■糖尿病胃肠功能障碍(DGD)是糖尿病(DM)的严重并发症,影响肠神经系统(ENS),特别是肠胶质细胞(EGCs)。本研究旨在阐明高血糖应激对DM体外和体内模型中EGCs的影响和潜在的分子机制。
■在体外研究中,肠胶质细胞系CRL-2690暴露于高血糖应激,和细胞活力,评估细胞凋亡和氧化损伤。在体内研究中,构建STZ诱导的糖尿病小鼠,并评估DM小鼠十二指肠EGCs的细胞凋亡和氧化损伤。
■结果表明,高血糖应激在DM的体外和体内模型中明显诱导EGCs的氧化损伤。发现这种损害取决于redoxosome的激活,其中涉及SRC和Vav2的磷酸化,活性RAC1-GTP的上调,和NADPH氧化酶(NOX)的活化。此外,redoxosomes的抑制剂,如RAC1抑制剂NSC23766和NOX抑制剂VAS2870,有效减轻高血糖应激诱导的EGCs氧化损伤。此外,抑制p66SHC,redoxosomes的下游靶标,在高血糖应激下减轻EGCs的氧化损伤。
■我们的发现表明,在DGD的病理过程中,redoxosomes/p66SHC信号参与了EGC的氧化损伤。该信号传导级联可以代表用于治疗DGD的潜在治疗靶标。
UNASSIGNED: Diabetic gastrointestinal dysfunction (DGD) is a serious complication of diabetic mellitus (DM), affecting the enteric nervous system (ENS), particular enteric glial cells (EGCs). This study aimed to elucidate the effects and underlying molecular mechanisms of hyperglycemic stress on EGCs in in vitro and in vivo models of DM.
UNASSIGNED: In in vitro studies, enteric glial cell line CRL-2690 was exposed to hyperglycemia stress, and cell viability, cell apoptosis and oxidative damage were assessed. In in vivo studies, STZ-induced diabetic mice were constructed, and cell apoptosis and oxidative damage of EGCs in the duodenum of DM mice were assessed.
UNASSIGNED: The results showed that hyperglycemic stress markedly induced oxidative damage of EGCs in in vitro and in vivo models of DM. This damage was found to be dependent on the activation of redoxosomes, which involved the phosphorylation of SRC and Vav2, the up-regulation of active RAC1-GTP, and the activation of NADPH oxidase (NOX). Moreover, inhibitors of redoxosomes, such as the RAC1 inhibitor NSC23766 and the NOX inhibitor VAS2870, effectively mitigated the hyperglycemic stress-induced oxidative damage of EGCs. Additionally, inhibition of p66SHC, a downstream target of redoxosomes, attenuated oxidative damage of EGCs under hyperglycemic stress.
UNASSIGNED: Our findings suggest that the redoxosomes/p66SHC signaling is involved in the oxidative damage of EGCs during the pathological process of DGD. This signaling cascade may represent a potential therapeutic target for the treatment of DGD.