Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence
Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence
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乌梅丸通过调节 IBD 中的 RAGE 信号通路减轻血管生成和炎症：网络药理学分析和实验证据
DOI：
10.1016/j.phymed.2023.154658
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发表时间：
2023-01-25
期刊：
影响因子：
7.9
通讯作者：
Chen, Yu-gen
中科院分区：
文献类型：
--
作者：
Duan, Zheng-lan;Wang, Yu-ji;Chen, Yu-gen
背景：乌梅丸 (WMW) 几个世纪以来一直被用于治疗消化系统疾病。既往研究已证实其抗结肠炎功效，但其作用机制仍有待进一步阐明。目的：通过网络药理学和实验验证，探讨中药治疗慢性溃疡性结肠炎（UC）的潜在机制。方法：利用中药系统药理学（TCMSP）平台鉴定中药成分和潜在靶点。来自 GEO 数据库的微阵列基因数据 GSE75214 数据集用于定义 UC 相关目标。 Cytoscape3.7.2用于构建蛋白质-蛋白质相互作用（PPI）网络和化合物-疾病靶标网络。通过R软件进行GO富集分析和KEGG通路分析进行功能注释。采用UPLC-TOF-MS/MS方法对WMW的活性成分进行定量分析。为了进行实验验证，使用3个周期的2%葡聚糖硫酸钠（DSS）构建慢性结肠炎模型。通过qPCR、ELISA、western blotting、免疫组化和免疫荧光检测中枢靶点和信号通路。结果：通过网络分析，从WMW中获得104个活性成分，其中47个成分具有UC的潜在靶点。总共确定了 41 个 WMW 潜在目标和 13 个枢纽目标。 KEGG分析显示WMW参与晚期糖基化终末产物-晚期糖基化终末产物受体(AGE-RAGE)信号通路。 WMW 中的紫杉叶素、芸香碱、山奈酚、槲皮素和木犀草素是与 AGE-RAGE 信号通路相关的预测性较高的成分。体内验证，WMW 改善了 DSS 诱导的结肠炎，减少了炎症细胞因子和趋化因子的表达。值得注意的是，它显着降低了与血管生成相关的 Spp1、Serpine1、Mmp2、Mmp9、Ptgs2、Nos2、Kdr 和 Icam1 的 mRNA 表达。此外，我们证实WMW抑制RAGE表达并减少DSS诱导的上皮屏障改变结论：我们的结果初步证明了WMW在实验性慢性结肠炎中的有效成分和强大的抗血管生成活性。本研究证实了 WMW 令人满意的抗结肠炎作用的充分证据，表明其作为治疗 UC 的颇有前景的药物的潜力。
Background: Wumei Wan (WMW) has been used to address digestive disorder for centuries in traditional Chinese medicine. Previous studies have demonstrated its anti-colitis efficacy, but the underlying mechanism of its action remains to be further clarified.Purpose: To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation.Methods: Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform were used to identify the ingredients and potential targets of WMW. The microarray gene data GSE75214 datasets from GEO database was used to define UC-associated targets. Cytoscape3.7.2 was employed to construct the protein-protein interaction (PPI) network and compounds-disease targets network. GO enrichment analysis and KEGG pathway analysis were performed by R software for functional annotation. UPLC-TOF-MS/MS method was used to quantitatively analyze the active ingredients of WMW. For experimental validation, three cycles of 2% dextran sulfate sodium salt (DSS) were used to construct chronic colitis model. The hub targets and signal pathway were detected by qPCR, ELISA, western blotting , immunohistochemical and immunofluorescence.Results: Through network analysis, 104 active ingredients were obtained from WMW, and 47 of these ingredients had potential targets for UC. A total of 41 potential targets of WMW and 13 hub targets were identified. KEGG analysis showed that WMW involved in advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE) signaling pathway. Taxifolin, rutaecarpine, kaempferol, quercetin, and luteolin of WMW were the more highly predictive components related to the AGE-RAGE signaling pathway. In vivo validation, WMW improved DSS-induced colitis, reduced the expression of inflammatory cytokines and chemokines. Notably, it significantly decreased the mRNA expression of Spp1, Serpine1, Mmp2, Mmp9, Ptgs2, Nos2, Kdr and Icam1, which were associated with angiogenesis. In addition, we confirmed WMW inhibited RAGE expression and diminished DSS-induced epithelial barrier alterationsConclusion: Our results initially demonstrated the effective components and the strong anti-angiogenic activity of WMW in experimental chronic colitis. Sufficient evidence of the satisfactory anti-colitis action of WMW was verified in this study, suggesting its potential as a quite prospective agent for the therapy of UC.