基于网络药理学分析附子理中汤治疗晚期胃癌的作用机制

Mechanism of Fuzi Lizhong Decoction in Treating Advanced Gastric Cancer Based on Network Pharmacology

[目的]基于网络药理学方法,对附子理中汤治疗晚期胃癌的靶点及作用机制进行分析。[方法]通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)、人类孟德尔遗传在线(Online Mendelian Inheritance in Man,OMIM)数据库、遗传关联数据库(Genetic Association Database,GAD)、人类基因综合数据库(Human Gene Comprehensive Database,GeneCards)等数据库获取晚期胃癌的相关靶点,以及附子理中汤治疗晚期胃癌活性成分的潜在靶点,而后基于韦恩图获取胃癌靶点与活性成分靶点的交集,利用Cytoscape 3.5.1软件构建潜在靶点间的蛋白互作(protein-protein interaction,PPI)网络,并通过KOBAS 3.0软件及DAVID在线分析网站(https://david.ncifcrf.gov/summary.jsp)对搜集的靶点蛋白进行基因本体(gene ontology,GO)富集分析和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路与基因功能富集分析。最后,基于蛋白质数据库(Protein Data Bank,PDB)与SystemsDock网站数据库(SystemsDock Web Site Database,SWSD)进行受体与配体的分子对接,并分析对接分数,以此来探究附子理中汤治疗晚期胃癌的有效性。[结果]从附子理中汤筛选出132个活性成分及306个防治晚期胃癌的潜在靶点。GO富集分析共获取980个GO条目,其中生物过程(biological process,BP)862个,细胞组分(cellular component,CC)29个,分子功能(molecular function,MF)89个。KEGG通路富集分析筛选出65条附子理中汤治疗晚期胃癌的潜在信号通路。分子对接实验显示肿瘤相关蛋白53(tumor protein p53,p53)、巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF)、信号传导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)具有最高的对接分数,且具有较好的结合性,能与胃癌受体蛋白稳定结合并发挥积极作用。[结论]附子理中汤治疗晚期胃癌具有多组分、多靶点、多途径的调控特点,p53、MIF、STAT3是附子理中汤作用的关键节点,本研究为更深入探索晚期胃癌的防治提供了新的方向与思路。

[Objective]Based on the method of network pharmacology,the target and mechanism of Fuzi Lizhong Decoction in the treatment of advanced gastric cancer were analyzed.[Methods]Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Online Mendelian Inheritance in Man(OMIM),Genetic Association Database(GAD)and Human Gene Comprehensive Database(GeneCards)were used to obtain the related targets of advanced gastric cancer and the potential targets of Fuzi Lizhong Decoction in treating advanced gastric cancer.Then,the intersection of gastric cancer targets and active ingredient targets was obtained based on Wayne map,and the protein-protein interaction(PPI)network between potential targets was constructed by using Cytoscape 3.5.1 software,and the KOBAS 3.0 software and DAVID online analysis website(https://david.ncifcrf.gov/summary.jsp)were used to perform gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis.Finally,based on Protein Data Bank(PDB)and systems dock website database,molecular docking of receptors and ligands was carried out,and docking scores were analyzed to explore the effectiveness of Fuzi Lizhong Decoction in the treatment of advanced gastric cancer.[Results]One hundred and thirty-two active ingredients and 306 potential targets for the prevention and treatment of advanced gastric cancer were screened out from Fuzi Lizhong Decoction.GO enrichment analysis obtained a total of 980 GO items,including 862 biological processes,29 cell ular components,and 89 molecular functions.KEGG pathway enrichment analysis screened out 65 potential signal pathways of Fuzi Lizhong Decoction for the treatment of advanced gastric cancer.Molecular docking experiments showed that tumor protein p53(p53),macrophage migration inhibitory factor(MIF),signal transducer and activator of transcription 3(STAT3)had the highest docking score,and had good binding,could stably bind to gastric cancer receptor protein and played an active role.[Conclusion]Fuzi Lizhong Decoction in the treatment of advanced gastric cancer has the characteristics of multi-component,multi-target,and multi-way regulation.p53,MIF and STAT3 are the key nodes of Fuzi Lizhong Decoction.This study provides a new way to explore the prevention and treatment of advanced gastric cancer.