State Key Laboratory of Analytacal Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
School of Chemistry and Life Sciences, Jinling College, Nanjing University, Nanjing, China.
Front Immunol. 2021 Aug 12;12:670159. doi: 10.3389/fimmu.2021.670159. eCollection 2021.
Intestinal fibrosis is induced by excessive myofibroblast proliferation and collagen deposition, which has been regarded as a general pathological feature in inflammatory bowel disease (IBD). Therefore, identifying clinical markers and targets to treat and prevent intestinal fibrosis is urgently needed. The traditional Chinese medicine maggot, commonly known as "wu gu chong", has been shown to reduce oxidative stress and alleviate inflammation in chronic colitis. This study investigated the mechanisms underlying the effects of maggot extract (ME) on inflammation-associated intestinal fibrosis in TGF-β1-stimulated human intestinal fibroblasts (CCD-18Co cells) and dextran sodium sulphate (DSS)-induced chronic colitis murine model. To assess the severity of inflammation and fibrosis, histological and macroscopic evaluation were carried out. The results showed that ME was a significant inhibitor of body weight loss and colon length shortening in mice with chronic colitis. In addition, ME suppressed the intestinal fibrosis by downregulating TGF-β1/SMADs pathway upregulation of Nrf2 expression at both protein and mRNA levels. ME markedly increased the expression of Nrf2, thus resulting in a higher level of HO-1. After treatment with Nrf2 inhibitor (ML385) or siRNA-Nrf2 for deactivating Nrf2 pathway, the protective effects of ME were abolished both and . Moreover, the histopathological results for the major organs of DSS mice treated with ME showed no signs of clinically important abnormalities. Treatment with ME had no effect on the viability of CCD-18Co cells, suggesting its low cytotoxicity. Furthermore, ME could mediate intestine health by keeping the balance of the gut microbes through the enhancement of beneficial microbes and suppression of pathogenic microbes. In conclusion, this is the first ever report demonstrating that ME ameliorates inflammation-associated intestinal fibrosis by suppressing TGF-β1/SMAD pathway upregulation of Nrf2 expression. Our findings highlight the potential of Nrf2 as an effective therapeutic target for alleviating intestinal fibrosis.
肠纤维化是由肌成纤维细胞过度增殖和胶原沉积引起的，这已被认为是炎症性肠病（IBD）的普遍病理特征。因此，迫切需要确定治疗和预防肠纤维化的临床标志物和靶点。中药蛆，俗称“五股虫”，已被证明可以减轻慢性结肠炎中的氧化应激和炎症。本研究探讨了蛆提取物（ME）在 TGF-β1 刺激的人肠成纤维细胞（CCD-18Co 细胞）和葡聚糖硫酸钠（DSS）诱导的慢性结肠炎小鼠模型中对炎症相关肠纤维化的作用机制。为了评估炎症和纤维化的严重程度，进行了组织学和宏观评估。结果表明，ME 显著抑制慢性结肠炎小鼠的体重减轻和结肠缩短。此外，ME 通过下调 TGF-β1/SMAD 通路抑制肠纤维化，上调 Nrf2 表达水平（蛋白和 mRNA 水平）。ME 显著增加了 Nrf2 的表达，从而导致 HO-1 水平升高。用 Nrf2 抑制剂（ML385）或 siRNA-Nrf2 处理以激活 Nrf2 通路后，ME 的保护作用均被消除。此外，用 ME 处理的 DSS 小鼠主要器官的组织病理学结果显示没有临床重要异常的迹象。ME 对 CCD-18Co 细胞的活力没有影响，提示其低细胞毒性。此外，ME 可以通过增强有益微生物和抑制致病微生物来调节肠道健康，从而维持肠道微生物的平衡。总之，这是首次报道 ME 通过抑制 TGF-β1/SMAD 通路上调 Nrf2 表达来改善炎症相关的肠纤维化。我们的研究结果强调了 Nrf2 作为缓解肠纤维化的有效治疗靶点的潜力。
