Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.
Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.
复制标题
DOI：
10.1042/bsr20230539
复制
发表时间：
2023-08-31
影响因子：
4
通讯作者：
Leng, Yu-fang
中科院分区：
文献类型：
--
作者：
Chen, Feng;Chai, Yi-hong;Zhang, Fa;Liu, Yong-qiang;Zhang, Yan;Shi, Ya-jing;Zhang, Jian-ming;Leng, Yu-fang
民族药理学相关性：红景天苷（Salidroside， SAL）是存在于红景天中的一种酚类天然产物，常用于治疗各种缺血-缺氧疾病，包括肠缺血-再灌注（IR）损伤。然而，它们在治疗肠道IR损伤中的疗效和潜在机制尚未得到研究。目的：采用网络药理学方法结合实验验证，探讨SAL对肠道IR损伤的药理作用机制。方法：本研究利用中药系统药理学（TCMSP）数据库及分析平台和比较毒物基因组学数据库（CTD）预测SAL可能的靶基因，并从GeneCards和DisGenet网站收集肠道IR损伤相关靶基因，收集汇总数据筛选常见靶基因。然后，利用STRING数据库和Cytoscape 3.8.2构建蛋白-蛋白相互作用（PPI）靶点网络，并对上述交叉基因进行分析。然后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析，构建组分-靶点-通路网络，利用分子对接和分子动力学模拟验证SAL与候选靶点之间可能的结合构象，进一步探索SAL治疗肠道IR损伤的潜在靶点。最后，建立小鼠肠系膜上动脉结扎的体内模型，通过HE染色评估小鼠小肠组织病理学变化，ELISA试剂盒检测炎症因子表达，Western blotting检测关键蛋白靶点表达，评估SAL抗肠道IR损伤作用。结果：共检索到166个SAL靶基因和1740个疾病相关靶点，获得88个重叠蛋白作为潜在的治疗靶点。通路富集分析显示，SAL对肠道IR损伤的药理作用与抗缺氧、抗炎和代谢通路有关，分子对接和分子动力学模拟结果显示，其核心生物活性成分对TXNIP和AMPK具有良好的结合亲和力。免疫印迹结果显示，与模型组相比，药物治疗组小鼠小肠组织中TXNIP和AMPK的表达水平发生了显著变化。结论：SAL可能靶向AMPK和TXNIP结构域作为肠道IR的治疗药物。这些发现全面揭示了SAL治疗肠道IR的潜在靶点，为SAL治疗肠道IR的临床应用提供了理论依据。
Ethnopharmacological relevance: Salidroside (SAL), a phenolic natural product present in Rhodiola rosea, are commonly used in the treatment of various ischemic-hypoxic diseases, including intestinal ischemia–reperfusion (IR) injury. However, their efficacy and potential mechanisms in the treatment of intestinal IR injury have not been investigated. Objective: The objective of the present study is to investigate the pharmacological mechanism of action of SAL on intestinal IR injury using a network pharmacology approach combined with experimental validation. Methods: In the present study, we used the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and analysis platform and Comparative Toxicogenomics Database (CTD) to predict possible target genes of SAL, collected relevant target genes of intestinal IR injury from GeneCards and DisGenet websites, and collected summary data to screen common target genes. Then, the protein–protein interaction (PPI) target network was constructed and analyzed by STRING database and Cytoscape 3.8.2 with the above intersecting genes. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed and the component-target-pathway network was constructed, followed by the use of molecular docking and molecular dynamic simulation to verify the possible binding conformation between SAL and candidate targets to further explore the potential targets of SAL in the treatment of intestinal IR injury. Finally, an in vivo model of mouse superior mesenteric artery ligation was established to assess the anti-intestinal IR injury effect of SAL by assessing histopathological changes in mouse small intestine by HE staining, detecting inflammatory factor expression by ELISA kit, and detecting the expression of key protein targets by Western blotting. Results: A total of 166 SAL target genes and 1740 disease-related targets were retrieved, and 88 overlapping proteins were obtained as potential therapeutic targets. The pathway enrichment analysis revealed that the pharmacological effects of SAL on intestinal IR injury were anti-hypoxic, anti-inflammatory and metabolic pathway related, and the molecular docking and molecular dynamic simulation results showed that the core bioactive components had good binding affinity for TXNIP and AMPK, and the immunoblotting results indicated that the expression levels of TXNIP and AMPK in the small intestinal tissues of mice in the drug-treated group compared with the model group were significantly changed. Conclusion: SAL may target AMPK and TXNIP domains to act as a therapeutic agent for intestinal IR. These findings comprehensively reveal the potential therapeutic targets for SAL against intestinal IR and provide theoretical basis for the clinical application of SAL in the treatment of intestinal IR.
DOI：
10.4049/jimmunol.1303124
发表时间：
2015-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Pope MR;Fleming SD
通讯作者：
Fleming SD