基于网络药理学和实验研究探讨胃转安方治疗胃癌前病变的作用机制

Mechanism of Weizhuan′an Prescription in the Treatment of Precancerous Lesions of Gastric Cancer Based on Network Pharmacology and Animal Experiments

目的基于网络药理学、分子对接和动物实验探讨胃转安方治疗胃癌前病变(Precancerous lesions of gastric cancer,PLGC)的作用机制。方法利用TCMSP数据库与OMIM、GeneCards、PharmGKB、DrugBank疾病数据库筛选胃转安方活性成分、作用靶点与PLGC疾病靶点,构建蛋白互作网络图,进行GO和KEGG通路富集分析,对关键靶点和活性成分进行分子对接,建立PLGC大鼠模型,观察胃转安方干预效果,检测胃转安方对关键信号通路的影响。结果胃转安方与PLGC共同靶点130个,共获得2337个GO条目,95条通路KEGG信号通路,其中关键通路为PI3 K信号通路,分子对接结果显示木樨草素、槲皮素、异鼠李素与关键靶点有较强的结合力。动物实验结果显示胃转安方可改善胃黏膜萎缩、肠化及异型增生病变程度。Western Blot结果显示胃转安方各剂量组降低p-PI3 K、p-AKT、p-FoxO4的蛋白表达,升高FoxO4蛋白表达水平,差异有统计学意义(P<0.05),证实胃转安方抑制PI3 K/AKT/FoxO4信号通路发挥治疗作用。结论胃转安方能够通过多成分、多靶点、多通路治疗PLGC,为进一步研究提供思路。

Objective To investigate the mechanism of Weizhuan′an Prescription in the treatment of precancerous lesions of gastric cancer(PLGC)based on network pharmacology,molecular docking,and animal experiments.Method The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Online Mendelian Inheritance in Man(OMIM),GeneCards,PharmGKB,and DrugBank were searched for the active ingredients and targets of Weizhuan′an Prescription and the targets of PLGC.The protein-protein interaction network was built,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were carried out.Molecular docking was performed between the key targets and active ingredients.Furthermore,a rat model of PLGC was established and used to study the therapeutic effect of Weizhuan′an Prescription and the effects of this prescription on the key signaling pathways.Results Weizhuan′an Prescription and PLGC shared 130 common targets,which were annotated into 2337 GO terms and enriched in 95 KEGG pathways.The key pathway was the phosphatidylinositol 3-kinase(PI3 K)signaling pathway.The Results of molecular docking showed that luteolin,quercetin,and isorhamnetin had strong binding affinity with the key targets.The animal experiments showed that Weizhuan′an Prescription alleviated the atrophy of gastric mucous,intestinal metaplasia,and atypical hyperplasia.Western blot showed that Weizhuan′an Prescription down-regulated the protein levels of p-PI3 K,p-AKT and p-FoxO4 and up-regulated the protein level of FoxO4(P<0.05),which confirmed that Weizhuan′an Prescription inhibited PI3 K/AKT/FoxO4 signaling pathway.Conclusion Weizhuan′an Prescription can treat PLGC in a multi-component,multi-target,and multi-pathway manner,which provides an idea for the further research.