基于网络药理学和分子对接探讨虎杖治疗脓毒症的作用机制

Exploring the Mechanism of Polygoni Cuspidati Rhizoma et Radix in the Treatment of Sepsis Based on Network Pharmacology and Molecular Docking

【目的】应用网络药理学探讨虎杖治疗脓毒症的作用机制,并通过分子对接技术进行初步验证。【方法】通过中药系统药理学数据库与分析平台(TCMSP)和相关文献获取虎杖主要化学成分并预测作用靶标,从GeneCards、OMIM数据库获得脓毒症的疾病靶标,将脓毒症靶标与虎杖有效成分靶标通过R软件处理并绘制韦恩图。利用Cytoscape 3.8.0软件和STRING数据库构建药物-成分-靶标网络、药物-疾病靶标蛋白互作网络(PPI)。对交集靶标进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析。最后对核心靶标和有效成分采用分子对接验证。【结果】筛选出虎杖10个药物活性成分和63个潜在作用靶标。活性成分主要为槲皮素、木犀草素、β-谷甾醇、毒扁豆次碱、大黄酚、儿茶酚、6,8-二羟基-7-甲氧基呫吨酮。TP53、IL6、ESR1、CASP3、HIF1A、VEGFA等是筛选出来的核心靶标。GO富集结果主要集中在氧化应激反应、活性氧代谢过程、凋亡信号通路的调控与负调控等功能。KEGG主要涉及磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)、晚期糖基化产物-晚期糖基化终末产物受体(AGE-RAGE)、肿瘤坏死因子(TNF)、丝裂原活化蛋白激酶(MAPK)等信号通路。分子对接验证了网络药理学结果。【结论】虎杖可能通过β-谷甾醇、毒扁豆次碱、大黄酚等多种活性成分,作用于TP53、IL6、CASP3、HIF1A、VEGFA等多种关键靶标,发挥对PI3K-Akt、AGE-RAGE、MAPK等多个信号通路的调节作用,进而在干预炎症反应、细胞自噬、免疫应答等方面对脓毒症治疗产生积极作用。

Objective To explore the mechanism of action of Polygoni Cuspidati Rhizoma et Radix in the treatment of sepsis by applying network pharmacology,and preliminary validation was carried out by molecular docking techniques.Methods The main chemical components of Polygoni Cuspidati Rhizoma et Radix were obtained and the targets of action were predicted through the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform(TCMSP)and literature.The disease targets of sepsis were obtained from GeneCards and OMIM databases,and the targets of sepsis and the active ingredients of Polygoni Cuspidati Rhizoma et Radix were processed by R software and plotted in Venn diagrams.The drug-component-target network and drug-disease target protein-protein interaction network(PPI)were constructed using Cytoscape 3.8.0 software and STRING database.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were used for the intersecting targets.Finally,molecular docking validation was used for core targets and active constituents.Results Ten active pharmaceutical components and 63 potential action targets were screened.The active components were quercetin,luteolin,β-sitosterol,physovenine,rhein,catechin,6,8-dihydroxy-7-methoxyxanthenone,etc..TP53,IL6,ESR1,CASP3,HIF1A and VEGFA were the screened core targets.The GO enrichment results focused on the functions of oxidative stress response,reactive oxygen metabolic processes,regulation and negative regulation of apoptotic signaling pathways.KEGG mainly involved signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt),advanced glycation end product-receptor(AGERAGE),tumour necrosis factor(TNF)and mitogen-activated protein kinase(MAPK).Molecular docking validated the network pharmacology results.Conclusion Polygoni Cuspidati Rhizoma et Radix may act on various key targets such as TP53,IL6,CASP3,HIF1A and VEGFA through various active components such asβ-sitosterol,physovenine,rhein,and exert a positive effect on the regulation of various signaling pathways such as PI3K-Akt,AGE-RAGE and MAPK,which in turn may interfere with the inflammatory response,cellular autophagy and immune response in the treatment of sepsis.