基于网络药理学探讨枳术丸治疗功能性便秘的作用机制

Exploration of the mechanism of Zhizhu Wan in treating functional constipation based on network pharmacology

目的:基于网络药理学方法探讨枳术丸治疗功能性便秘(Functional Constipation,FC)的潜在分子作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)数据库检索枳实、白术的主要化学成分及其靶点,并根据药物代谢动力学参数筛选枳实、白术的活性组分;通过GeneCards数据库获取FC主要靶点,采用Cytoscape 3.7.2软件构建枳术丸活性成分-疾病共同作用靶点的可视化网络;基于STRING数据库,构建枳术丸治疗FC的共同作用靶点的蛋白质-蛋白质相互作用网络,根据拓扑学参数分析筛选出核心靶点;对共同作用靶点进行基因本体论(GO)功能富集分析和京都基因与基因组百科全书(KEGG)信号通路富集分析。结果:筛选出枳术丸主要的活性成分共28个,获得枳术丸与FC的共同作用靶点98个,核心靶点有丝氨酸/苏氨酸蛋白激酶1(Akt Serine/Threonine Kinase 1,AKT1)、血管内皮生长因子A(Vascular Endothelial Growth Factor A,VEGFA)、细胞肿瘤蛋白p53(Tumor Protein p53,TP53)、半胱氨酸蛋白酶3(Caspase 3,CASP3)、Jun原癌基因(Jun Proto-Oncogee,JUN)等。GO富集分析得到生物学过程相关条目1965条、分子功能相关条目137条及细胞组分相关条目98条(P<0.05);KEGG通路富集分析得到160条信号通路(P<0.05),枳术丸治疗FC的靶点基因主要富集在PI3K-Akt信号通路、脂质与动脉粥样硬化、化学致癌-受体激活等相关通路上。结论:枳术丸治疗FC具有多成分、多靶点、多通路的特点,其作用机制可能主要与磷脂酰肌醇3激酶(Phosphatidylinositol 3-kinase,PI3K)-蛋白激酶B(Akt)信号通路相关。

Objective:To explore the potential molecular mechanism of Zhizhu Wan(枳术丸)in the treatment of functional constipation based on network pharmacology.Methods:The main chemical constituents and targets of Zhishi(Citrus aurantium)and Baizhu(White atractylodes rhizome)were retrieved by TCMSP database,and the active components were screened by ADME.The main targets of functional constipation were obtained from GeneCards database,and Cytoscape 3.7.2 software was used to construct the visual network of the active ingredient of Zhizhu Wan and disease targets.Based on the STRING database,the protein-protein interaction network of the common target of Zhizhu Wan in the treatment of functional constipation was constructed,and the core target was screened out according to the analysis of topological parameters.GO functional enrichment analysis and KEGG signaling pathway enrichment analysis were performed for the co-acting targets.Results:A total of 28 main active ingredients of Zhizhu Wan were screened out,and 98 related targets of them which could act on functional constipation were obtained.The core targets were AKT1,VEGFA,TP53,CASP3,JUN,etc.By GO enrichment analysis,there were 1965 biological process related items,137 molecular function related items and 98 cell component related items(P<0.05).KEGG pathway enrichment analysis showed 160 signaling pathways(P<0.05).The target genes of Zhizhu Wan for functional constipation were mainly concentrated in PI3K-Akt signaling pathway,lipid and atherosclerosis,and chemical carcinogenic-receptor activation pathways.Conclusion:Zhizhu Wan has the characteristics of multiple components,multiple targets and multiple pathways in the treatment of functional constipation,and its mechanism of action may be mainly related to PI3K-Akt signaling pathway.