加减半夏泻心汤治疗幽门螺杆菌相关性胃炎的作用机制

Mechanism of Modified Banxia Xiexin Decoction in the Treatment of Helicobacter Pylori Related Gastritis

目的:运用网络药理学方法研究加减半夏泻心汤治疗幽门螺杆菌相关性胃炎的作用机制。方法:运用中药系统药理学数据库和分析平台(traditional Chinese medicine systems pharmacology,TCMSP)获取加减半夏泻心汤化合物及靶标,以口服生物利用度(oral bioavailability,OB)≥30%和类药性(drug likeness,DL)≥0.18及半衰期(half-life,HL)≥4 h为阈值进行化合物筛选,将靶标输入Uniprot获取靶标对应的基因Symbol;从人类基因数据库(Gene Card:The Human Gene Database)获取幽门螺杆菌相关性胃炎疾病基因,并筛选出与加减半夏泻心汤靶标基因的交集基因;运用Cytoscape 3.7.2软件绘制"疾病-中药-化合物-交集靶标(基因)"网络图、STRING构建蛋白互作网络、利用分子对接技术对关键靶点和化合物的相互作用进行验证。Profiler数据分析平台进行基因本体(gene ontology,GO)富集以及京都基因和基因组百科全书(kyoto encyclopaedia of gene and genomes,KEGG)通路富集分析。结果:通过设置OB和DL及HL值筛选得到加减半夏泻心汤化合物239种,涉及加减半夏泻心汤治疗幽门螺杆菌相关性胃炎作用预测靶点有189个。网络拓扑分析结果表明,Cytoscape 3.7.2拓扑分析得到肿瘤坏死因子(tumor necrosis factor,TNF)、JUN、丝裂原活化蛋白激酶1(mitogen activated protein kinases 1,MAPK1)、MAPK14等22个关键靶点,槲皮素、β-谷甾醇、汉黄芩素、豆甾醇、黄芩素、芦荟大黄素等10个核心成分。生物信息学富集分析结果表明,共获取482个GO条目,101条KEGG通路,主要涉及调节P53信号通路、T细胞受体信号通路等。分子对接结果表明,槲皮素、β-谷甾醇、汉黄芩素、豆甾醇、黄芩素、芦荟大黄素等成分与TNF、JUN、MAPK1、MAPK14等靶点均有较强亲和能力,结果提示加减半夏泻心汤可能通过抑制细胞增殖,调控细胞周期,诱导细胞凋亡及抗炎作用起到治疗幽门螺杆菌相关性胃炎作用。结论:半夏泻心汤治疗幽门螺杆菌相关性胃炎具有多成分、多靶点、多通路的作用机制。

Objective:To study the mechanism of modified Banxia Xiexin Decoction in the treatment of Helicobacter pylori related gastritis by using the method of network pharmacology.Methods:The traditional Chinese medicine systems pharmacology(TCMSP)was used to obtain the compounds and targets of modified Banxia Xiexin Decoction.The compounds were screened with oral bioavailability(OB)≥30%,drug likeness(DL)≥0.18 and half-life(HL)≥4 as thresholds,and the target was input into UniProt to obtain the gene symbol corresponding to the target.The gene of helicobacter pylori related gastritis was obtained from the human gene database(Gene Card:The Human Gene Database),and the intersection gene with the target gene of modified Banxia Xiexin Decoction was screened;Cytoscape 3.7.2 the software was used to draw the network diagram of"disease traditional-Chinese medicine-compound-intersection target(gene)",construct protein interaction(PPI)network with string,and molecular docking technology was used to verify the interaction between key targets and compounds.G:Profiler Data analysis platform was used for gene ontology(GO)enrichment and kyoto encyclopaedia of gene and genomes(KEGG)pathway was used for enrichment analysis.Results:By setting OB,DL and HL values,239 compounds of modified Banxia Xiexin Decoction were screened,involving 189 prediction targets of modified Banxia Xiexin Decoction in the treatment of Helicobacter pylori related gastritis.The results of network topology analysis show that Cytoscape 37.2 topological analysis revealed 22 key targets including tumor necrosis factor(TNF),JUN,mitogen activated protein kinases(MAPK1),MAPK14,quercetinβ-Sitosterol,wogonin,stigmasterol,baicalein,aloe emodin and other 10 core components.Bioinformatics enrichment analysis showed that 482 GO entries and 101 KEGG pathways were obtained,mainly involving the regulation of p53 signaling pathway and T cell receptor signaling pathway.Molecular docking results showed that quercetinβ-Sitosterol,wogonin,stigmasterol,baicalein,aloe emodin and other components have strong affinity with TNF,UN,APK1,APK14 and other targets.The results suggest that modified Banxia Xiexin Decoction may play a role in the treatment of Helicobacter pylori related gastritis by inhibiting cell proliferation,regulating cell cycle,inducing apoptosis and anti-inflammatory effect.Conclusion:Banxia Xiexin Decoction has a multi-component,multi-target and multi-channel mechanism in the treatment of Helicobacter pylori related gastritis.