基于GEO芯片联合网络药理学探讨胃复春治疗胃低级别上皮内瘤变机制

Exploration on the Mechanism of Weifuchun in the Treatment of Low-grade Gastric Intraepithelial Neoplasia Based on GEO and Network Pharmacology

目的基于胃低级别上皮内瘤变(LGIN)患者GEO芯片及网络药理学,探究胃复春治疗胃LGIN的作用机制。方法从GEO数据库下载LGIN芯片,以logFoldChange=1、adjust P=0.05为标准筛选差异表达基因作为疾病靶点,检索文献收集胃复春入血成分并预测得到药物靶点,疾病靶点与药物靶点交集得到潜在作用靶点,采用蛋白互作网络及构建“入血成分-疾病”筛选核心靶点及化合物。通过ClusterProfiler包对交集靶点进行GO富集分析、KEGG通路富集分析并构建核心通路-靶点关系。核心靶点及核心通路共有靶点整合得到药效靶点,构建药效团模型预测核心化合物对药效靶点作用,采用分子对接进一步验证。结果基于数据集GSE130823/GSE55696筛选得到差异表达基因2871个,文献整理分析得到入血成分75个,对应靶点663个,潜在作用靶点131个,蛋白互作网络分析显示,白细胞介素6、表皮生长因子受体、JUN、细胞色素P4503A4酶、肝细胞核因子4α、肾上腺素受体等为核心靶点,药材-入血成分-靶点网络分析显示,槲皮素、香茶菜素O、线纹香茶菜酸、异橙黄酮、桔皮素、蓝萼甲素、蓝萼乙素为核心化合物。网络药理学分析结果显示,神经活性配体-受体相互作用、化学致癌作用、Rap1信号通路、类固醇激素生物合成、HIF-1、FoxO信号通路等为胃复春治疗慢性胃炎进展性LGIN病变的核心通路,药效团及分子对接显示核心化合物可调节药效靶点表达,发挥抗炎、调节能量代谢及癌症形成、调节黏膜血流量及黏膜损伤修复等作用。结论胃复春通过作用于神经活性受体-配体互作、钙离子、化学致癌、胆碱能、Rap1、药物代谢酶、HIF-1、FoxO等信号通路干预胃LGIN进程。

Objective To explore the mechanism of Weifuchun in the treatment of gastric low grade intraepithelial neopla(LGIN)based on the GEO chips of LGIN patients and network pharmacology.Methods The gastric LGIN chip was downloaded from the GEO database,the differentially expressed genes were screened as disease targets with logFoldChange=1,adjust P=0.05 as the standard,and the literature was retrieved to collect the blood components of Weifuchun and predict the drug targets.Potential targets of interaction between disease targets and drug targets were obtained.Protein interaction network and constructing“blood-influencing components-disease”were used to screen core targets and compounds.GO enrichment analysis and KEGG pathway analysis were performed on the intersection targets by ClusterProfiler package,and the core pathway-target relationship was constructed.The core target and the core pathway shared targets were integrated to obtain the pharmacodynamic target,and a pharmacophore model was constructed to predict the effect of the core compound on the pharmacodynamic target,which was further verified by molecular docking.Results Based on the data set GSE130823/GSE55696,2871 differentially expressed genes were screened,and 75 blood components were collected and analyzed,and 663 corresponding targets and 131 potential targets were found.The protein interaction network analysis showed that IL6,EGFR,JUN,CYP3A4,HNF4A,AR were the core targets.The medicinal material-blood-influencing components-target network analysis showed that quercetin,carawayin O,caraway acid,iso orange flavonoid,orange peretin,blue calyx,calyxine and blue calyxine B were the core compounds.The results of network pharmacology analysis showed that neuroactive ligand-receptor interaction,chemical carcinogenesis,Rap1 signaling pathway,steroid hormone biosynthesis,HIF-1,FoxO signaling pathway,etc.were the core onset pathways.Pharmacophore and molecular docking showed that the core compounds could regulate the expression of pharmacodynamic targets,exert anti-inflammatory,regulate energy metabolism and cancer formation,regulate mucosal blood flow,and repair mucosal damage.Conclusion Weifuchun interferes with the process of gastric LGIN by acting on neuroactive receptor-ligand interaction,calcium ion,chemical carcinogenesis,cholinergic,Rap1,drug metabolism,HIF-1,FoxO and other signaling pathways.