运用网络药理学方法探究乌梅丸治疗胰腺肿瘤的作用机制。

BACKGROUND: Wumei Pill (WMP), a famous herbal formula, has been widely used to treat digestive system diseases in clinical practice in China for centuries. We have found a correlation between the indications of WMP and the typical symptoms of pancreatic neoplasms. However, the pharmacological mechanisms of WMP still remain unknown. METHODS: In the present work, we used a network pharmacological method to predict its underlying complex mechanism of treating pancreatic neoplasms. Firstly, we obtained relative compounds of WMP based on TCMSP database, TCM database@Taiwan and TCMID database and collected potential targets of these compounds by target fishing. Then we built the pancreatic neoplasms target database by CTD, TTD, PharmGKB. Based on the matching results between WMP potential targets and pancreatic neoplasms targets, we built a PPI network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, DAVID bioinformatics resources were utilized for the enrichment analysis on GO_BP and KEGG. RESULTS: A total of 80 active ingredients and 77 targets of WMP were picked out. The results of DAVID enrichment analysis indicated that 58 cellular biological processes (FDR < 0.01) and 17 pathways (FDR < 0.01) of WMP mostly participated in the complex treating effects associated with proliferation, apoptosis, inflammatory response and angiogenesis. Moreover, 17 hub nodes of WMP (PTGS2, BCL2, TP53, IL6, MAPK1, EGFR, EGF, CASP3, JUN, MAPK8, MMP9, VEGFA, TNF, MYC, AKT1, FOS and TGFB1) were recognized as potential targets of treatments, implying the underlying mechanisms of WMP acting on pancreatic neoplasms. CONCLUSION: WMP could alleviate the symptoms of pancreatic neoplasms through the molecular mechanisms predicted by network pharmacology. This study proposes a strategy to elucidate the mechanisms of Traditional Chinese Medicine (TCM) at the level of network pharmacology.

背景：乌梅丸（WMP）是一种著名的草药方剂，在中国临床实践中已被广泛用于治疗消化系统疾病数百年。我们发现 WMP 的适应症与胰腺肿瘤的典型症状之间存在相关性。然而，WMP 的药理机制仍不清楚。

方法：在本工作中，我们使用网络药理学方法预测其治疗胰腺肿瘤的潜在复杂机制。首先，我们基于 TCMSP 数据库、TCM 数据库@台湾和 TCMID 数据库获得 WMP 的相关化合物，并通过靶标捕捞收集这些化合物的潜在靶标。然后，我们通过 CTD、TTD、PharmGKB 构建胰腺肿瘤靶标数据库。基于 WMP 潜在靶标与胰腺肿瘤靶标之间的匹配结果，我们构建了一个 PPI 网络，以分析这些靶标之间的相互作用，并通过拓扑筛选出枢纽靶标。此外，我们还利用 DAVID 生物信息学资源对 GO_BP 和 KEGG 进行富集分析。

结果：共筛选出 WMP 的 80 种活性成分和 77 个靶标。DAVID 富集分析结果表明，WMP 主要参与与增殖、凋亡、炎症反应和血管生成相关的复杂治疗作用的 58 个细胞生物学过程（FDR<0.01）和 17 条途径（FDR<0.01）。此外，WMP 的 17 个枢纽节点（PTGS2、BCL2、TP53、IL6、MAPK1、EGFR、EGF、CASP3、JUN、MAPK8、MMP9、VEGFA、TNF、MYC、AKT1、FOS 和 TGFB1）被认为是治疗的潜在靶标，提示 WMP 作用于胰腺肿瘤的潜在机制。

结论：WMP 可以通过网络药理学预测的分子机制缓解胰腺肿瘤的症状。本研究提出了一种在网络药理学水平上阐明中药（TCM）机制的策略。