基于网络药理学探讨黄芪治疗慢传输型便秘的作用机制

Mechanism of Radix Astragali seu Hedysari in the Treatment of Slow Transit Constipation Based on Network Pharmacology

目的:借助网络药理学和分子对接技术探讨黄芪治疗慢传输型便秘的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)筛选黄芪的活性化合物并预测其作用靶点,借助Cytoscape 3.7.2软件构建黄芪活性成分-靶点网络图;以“slow transit contipation”为关键词在OMIM及GeneCards数据库检索慢传输型便秘相关靶点,并与黄芪化合物作用靶点取交集,将共同靶点导入String数据库构建蛋白质-蛋白质相互作用(PPI)网络图,将PPI导入Cytoscape 3.7.2进行拓扑分析;利用R语言进行基因本体(GO)富集分析和京都基因和基因组百科全书(KEGG)通路富集分析预测其作用机制;通过Swiss Dock在线分子对接工具对关键靶点进行分子对接。结果:黄芪筛选得到20个活性成分,对应作用靶点189个,与慢传输型便秘的共同靶点143个,交集String数据库和Cytoscape 3.7.2拓扑分析度值靠前的靶标为血管内皮生长因子A(VEGFA)、丝氨酸苏氨酸蛋白激酶1(AKT1)、胱天蛋白酶3(CASP3)、白细胞介素-6(IL-6)。GO功能富集分析得到生物过程、细胞组分、分子功能条目分别有1943、77、153个,KEGG功能富集分析得到信号通路163条。分子对接结果显示叶酸、1,7-二羟基-3,9-二甲氧基紫檀素、山柰酚、槲皮素是黄芪发挥治疗作用的主要成分。结论:黄芪中的活性化合物叶酸、山柰酚、槲皮素等能作用于JUN、VEGFA、AKT1、CASP3、IL-6等靶点,通过调控对抗生素反应、对氧化应激的反应、对营养水平的反应、薄膜筏、核受体活性、细胞因子受体结合等信号通路发挥治疗慢传输型便秘的作用。

Objective:To investigate the mechanism of Radix Astragali seu Hedysari in the treatment of slow transit constipation by network pharmacology and molecular docking.Methods:Traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP)was used to screen the active compounds of Radix Astragali seu Hedysari and predict the targets.Cytoscape 3.7.2 was employed to construct the active components-targets network.The keyword“slow transit contipation”was searched for slow transit constipation-related disease targets in OMIM and GeneCards.Then the disease targets were intersected with the targets of Radix Astragali seu Hedysari to obtain the common targets,which were imported into String to construct protein-protein interaction(PPI)network.The PPI network was then imported into Cytoscape 3.7.2 for topological analysis.The Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed by R language to predict the mechanism,and molecular docking of key targets was conducted using SwissDock.Results:There were 20 active components and 189 targets of Radix Astragali seu Hedysari,and 143 common targets.According to String and Cytoscape 3.7.2,the top targets were vascular endothelial growth factor A(VEGFA),serine/threonine protein kinase 1(AKT1),caspase-3(CASP3),and interleukin-6(IL-6).The GO analysis revealed that 1943 biological processes,77 cellular components and 153 molecular functions were obtained,and the KEGG analysis indicated that 163 signaling pathways were involved.From molecular docking,it was found that folic acid,1,7-dihydroxy-3,9-dimethoxy pterocarpene,kaempferol and quercetin were the main components of Radix Astragali seu Hedysari.Conclusion:Folic acid,kaempferol,quercetin and other active compounds in Radix Astragali seu Hedysari could act on the targets of Jun proto-oncogene(JUN),VEGFA,AKT1,CASP3,and IL-6,and treat slow transit constipation mainly by regulating signaling pathways of response to antibiotics,response to oxidative stress,response to nutrient levels,membrane raft,nuclear receptor activity,and cytokine receptor binding.