Intestinal mucosal barrier loss is responsible for the chronic and recurrent ulcerative colitis. Myosin light chain kinase (MLCK) is a potential therapeutic target of the intestinal mucosal barrier dysfunction. Here, we developed a reactive oxygen species (ROS)-sensitive hydrogel (ATG-CS-Gel) derived from a diselenide-bridged arctigenin (ATG) and chitosan (CS) conjugate, with the aims of targeting to inflamed mucosa and modulating MLCK. Our results demonstrated that ATG-CS-Gel achieved ROS-responsive release and significantly inhibited ROS production and mitochondrial depolarization in the Caco-2 and HT-29/MTX-E12 cells under H2O2-induced stress conditions. Compared with normal tissues, orally-administrated ATG-CS-Gel preferentially adhered to the inflamed mucosa for 24 h, which was attributed to the adhesion between CS and mucin. Therapeutically, ATG-CS-Gel reduced inflammatory symptoms, accelerated intestinal mucosal healing, scavenged excessive ROS, reshaped intestinal flora, and eventually achieved much better therapeutic efficacy in DSS-induced colitis mice when compared to 5-aminosalicylic acid. Moreover, ATG-CS-Gel was demonstrated to reverse intestinal mucosal barrier loss by blocking MLCK activation and maintaining tight junction expression. In summary, this study highlights the potential of MLCK modulation in the restoration of intestinal mucosal barrier using ATG-CS-Gel. The development of ATG-CS-Gel represents a novel and promising strategy for the treatment of ulcerative colitis.

中文翻译：

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一种 ROS 反应性水凝胶，靶向发炎的粘膜，通过逆转肠粘膜屏障的丧失来缓解溃疡性结肠炎


肠粘膜屏障丧失是导致慢性和复发性溃疡性结肠炎的原因。肌球蛋白轻链激酶 （MLCK） 是肠粘膜屏障功能障碍的潜在治疗靶点。在这里，我们开发了一种活性氧 （ROS） 敏感的水凝胶 （ATG-CS-Gel），来源于二硒化物桥的牛蓟素 （ATG） 和壳聚糖 （CS） 偶联物，旨在靶向发炎的粘膜并调节 MLCK。我们的结果表明，在 H2O2 诱导的胁迫条件下，ATG-CS-Gel 实现了 ROS 响应性释放，并显着抑制了 Caco-2 和 HT-29/MTX-E12 细胞的 ROS 产生和线粒体去极化。与正常组织相比，口服 ATG-CS-Gel 优先粘附在发炎的粘膜上 24 h，这归因于 CS 与粘蛋白之间的粘附。在治疗方面，ATG-CS-Gel 减轻了炎症症状，加速了肠粘膜愈合，清除了过量的 ROS，重塑了肠道菌群，最终与 5-氨基水杨酸相比，在 DSS 诱导的结肠炎小鼠中取得了更好的治疗效果。此外，ATG-CS-Gel 被证明可以通过阻断 MLCK 激活和维持紧密连接表达来逆转肠粘膜屏障的丧失。综上所述，本研究强调了 MLCK 调节在使用 ATG-CS-Gel 恢复肠粘膜屏障方面的潜力。ATG-CS-Gel 的开发代表了一种治疗溃疡性结肠炎的新型且有前途的策略。