基于网络药理学探讨乌贝散异病同治反流性食管炎和胃溃疡作用机制

Mechanism of Action of Wubei Powder in Treating Reflux Esophagitis and GastricUlcer with Different Diseases ,Same Treatment Based on Network Pharmacology

目的:探讨乌贝散异病同治反流性食管炎(RE)与胃溃疡(GU)的分子机制。方法:运用中药系统药理数据库和分析平台(TCMSP)、HERB数据库、SymMap数据库、BATMAN-TCM数据库筛选乌贝散的主要活性成分及靶点;利用GeneCards、OMIM数据库获取2种疾病相关靶点,取交集获取药物与疾病的共有靶点;将交集靶点导入STRING数据库构建蛋白互作网络,利用Cytoscape 3.10.1软件进行可视化处理并获取关键靶点。利用DAVID数据库对共有靶点进行基因本体论(GO)功能分析和京都基因与基因组百科全书(KEGG)通路富集分析,并构建有效成分-交集靶点-通路网络图,并对关键靶点及主要活性成分进行分子对接验证。结果:共获得乌贝散治疗RE与GU的活性成分20个,其中主要活性成分为槲皮素、天竺葵素与β-谷甾醇等;RE与GU交集疾病靶点730个,乌贝散与疾病的交集靶点共92个。乌贝散治疗RE与GU的关键靶点有S非受体酪氨酸激酶(SRC)、表皮生长因子受体(EGFR)、AKT丝氨酸/苏氨酸激酶(AKT1)等。富集分析提示,乌贝散能够通过MAP激酶活性的正调控、细胞增殖的正调控、细胞凋亡过程的负调控、对外源性刺激的反应等生物过程,对癌症途径、EGFR酪氨酸激酶抑制剂耐药性通路、磷脂酰肌醇-3激酶/蛋白激酶B (PI3K-AKT)信号通路、丝裂原活化蛋白激酶(MAPK)信号通路等进行调控。分子对接显示,关键靶点(SRC、EGFR、AKT1)与主要活性成分(槲皮素、天竺葵素与β-谷甾醇)之间能自由结合,且β-谷甾醇与SRC结合活性最强。结论:乌贝散中槲皮素、天竺葵素与β-谷甾醇等成分能够作用于SRC、EGFR、AKT1等靶点,调控癌症途径、EGFR酪氨酸激酶抑制剂耐药性通路等发挥异病同治RE与GU的作用。

Objective:To discuss the molecular mechanism of Wubei Powder in treating reflux esophagitis(RE)and gastric ulcer(GU)with different diseases,same treatment.Methods:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),HERB database,SymMap database,and BATMAN-TCM database were used to screen the main active ingredients and targets of Wubei Powder;GeneCards and OMIM database were used to obtain two disease-related targets and take the intersection to obtain common targets between the medicine and diseases;the target intersections were imported into the STRING database to construct a protein interaction network, andCytoscape software was used for visualization processing and obtaining key targets. Gene Ontology (GO)functional analysis on common targets was performed with the DAVID database,and pathway enrichmentanalysis on common targets was performed with the Kyoto Encyclopedia of Genes and Genomes (KEGG);adiagram of effective ingredients, target intersection, and pathways was constructed;molecular dockingverification was performed on key targets and main active ingredients. Results: A total of 20 activeingredients were obtained from Wubei Powder for the treatment of RE and GU, among which the mainactive ingredients were quercetin, geranium extract, and β -sitosterol;there were 730 intersectiondisease targets between RE and GU,and 92 intersection targets between Wubei Powder and the diseases.The key targets of Wubei Powder in the treatment of RE and GU included S non-receptor tyrosine kinase(SRC), epidermal growth factor receptor (EGFR), AKT serine/threonine kinase (AKT1), etc. Enrichmentanalysis suggested that Wubei Powder can regulate the cancer pathways, EGFR tyrosine kinase inhibitorresistance pathway, phosphatidylinositol-3 kinase/protein kinase B (PI3K-AKT) signaling pathway, andmitogen-activated protein kinase (MAPK) signaling pathway through biological processes such as positiveregulation of MAP kinase activity, positive regulation of cell proliferation, negative regulation of cellapoptosis process, and response to exogenous stimuli. In molecular docking display, key targets (SRCEGFR, and AKT1) could freely bind with the main active ingredients (quercetin, geranium, and β-sitosterol),and β-sitosterol had the strongest binding activity with SRC. Conclusion:The components ofquercetin,geranium extract,and β-sitosterol in Wubei Powder can act on SRC EGFR,AKT1,and othertargets,and regulate cancer pathways and the resistance pathway of EGFR tyrosine kinase inhibitors,thusplaying a role in the treatment of RE and GU with different diseases,same treatment.