PDF(Sci-hub)
Abstract：
Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1-(2,2-dimethyltetrahydrofuro[2,3][1,3]dioxol-5-yl)ethane-1,2-diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia-induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose-induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na+/K+-ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca2+ level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na+/K+-ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose-induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM-associated complications.
摘要：
慢性高血糖是与糖尿病（DM）相关的特征性疾病之一，通常对红细胞形态和血液动力学特性产生有害影响，导致贫血和糖尿病相关血管并发症。高糖诱导的活性氧（ROS）的过度产生可以改变血细胞代谢和生化功能，随后导致红细胞凋亡（红细胞死亡）。糖尿病的另一个令人担忧的并发症。因此,阻断高糖诱导的氧化损伤和随后的细胞凋亡对于更好地管理DM和相关血管并发症非常重要.在这项研究中,我们合成了氧戊环衍生物1-(2,2-二甲基四氢呋喃[2,3][1,3]二氧杂环戊醇-5-基)乙烷-1,2-二醇(DMTD)，并证明了其减轻高血糖诱导的ROS产生和随后的细胞凋亡的功效。我们发现DMTD能有效抑制高糖诱导的ROS生成,细胞内钙水平，磷酸腺苷丝氨酸(PS)加扰，钙蛋白酶和带3激活，LDH泄漏,蛋白质糖基化和脂质过氧化，同时提高抗氧化指标，红细胞渗透脆性和Na+/K+-ATP酶活性。DMTD在体外剂量依赖性地降低糖化血红蛋白水平并增强红细胞对葡萄糖的利用。Further,DMTD缓解了ROS产量的增加，人糖尿病受试者红细胞中的细胞内Ca2水平和PS外化，并增强了Na/K-ATPase活性。一起来看,合成的氧戊环衍生物DMTD可能是高糖诱导的氧化应激和细胞凋亡的新型合成抑制剂。考虑到目前的结果，DMTD可能是治疗DM和相关并发症的潜在治疗剂，并为开发DM相关并发症的合成治疗靶向开辟了新的途径。
