Jagadish Swamy, Hemshekhar Mahadevappa, NaveenKumar Somanathapura K, Sharath Kumar Kothanahally S, Sundaram Mahalingam S, Girish Kesturu S, Rangappa Kanchugarakoppal S
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru 570 006, India; Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru 570 006, India.
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru 570 006, India.
Toxicol Appl Pharmacol. 2017 Nov 1;334:167-179. doi: 10.1016/j.taap.2017.09.008. Epub 2017 Sep 11.
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 Ca 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.
慢性高血糖是糖尿病（DM）的特征性病症之一，它常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的血管并发症。高糖诱导的活性氧（ROS）过量产生会改变血细胞代谢和生化功能，进而导致红细胞凋亡（红细胞死亡），这也是糖尿病中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红细胞凋亡对于更好地管理糖尿病及相关血管并发症至关重要。在本研究中，我们合成了一种氧杂环戊烷衍生物1-(2,2-二甲基四氢呋喃并[2,3][1,3]二氧杂环戊-5-基)乙烷-1,2-二醇（DMTD），并证明了其减轻高血糖诱导的ROS生成和随后红细胞凋亡的功效。我们表明，DMTD有效抑制高糖诱导的ROS生成、细胞内钙水平、磷脂酰丝氨酸（PS）外翻、钙蛋白酶和带3激活、乳酸脱氢酶泄漏、蛋白质糖基化和脂质过氧化，同时提高红细胞中的抗氧化指标、渗透脆性和钠钾ATP酶活性。DMTD剂量依赖性地降低糖化血红蛋白水平，并在体外增强红细胞对葡萄糖的利用。此外，DMTD减轻了人类糖尿病受试者红细胞中ROS产生、细胞内钙水平和PS外化的增加，并增强了钠钾ATP酶活性。综上所述，合成的氧杂环戊烷衍生物DMTD可能是一种新型的高糖诱导氧化应激和红细胞凋亡的合成抑制剂。考虑到目前的结果，DMTD可能是治疗糖尿病及相关并发症的潜在疗法，并为开发针对糖尿病相关并发症的合成治疗方法开辟新途径。
