基于基因表达综合数据库及网络药理学分析连翘叶治疗非酒精性脂肪肝病的作用机制

Mechanism of Forsythia suspensa leaves in treating non-alcoholic fatty liver disease based on gene expression omnibus database and network pharmacology analysis

中文关键词:  连翘叶  非酒精性脂肪肝病  网络药理学  数据库

英文关键词:Forsythia suspensa leaves  non-alcoholic fatty liver disease  network pharmacology  database

中文摘要:

      目的 基于网络药理学及分子对接技术分析连翘叶活性成分干预非酒精性脂肪肝病(non-alcoholic fatty liver disease, NAFLD)的分子作用机制。方法 从基因表达综合(gene expression omnibus, GEO)数据库选取3个NAFLD数据集(GSE126848、GSE89632、GSE63067), 以“健康人群”为对照组、“NAFLD”为试验组, 利用limma R包筛选差异表达基因(differentially expressed genes, DEGs); 获取连翘叶活性成分并预测靶点, 与DEGs取交集获得潜在靶点; 利用基因本体论(gene ontology, GO)/京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)富集分析细胞功能和信号通路, 构建蛋白互作(protein-protein interaction, PPI)网络筛选核心靶点; 通过AutoDock Vina分子对接, 并在线分析核心靶点与成分的分子互作机制。结果 共获得17种连翘叶主要活性成分、576个DEGs、61个交集靶点; 核心靶点为细胞间黏附分子 1、胰岛素样生长因子1、一氧化氮合酶3、基质金属蛋白酶2等, 涉及糖尿病并发症中的晚期糖基化终产物-其受体(the advanced glycation end products-receptor for advanced glycation end products, AGE-RAGE)信号通路、磷脂酰肌醇3-激酶-蛋白激酶B (phosphatidylinositol 3-kinase-protein kinase B, PI3K-Akt)、视黄醇代谢等信号通路; 分子对接显示关键成分与核心靶点均结合紧密, 其中芦丁与一氧化氮合酶3 (nitric oxide synthase 3, NOS3)的亲和能最低(–10.9 kcal/mol), 涉及氢键、疏水键、π-π堆积及π-阳离子相互作用。结论 连翘叶可能通过多成分、多靶点、多信号通路抑制肝脏脂质蓄积、缓解氧化应激、减轻慢性炎症、改善胰岛素抵抗及延缓肝纤维化等方式达到多维度干预NAFLD病理进程的目的, 芦丁等核心活性成分在治疗NAFLD中发挥着重要作用。

英文摘要:

      Objective To analyze the molecular mechanism of active components from Forsythia suspensa leaves in intervening non-alcoholic fatty liver disease (NAFLD) based on network pharmacology and molecular docking technology. Methods The 3 NAFLD datasets (GSE126848, GSE89632, GSE63067) were selected from the gene expression omnibus (GEO) database. With healthy population as the control group and “NAFLD patients” as the experimental group, the limma R package was used to screen differentially expressed genes (DEGs). The active components of Forsythia suspensa leaves were obtained and their targets were predicted. The intersection with DEGs was taken to obtain potential targets. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed to explore cell functions and signaling pathways. A protein-protein interaction (PPI) network was constructed to screen core targets. Molecular docking was conducted via AutoDock Vina, and the molecular interaction mechanism between core targets and components was analyzed online. Results A total of 17 kinds of main active components of Forsythia suspensa leaves, 576 DEGs and 61 intersecting targets were obtained. The core targets included intercellular adhesion molecule 1, insulin-like growth factor 1 , nitric oxide synthase 3, matrix metalloproteinase 2, etc. The involved signaling pathways included the advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, retinol metabolism, etc. Molecular docking results showed that key components bound tightly to core targets. Among them, rutin had the lowest binding affinity with nitric oxide synthase 3 (NOS3) (–10.9 kcal/mol), involving hydrogen bonds, hydrophobic bonds, π-π stacking and π-cation interactions. Conclusion Forsythia suspensa leaves may interfere with the pathological process of NAFLD in multiple dimensions by inhibiting hepatic lipid accumulation, alleviating oxidative stress, reducing chronic inflammation, improving insulin resistance and delaying hepatic fibrosis through a multi-component, multi-target and multi-signaling pathway mode. Core active components such as rutin play an important role in the treatment of NAFLD.