Xu Ying, Chen Li, Hu Xiaoxia, Lai Zixuan, Chen Baoyi, Wu Minghui, Mai Liting, Su Ziren, Chen Jiannan, Lai Zhengquan, Ai Weipeng, Xie Jianhui, Liao Huijun, Xie Youliang
Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Pharmacy Center, Shenzhen Nanshan Medical Group Headquarters, Shenzhen, PR China.
Int Immunopharmacol. 2025 Apr 24;153:114482. doi: 10.1016/j.intimp.2025.114482. Epub 2025 Mar 17.
Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.
鸦胆子苦醇（BR）是从鸦胆子中分离出的一种活性化合物，鸦胆子是一种以止泻作用而闻名的中草药。我们之前报道过，BR可减轻小鼠溃疡性结肠炎（UC）模型中的炎症。然而，BR在肠道黏膜愈合中的作用尚不清楚，而肠道黏膜愈合最近已被确立为预防和治疗UC的核心策略。在本研究中，我们在葡聚糖硫酸钠（DSS）诱导的UC小鼠中研究了BR对肠道黏膜损伤的改善作用。BR显著减轻了结肠炎症状，通过防止杯状细胞丢失、下调粘蛋白和紧密连接蛋白来改善肠道屏障功能，并维持UC小鼠结肠上皮中的增殖和凋亡稳态。机制上，BR提高了UC小鼠血清和肠道组织以及MNK3细胞（一种研究3型固有淋巴细胞的有效细胞模型）中IL-22的水平和分泌，但抑制了IL-22的抑制蛋白IL-22BP。此外，BR提高了IL-22受体（IL-10R2和IL-22R1）的表达，并激活了其下游的STAT3信号通路。此外，我们使用重组IL-22（rIL-22）和IL-22抗体（抗IL-22）进一步研究了IL-22的作用。BR在减轻肠道炎症和修复肠道黏膜损伤方面表现出与rIL-22相当的效果。抗IL-22治疗消除了BR的黏膜保护作用。本研究结果为BR通过激活UC中的IL-22/STAT3信号通路在肠道黏膜愈合中的作用提供了新的见解。
