网络药理学和分子对接阐明杜仲在肝缺血再灌注损伤中的潜在作用机制。

Network pharmacology and molecular docking elucidate potential mechanisms of Eucommia ulmoides in hepatic ischemia-reperfusion injury.

机构信息

Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.

Department of Biochemistry and Molecular Biology, Zunyi Medical University, Zunyi, 563000, Guizhou, China.

出版信息

Sci Rep. 2023 Nov 24;13(1):20716. doi: 10.1038/s41598-023-47918-8.

Abstract

Eucommia ulmoides (EU) and its diverse extracts have demonstrated antioxidative, anti-inflammatory, and cytoprotective properties against hepatic ischemia-reperfusion injury (HIRI). However, the primary constituents of EU and their putative mechanisms remain elusive. This study aims to explore the potential mechanisms of EU in the prevention and treatment of HIRI by employing network pharmacology and molecular docking methodologies. The main components and corresponding protein targets of EU were searched in the literature and TCMSP, and the compound target network was constructed by Cytoscape 3.9.1. Liver ischemia-reperfusion injury targets were searched in OMIM and GeneCards databases. The intersection points of compound targets and disease targets were obtained, and the overlapping targets were imported into the STRING database to construct the PPI network. We further analyzed the targets for GO and KEGG enrichment. Finally, molecular docking studies were performed on the core targets and active compounds. The component-target network unveiled a total of 26 efficacious bioactive compounds corresponding to 207 target proteins. Notably, the top-ranking compounds based on degree centrality were quercetin, β-sitosterol, and gallic acid. Within the PPI network, the highest degree centrality encompassed RELA, AKT1, TP53. GO and KEGG enrichment analysis elucidated that EU in HIRI primarily engaged in positive regulation of gene expression, positive transcriptional regulation via RNA polymerase II promoter, negative modulation of apoptotic processes, positive regulation of transcription from DNA templates, and drug responsiveness, among other biological processes. Key pathways included cancer pathways, RAGE signaling pathway, lipid metabolism, atherosclerosis, TNF signaling pathway, PI3K-Akt signaling pathway, and apoptotic pathways. Molecular docking analysis revealed robust affinities between quercetin, β-sitosterol, gallic acid, and RELA, AKT1, TP53, respectively. This study reveals EU exhibits substantial potential in mitigating and treating HIRI through multifaceted targeting and involvement in intricate signaling pathways.

摘要

杜仲及其多种提取物具有抗氧化、抗炎和细胞保护作用,可对抗肝缺血再灌注损伤 (HIRI)。然而,杜仲的主要成分及其潜在机制仍不清楚。本研究旨在通过网络药理学和分子对接方法探讨杜仲预防和治疗 HIRI 的潜在机制。在文献和 TCMSP 中搜索杜仲的主要成分及其相应的蛋白质靶标,并用 Cytoscape 3.9.1 构建化合物靶标网络。在 OMIM 和 GeneCards 数据库中搜索肝缺血再灌注损伤靶标。获得化合物靶标和疾病靶标的交集点,并将重叠靶标导入 STRING 数据库构建 PPI 网络。我们进一步对靶标进行 GO 和 KEGG 富集分析。最后,对核心靶标和活性化合物进行分子对接研究。成分-靶标网络揭示了 26 种有效的生物活性化合物,对应 207 个靶标蛋白。值得注意的是,基于度中心性排名靠前的化合物是槲皮素、β-谷甾醇和没食子酸。在 PPI 网络中,度中心性最高的是 RELA、AKT1、TP53。GO 和 KEGG 富集分析表明,杜仲在 HIRI 中主要参与基因表达的正调控、RNA 聚合酶 II 启动子的正转录调控、凋亡过程的负调节、DNA 模板转录的正调节和药物反应等生物学过程。关键途径包括癌症途径、RAGE 信号通路、脂质代谢、动脉粥样硬化、TNF 信号通路、PI3K-Akt 信号通路和凋亡途径。分子对接分析表明,槲皮素、β-谷甾醇、没食子酸与 RELA、AKT1、TP53 分别具有较强的亲和力。本研究表明,杜仲通过多靶点作用和参与复杂的信号通路,在减轻和治疗 HIRI 方面具有很大的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e3/10673959/b0ffb862f63f/41598_2023_47918_Fig1_HTML.jpg

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