背景:溃疡性结肠炎(UC)是一种常见的炎症性肠病。由于发病机制难以捉摸,仍然缺乏安全有效的治疗策略。FraxiniCortex(FC)已被广泛用作治疗某些疾病的草药。然而,FC治疗UC的药理机制尚不清楚.
方法:引入网络药理学和实验研究相结合的集成平台来破译FC抗UC的机制。活性化合物,治疗目标,通过网络药理学获得了分子作用机制,并通过分子对接验证了化合物与靶蛋白之间的相互作用。采用葡聚糖硫酸钠(DSS)诱导的结肠炎模型评估FC对UC的治疗效果。并验证了网络药理学预测的分子作用机制。
结果:共检索到20种生物活性化合物,并使用在线数据库预测了115个目标。熊果酸,fraxetin,β-谷甾醇,和七叶乙素被确定为FC抗UC的主要活性化合物。PPI网络分析确定了28个主要富集在IL-17信号通路中的FC-UChub基因,TNF信号通路,和癌症的途径。分子对接证实活性化合物对预测的靶蛋白具有高结合亲和力。GEO数据集分析表明,与健康对照相比,这些靶基因在UC临床样本中高表达。实验研究表明,FC可以缓解DSS引起的结肠炎症状,减少炎症细胞因子的释放,并抑制IL1β的表达水平,结肠组织中的COX2、MMP3、IL-17和RORγt。
结论:FC通过使用多组分调节多靶标和多途径表现出抗UC特性。体内结果表明FC减轻了DSS诱导的结肠炎。
BACKGROUND: Ulcerative colitis (UC) is a common type of inflammatory bowel disease. Due to the elusive pathogenesis, safe and effective treatment strategies are still lacking. Fraxini Cortex (FC) has been widely used as a medicinal herb to treat some diseases. However, the pharmacological mechanisms of FC for UC treatment are still unclear.
METHODS: An integrated platform combining network pharmacology and experimental studies was introduced to decipher the mechanism of FC against UC. The active compounds, therapeutic targets, and the molecular mechanism of action were acquired by network pharmacology, and the interaction between the compounds and target proteins were verified by molecular docking. Dextran sulfate sodium (DSS)-induced colitis model was employed to assess the therapeutic effect of FC on UC, and validate the molecular mechanisms of action predicted by network pharmacology.
RESULTS: A total of 20 bioactive compounds were retrieved, and 115 targets were predicted by using the online databases. Ursolic acid, fraxetin, beta-sitosterol, and esculetin were identified as the main active compounds of FC against UC. PPI network analysis identified 28 FC-UC hub genes that were mainly enriched in the IL-17 signaling pathway, the TNF signaling pathway, and pathways in cancer. Molecular docking confirmed that the active compounds had high binding affinities to the predicted target proteins. GEO dataset analysis showed that these target genes were highly expressed in the UC clinical samples compared with that in the healthy controls. Experimental studies showed that FC alleviated DSS-induced colitis symptoms, reduced inflammatory cytokines release, and suppressed the expression levels of IL1β, COX2, MMP3, IL-17 and RORγt in colon tissues.
CONCLUSIONS: FC exhibits anti-UC properties through regulating multi-targets and multi-pathways with multi-components. In vivo results demonstrated that FC alleviated DSS-induced colitis.