基于网络药理学的补肾和脉方治疗高血压作用机制研究

目的:利用网络药理学研究由当归芍药散合金匮肾气丸化裁而来的补肾和脉方治疗高血压的作用机制。方法:基于中药系统药理学数据库与分析平台(TCMSP)获取补肾和脉方的化学成分和作用靶点,构建化合物-靶点网络。通过TTD、OMIM、DrugBank、GAD、PharmGKB、DisGeNET数据库筛选高血压靶点。基于补肾和脉方作用靶点与高血压靶点的交集结果,建立蛋白质-蛋白质相互作用(PPI)网络,分析交集靶点之间的相互作用,通过拓扑结构筛选关键靶点。利用DAVID 6.8数据库对交集靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。结果:从补肾和脉方中筛选出110个有效成分,得到可能作用于高血压的83个交集靶点。进一步筛选出11个关键靶点,包括白细胞介素-6 (IL-6)、一氧化氮合酶3 (NOS3)、肿瘤坏死因子(TNF)、表皮生长因子(EGF)、血管内皮生长因子(VEGFA)、前列腺素G/H合成酶2 (PTGS2)、过氧化氢酶(CAT)、乙酰胆碱酯酶(ACHE)、JUN、钠依赖性血清素转运体(SLC6A4)和凝血酶(F2)。GO分析得到28条生物过程,主要涉及腺苷酸环化酶激活肾上腺素能受体信号通路、药物反应、缺氧反应、磷脂酶C激活G蛋白偶联受体信号通路、血管收缩的正调节等;KEGG富集分析得到45条信号通路,主要涉及神经活性配体-受体相互作用通路、钙信号通路、5-羟色胺能突触通路、环磷酸鸟苷(cGMP)-蛋白激酶(PKG)信号通路、环磷酸腺苷(cAMP)信号通路、TNF信号通路等。结论:补肾和脉方治疗高血压是多靶点、多途径的直接或间接协同作用。

Study on Mechanism of Bushen Hemai Fang in Treatment of Hypertension Based on Network Pharmacology

Objective To explore the mechanism of Bushen Hemai Formula (BHF) modified from Danggui Shaoyao Powder and Jingui Shenqi Pill in the treatment of hypertension based on network pharmacology.Methods The chemical components and targets of BHF were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) for constructing the compound-target network. The hypertension-related targets were retrieved from six databases including TTD, OMIM, DrugBank, GAD, PharmGKB, and DisGeNET. Based on the intersections of BHF targets with hypertension-related targets, a protein-protein interaction (PPI) network was constructed for analyzing their interactions and screening the key targets by topology. Furthermore, these intersections were subjected to gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis using DAVID 6.8 database.Results A total of 110 active components of BHF were collected, which possibly acted on 83 targets of hypertension. Further screening yielded 11 key targets, including interleukin-6 (IL-6), nitric oxide synthase 3 (NOS3), tumor necrosis factor (TNF), epidermal growth factor (EGF), vascular endothelial growth factor A (VEGFA), prostaglandin-endoperoxide synthase 2 (PTGS2), catalase (CAT), acetylcholinesterase (ACHE), JUN, sodium-dependent serotonin transporter (SLC6A4), and thrombin (F2). GO analysis revealed 28 biological processes, mainly involving the adenylate cyclase activating adrenergic receptor signaling pathway, response to drug treatment, response to hypoxia, phospholipase C activating G protein-coupled receptor signaling pathway, and positive regulation of vasoconstriction. As demonstrated by the KEGG pathway enrichment analysis, 45 pathways were obtained, mainly involving the neuroactive ligand-receptor interaction pathway, calcium signaling pathway, serotonergic synapse pathway, cyclic guanosine monophosphate (cGMP)-protein kinase (PKG) signaling pathway, cyclic adenosine monophosphate (cAMP) signaling pathway, and TNF signaling pathway.Conclusion The therapeutic effect of BHF against hypertension might be achieved via the direct or indirect synergistic action of multiple targets through multiple pathways.