Department of Biomedical Laboratory Science, Konyang University, Daejeon 302-718, Republic of Korea.
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Eur J Pharmacol. 2014 Aug 5;736:26-34. doi: 10.1016/j.ejphar.2014.04.031. Epub 2014 May 4.
Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti-inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks. KHG26693 administration significantly decreased blood glucose, triglycerides, and cholesterol and increased insulin. KHG26693 also suppressed several inflammatory responses in STZ-induced diabetic rats, as evidenced by decreased levels of serum tumor necrosis factor-α, interleukin-1β, and nitric oxide. Additionally, KHG26693 significantly modulated hepatic lipid peroxidation, catalase and superoxide dismutase activity, and the nonenzymatic antioxidant status (e.g., vitamins C and E), and reduced the glutathione content. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of inducible nitric oxide synthase and nuclear factor-kappa B. Taken together, our results suggest that KHG26693 successfully reduces the production of oxidative stress in STZ-induced diabetic rats by regulating the oxidation-reduction system, specifically increasing antioxidant capacity. Furthermore, KHG26693 treatment significantly reverted the key enzymes of glucose metabolism, such as glucokinase, glucose-6-phosphatase, glycogen synthase, glycogen phosphorylase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissues. These results indicate that KHG26693 normalizes disturbed glucose metabolism by enhancing glucose utilization and decreasing liver glucose production via insulin release, suggesting the possibility of future diabetes treatments.
噻唑衍生物是药物开发的有吸引力的候选物，因为它们可以有效地合成，并且对许多疾病和病症具有活性，包括糖尿病。在本研究中，我们研究了一种新的噻唑衍生物 N-金刚烷基-4-甲基噻唑-2-胺（KHG26693）在链脲佐菌素（STZ）诱导的糖尿病模型中的抗炎和抗氧化特性。STZ 诱导的糖尿病大鼠每天腹膜内给予 KHG26693（3mg/kg 体重）4 周。KHG26693 给药显著降低了血糖、甘油三酯和胆固醇，并增加了胰岛素。KHG26693 还抑制了 STZ 诱导的糖尿病大鼠的几种炎症反应，表现为血清肿瘤坏死因子-α、白细胞介素-1β和一氧化氮水平降低。此外，KHG26693 显著调节肝脂质过氧化、过氧化氢酶和超氧化物歧化酶活性以及非酶抗氧化状态（例如维生素 C 和 E），并降低谷胱甘肽含量。这些抗炎/抗氧化作用是由于诱导型一氧化氮合酶和核因子-κB 的下调。总的来说，我们的结果表明，KHG26693 通过调节氧化还原系统成功减少 STZ 诱导的糖尿病大鼠氧化应激的产生，特别是增加抗氧化能力。此外，KHG26693 治疗使肝脏组织中葡萄糖代谢的关键酶，如葡糖激酶、葡萄糖-6-磷酸酶、糖原合酶、糖原磷酸化酶和果糖-1,6-二磷酸酶，恢复到接近正常水平。这些结果表明，KHG26693 通过增强葡萄糖利用和减少肝脏葡萄糖产生来释放胰岛素，从而使葡萄糖代谢恢复正常，这表明未来治疗糖尿病的可能性。
