Diabetes is associated with increased oxidative stress, leading to altered tight junction formation and increased apoptosis in colonic epithelial cells. These changes may lead to intestinal barrier dysfunction and corresponding gastrointestinal symptoms in patients with diabetes, including diarrhea. The aim of this study was to characterize the effect and mechanism of Resolvin D1 (RvD1) on diabetes-induced oxidative stress and barrier disruption in the colon. Mice with streptozotocin-induced diabetes were treated with RvD1 for 2 weeks, then evaluated for stool frequency, stool water content, gut permeability, and colonic transepithelial electrical resistance as well as production of reactive oxygen species (ROS), apoptosis, and expression of tight junction proteins Zonula Occludens 1 (ZO-1) and occludin. The same parameters were assessed in human colonoid cultures subjected to elevated glucose. We found that RvD1 treatment did not affect blood glucose, but normalized stool water content and prevented intestinal barrier dysfunction, epithelial oxidative stress, and apoptosis. RvD1 also restored ZO-1 and occludin expression in diabetic mice. RvD1 treatment increased phosphorylation of Akt and was accompanied by a 3.5-fold increase in heme oxygenase-1 (HO-1) expression in the epithelial cells. The protective effects of RvD1 were blocked by ZnPP, a competitive inhibitor of HO-1. Similar findings were observed in RvD1-treated human colonoid cultures subjected to elevated glucose. In conclusion, Oxidative stress in diabetes results in mucosal barrier dysfunction, contributing to the development of diabetic diarrhea. Resolvins prevent ROS-mediated mucosal injury and protect gut barrier function by intracellular PI3K/Akt activation and subsequent HO-1 upregulation in intestinal epithelial cells. These actions result in normalizing stool frequency and stool water content in diabetic mice, suggesting that resolvins may be useful in the treatment of diabetic diarrhea.

中文翻译：

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Resolvins 通过 HO-1 途径预防糖尿病引起的结肠氧化应激、屏障功能障碍和相关腹泻

糖尿病与氧化应激增加有关，导致紧密连接形成改变和结肠上皮细胞凋亡增加。这些变化可能导致糖尿病患者肠道屏障功能障碍和相应的胃肠道症状，包括腹泻。本研究的目的是表征 Resolvin D1 (RvD1) 对糖尿病引起的氧化应激和结肠屏障破坏的作用和机制。链脲佐菌素诱导的糖尿病小鼠接受 RvD1 治疗 2 周，然后评估排便频率、粪便含水量、肠道通透性和结肠跨上皮电阻，以及活性氧 (ROS) 的产生、细胞凋亡和紧密相关蛋白的表达。连接蛋白闭合小带 1 (ZO-1) 和闭合蛋白。在葡萄糖升高的人类结肠培养物中评估了相同的参数。我们发现 RvD1 治疗不影响血糖，但使粪便含水量正常化，并防止肠道屏障功能障碍、上皮氧化应激和细胞凋亡。RvD1 还恢复了糖尿病小鼠中 ZO-1 和 occludin 的表达。RvD1 处理增加了 Akt 的磷酸化，并伴随上皮细胞中血红素加氧酶-1 (HO-1) 表达增加 3.5 倍。RvD1 的保护作用被 HO-1 的竞争性抑制剂 ZnPP 阻断。在经 RvD1 处理且葡萄糖升高的人类结肠培养物中也观察到了类似的结果。总之，糖尿病中的氧化应激导致粘膜屏障功能障碍，导致糖尿病腹泻的发生。Resolvins 通过细胞内 PI3K/Akt 激活和随后肠上皮细胞中 HO-1 的上调来防止 ROS 介导的粘膜损伤并保护肠道屏障功能。这些作用导致糖尿病小鼠的大便频率和粪便水含量正常化，表明消解素可能有助于治疗糖尿病腹泻。