【摘要】 目的：基于网络药理学和分子对接技术分析山楂叶治疗2型糖尿病(type 2 diabetes mellitus, T2DM)的作用机制。方法：从中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)、BATMAN、HERB、SymMap、TCM-ID等数据库筛选山楂叶中的化学成分，构建山楂叶化学成分库并导入SwissADME数据库筛选山楂叶的活性成分，从Swiss Target Prediction数据库检索相关文献并获取山楂叶的潜在靶点。利用DrugBank、TTD、GeneCards、CTD、OMIM数据库检索T2DM相关靶点，绘制韦恩图得到两者的交集靶点。借助STRING数据库和Cytoscape 3.9.1软件构建蛋白质相互作用网络，进行拓扑分析从而筛选关键靶点和核心成分，并采用AutoDock 4.2.6软件进行分子对接验证。在DAVID 6.8数据库中进行基因本体(gene ontology, GO)功能富集分析和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)通路富集分析，并筛选关键通路。利用BioGPS和The Human Protein Atlas数据库分析关键组织及高表达基因在不同细胞的分布情况。结果：山楂叶活性成分92个及潜在靶点622个，山楂叶与T2DM的交集靶点306个，进一步筛选得到16个关键靶点，包括ALB、GAPDH、IL-6、SRC、TNF、AKT1、EGFR、VEGFA、MAPK3、ESR1、STAT3、PTGS2、mTOR、HSP90AA1、NR3C1、PPARA。山楂叶核心成分28个，包括α-亚麻酸、柚皮素、桑黄素等。KEGG富集分析筛选得到170条通路，其中血糖调节相关通路包括AGE-RAGE信号通路在糖尿病并发症中的作用、PI3K-Akt信号通路、血管内皮生长因子信号通路、胰岛素抵抗、胰岛素信号通路等。分子对接结果显示，14个关键靶点与27个核心成分均具有良好的亲和力和结合活性。交集基因在甲状腺、肝脏、心脏和肺中的数量最多，主要分布在甲状腺腺细胞、肝细胞、肺泡细胞、平滑肌细胞等。结论：山楂叶治疗T2DM具有多成分、多靶点、多通路、多组织的特点，其可能通过柚皮素、桑黄素、木犀草素等多种活性成分作用于IL-6、AKT1、VEGFA、STAT3等关键靶点，调节AGE-RAGE信号通路、胰岛素抵抗等多条通路。更多还原

【Abstract】 Objective: To analyze the action mechanism of hawthorn leaves in the treatment of type 2 diabetes mellitus(T2DM) based on network pharmacology and molecular docking technology.Methods: The active ingredients of hawthorn leaves were screened through traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP),BATMAN,HERB,SymMap, TCM-ID database, literature retrieval and SwissADME database, and the potential targets of hawthorn leaves were obtained by Swiss Target Prediction database.DrugBank, TTD,GeneCards, CTD,OMIM database were used to search for T2DM-related targets, and the intersection targets were obtained by drawing Wayne diagram.With the help of STRING database and Cytoscape3.9.1 software, protein interaction network was constructed for topological analysis to screen key targets and core components, and molecular docking verification was performed by AutoDock 4.2.6 software.Gene ontology(GO) function enrichment and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed in DAVID6.8 database, and key pathways were screened.BioGPS and The Human Protein Atlas database were used to analyze the distribution of key tissues and high expression genes in different cells.Results: There were 92 active ingredients and 622 potential targets in hawthorn leaves, and 306 intersection targets between hawthorn leaves and T2DM.A total of 16 key targets were obtained through further screening, including ALB,GAPDH,IL-6,SRC,TNF,AKT1,EGFR,VEGFA,MAPK3,ESR1,STAT3,PTGS2,mTOR,HSP90AA1,NR3C1,and PPARA.There were 28 core ingredients in hawthorn leaves, including alpha linolenic acid, naringenin, and formononetin.A total of 170 pathways were screened by KEGG enrichment analysis, among which blood glucose regulation related pathways included the role of AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, vascular endothelial growth factor signaling pathway, insulin resistance, insulin signaling pathway, etc.Molecular docking results showed that the key targets and core ingredients had good affinity and binding activity.The number of intersection genes was the largest in thyroid, liver, heart and lung, mainly distributed in thyroid gland cells, hepatocytes, alveolar cells, smooth muscle cells, etc.Conclusion: Hawthorn leaves have the characteristics of multi-ingredients, multi-targets, multi-pathways, and multi-tissues in the treatment of T2DM.They may act on IL-6,AKT1,VEGFA,STAT3 and other key targets through naringenin, formononetin, luteolin and other active ingredients to regulate AGE-RAGE signaling pathway, insulin resistance and other pathways to treat T2DM.更多还原