基于网络药理-分子对接探析小茴香挥发油治疗术后肠梗阻机制

Mechanism Study of Foeniculi Fructus Volatile Oil Against Postoperative Ileus Based on Network Pharmacology and Molecular Docking

关键词:  小茴香挥发油  术后肠梗阻  GC-MS  网络药理  分子对接

Key words:  Foeniculi Fructus volatile oil  postoperative ileus  GC-MS  network pharmacology  molecular docking

摘要:

目的 基于网络药理及分子对接等数据挖掘手段探析小茴香挥发油改善手术后肠梗阻(postoperative ileus,POI)的分子机制。方法 提取小茴香挥发油并采用GC-MS分析化学成分,筛选活性化合物,通过STITCH、Swiss、TCMSP等数据库获得活性化合物缓解POI的潜在治疗靶点;构建靶点相互作用网络图,并通过拓扑分析获得关键靶点;利用DAVID数据库对关键靶点进行GO和KEGG富集分析;HPA数据库分析关键靶点在消化道的表达;分子对接分析关键靶蛋白和活性成分的结合。结果 GC-MS鉴定发现小茴香挥发油中共23个化合物,其中5个首次在小茴香挥发油中发现,筛选出潜在活性化合物10个,通过挖掘并分析活性成分治疗POI的关键靶点10个(HMOX1、KDR、PTPRC、RELA等),对靶点的富集分析发现,小茴香挥发油中的活性成分主要通过HMOX1、RELA、JAK2等关键靶点调节PI3K-Akt、HIF-1、NF-κB等多条信号通路,影响NO生物合成正调节、经死亡结构域受体介导的外源性凋亡信号通路的负调控等生物过程。大部分的关键靶点在消化道腺细胞有丰富分布,部分关键靶点在消化道淋巴细胞和外周神经/神经节也有分布。分子对接确证活性化合物均可嵌入关键靶蛋白的活性口袋。结论 小茴香挥发油中以anethole和terragon为主的多个活性成分,通过分布在消化道的HMOX1和RELA等多个靶点,调节以PI3K/Akt信号通路为核心的多个信号通路,影响消化道腺体及因子分泌,调节肠神经及炎症反应,缓解POI。本研究为小茴香挥发油缓解POI的深入研究提供依据。

Abstract:

OBJECTIVE To investigate the molecular mechanism of the Foeniculi Fructus volatile oil in improving postoperative ileus(POI) based on network pharmacology, molecular docking and other data mining means. METHODS The volatile oil of Foeniculi Fructus was extracted and analyzed by GC-MS. Then the active compounds were screened. The potential effective targets of active compounds against POI were obtained by searching and analyzing the data from STITCH, Swiss, TCMSP and other databases. Protein-protein interaction network of potential effective targets was established and hub targets were acquired by topology analysis. GO and KEGG enrichment analyses were carried out through DAVID database. The expression of the hub targets in gastrointestinal tract were analyzed through HPA database. Molecular docking was used to analyze the binding between hub proteins and active compounds. RESULTS GC-MS results showed that 23 compounds were found in Foeniculi Fructus volatile oil. Among them, 5 compounds were first found in Foeniculi Fructus volatile oil. Then 10 hub targets(e.g., HMOX1, KDR, PTPRC, RELA) were obtained by screening. GO and KEGG analysis of the hub targets found that the active components in Foeniculi Fructus volatile oil mainly regulate PI3K-Akt, HIF-1 and NF-κB and other signaling pathways through hub targets (e.g., HMOX1, RELA, JAK2), then affecting biological processes(positive regulation of NO biosynthesis, negative regulation of exogenous apoptosis signal pathway mediated by death domain receptor, and so on). Most of the hub targets were abundantly distributed in gastrointestinal gland cells, and some of the hub targets were also distributed in gastrointestinal lymphocytes and peripheral nerves/ganglia. Molecular docking found that the active compounds could be embedded into the active pocket of the hub targets. CONCLUSION Foeniculi Fructus volatile oil is composed of several active components mainly anethole and terragon. They regulate multi-signaling pathways with PI3K/Akt signaling pathway as the core through HMOX1, RELA and other hub targets. Then the secretion of digestive tract glands and factors, intestinal nerve and inflammatory response are affected, which ultimately achieving improvement of POI. This study provides the basis for an in-depth study on the improvement of POI by Foeniculi Fructus volatile oil.