Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.
Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.
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DOI：
10.1016/j.ejphar.2014.04.031
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发表时间：
2014-08
影响因子：
5
通讯作者：
S. Yang;Woo Je Lee;Eun-A Kim;Kee Dal Nam;H. Hahn;Soo Young Choi;Sung-Woo Cho
中科院分区：
文献类型：
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作者：
S. Yang;Woo Je Lee;Eun-A Kim;Kee Dal Nam;H. Hahn;Soo Young Choi;Sung-Woo Cho
噻唑类化合物是很有吸引力的药物开发候选者，因为它们可以有效地合成，并且对包括糖尿病在内的许多疾病和条件都有活性。本研究采用链脲佐菌素(STZ)诱导的糖尿病模型，研究了新型噻唑类化合物N-金刚烷基-4-甲基噻唑-2-胺(KHG26693)的抗炎和抗氧化作用。链脲佐菌素诱导的糖尿病大鼠给予KHG26693(3 mg/kg体重/d)，连续4周。KHG26693能显著降低血糖、甘油三酯和胆固醇，升高胰岛素水平。KHG26693还抑制链脲佐菌素诱导的糖尿病大鼠的几种炎症反应，其证据是血清肿瘤坏死因子-α、白介素1β和一氧化氮水平的降低。此外，KHG26693显著调节肝脏脂质过氧化、过氧化氢酶和超氧化物歧化酶活性，以及非酶类抗氧化状态(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-kappaB的下调所致。综上所述，我们的结果表明，KHG26693通过调节氧化还原系统，特别是提高抗氧化能力，成功地减少了STZ诱导的糖尿病大鼠氧化应激的产生。此外，KHG26693还可使肝组织中葡萄糖激酶、葡萄糖-6-磷酸酶、糖原合成酶、糖原磷酸化酶、果糖-1，6-二磷酸酶等糖代谢关键酶恢复到接近正常水平。这些结果表明，KHG26693通过提高葡萄糖利用率和通过胰岛素释放减少肝脏葡萄糖产生而使紊乱的葡萄糖代谢正常化，暗示了未来治疗糖尿病的可能性。
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 ofN-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 (3 mg/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.