on network pharmacology.Methods:The active components and target of five core drugs of BHF including eucommia ulmoides,alisma,Radix Astragalus,Achyranthes bidentata,and Pheretima were obtained by searching TCMSP,CNKI database,SwissTargetPrediction database,and SEA database.Targets related to hypertension were retrived from OMIM and GeneCards.Then,the intersection targets of BHF and hypertension were mapped by Venny 2.1.The component-target network was constructed by Cytoscape 3.9.0.STRING 11.5 database were used for protein-protein interaction(PPI)network construction,and the core targets were screened.Finally,gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were conducted.Results:A total of 70 active components of BHF and 432 potential targets related to the treatment of hypertention were selected,including the following hub genes:signal transduction and transcriptional activator 3(STAT3),steroid receptor coactivator(SRC),phosphoinositide-3-kinase regulatory subunit 1(PIK3R1),protein tyrosine phosphatase non-receptor type 11(PTPN11),phosphatidylinositol-4,5-bisphos-phate 3-kinase catalytic subunit alpha(PIK3CA),epidermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),mitogen-activated protein kinase 3(MAPK3),vascular endothelial growth factor A(VEGFA),estrogen receptor 1(ESR1)and so on.GO function analysis mainly involved biological processes such as oxygen-containing compound reaction,exogenous stimulus,and reaction to organic substances.KEGG pathway mainly included cancer pathway,advanced glycation end products(AGE)-receptor for advanced glycation end products(RAGE)signaling pathway in diabetes complications,blood flow shear stress and atherosclerosis,EGFR kinase inhibitor antagonism,MAPK signaling pathway,etc.Conclusion:BHF can improve hypertension in synergistic effects through multiple components,multiple targets,and multiple pathways.