乌梅丸通过Notch调控NF-κB/NLPR3炎症小体信号通路抑制巨噬细胞超活化防治溃疡性结肠炎的作用机制研究。

The main cause of ulcerative colitis (UC) 's growing  is the inflammatory response induced by hyperactivation of macrophages. Hyperactivation of macrophages is closely related to the activation of signaling pathways about NF-κB/NLPR3 inflammatory corpuscle, and regulated this signaling pathway can treat UC by inhibiting macrophage activation. In similar to UC pathogenesis of diseases, Notch has an effect on regulating the signaling pathway of NF-κB/NLPR3 inflammatory corpuscle, however, there has been no relevant report that Notch can regulate this signaling pathway about UC pathogenesis. Wumei Pill is effective for treatment of ulcerative colitis. A previous study found that Wumei Pill can inhibit colon mucosal injury and promote healing of ulcer in UC rats. It is closely related between promote tissue repair with Notch signaling pathway, but were the inhibition of intestinal inflammation is also associated with Notch? So this study is to explore whether the Notch can regulate the signaling pathway of NF-κB/NLPR3 inflammatory corpuscle,and whether the Wumei Pill contributes to treating UC by regulate the signaling pathway of NF-κB/NLPR3 inflammatory corpuscle with Notch signal pathway. Then, Clarify the molecular mechanism of treatment of UC Wumei Pill, and provides experimental basis for clinical treatment of ulcerative colitis.

巨噬细胞超活化所引起的炎症反应是导致溃疡性结肠炎（UC）不断进展的主要原因。巨噬细胞超活化与NF-κB/NLPR3炎症小体信号通路被激活密切相关，而调控这条通路就能抑制巨噬细胞超活化，治疗UC。在与UC发病机制类似的疾病中Notch具有调控NF-κB/NLPR3炎症小体信号通路的作用，但在UC的发病进程中，Notch是否能调控这一信号通路，尚无相关报道。乌梅丸是治疗UC疗效确切的经方，我们研究发现该方能促进组织修复、抑制肠道炎症，其促进组织修复的作用与Notch信号通路密切相关，但抑制肠道炎症是否也与Notch相关呢？因此，本项目拟通过在体和离体实验，研究在UC发病进程中，Notch是否能调控NF-κB/NLPR3炎症小体信号通路，乌梅丸是否通过Notch调控NF-κB/NLPR3炎症小体信号通路抑制巨噬细胞超活化，治疗UC。阐明乌梅丸防治UC的分子机制，为其临床应用提供实验依据。

巨噬细胞超活化所引起的炎症反应是导致溃疡性结肠炎（UC）不断进展的主要原因。巨噬细胞超活化与Notch/NF-κB/NLPR3炎症小体信号通路被激活密切相关，而调控这条通路就能抑制巨噬细胞超活化，治疗UC。通过本项目研究证实，乌梅丸不但能抑制巨噬细胞的超活化，还有调控巨噬细胞M1/M2极化，其抑制巨噬细胞超活化的作用机制与抑制Notch/NF-κB/NLPR3信号通路激活相关，其调控巨噬细胞M1/M2极化与MAPK、NF-κB和STAT6信号通路相关。本次研究还发现乌梅丸能促进受损肠粘膜的修复，其作用机制与抑制Hippo/YAP信号通路激活有关。进一步的转录组学结果提示乌梅丸能促进肠道杯装细胞分泌和合成MUC2，并且促进了MUC2的O-糖基化相关，其作用机制与干预细胞内内质网蛋白组装过程密切相关。而MUC2蛋白的O-糖基化在抑制炎症，维护肠粘膜屏障完整性，维持肠道菌群平衡方面发挥着重要作用，这为进一步的研究奠定了基础。