Liu Yucheng, Wang Yonggang, Miao Xiao, Zhou Shanshan, Tan Yi, Liang Guang, Zheng Yang, Liu Quan, Sun Jian, Cai Lu
Kosair Children Hospital Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, KY, USA.
J Cell Mol Med. 2014 Jun;18(6):1203-12. doi: 10.1111/jcmm.12267. Epub 2014 Apr 10.
Cardiovascular diseases as leading causes of the mortality world-wide are related to diabetes. The present study was to explore the protective effect of curcumin analogue C66 on diabetes-induced pathogenic changes of aortas. Diabetes was induced in male C57BL/6 mice with a single intraperitoneal injection of streptozotocin. Diabetic mice and age-matched non-diabetic mice were randomly treated with either vehicle (Control and Diabetes), C66 (C66 and Diabetes/C66) or c-Jun N-terminal kinase (JNK) inhibitor (sp600125, JNKi and Diabetes/JNKi). All three treatments were given by gavage at 5 mg/kg every other day for 3 months. Aortic inflammation, oxidative stress, fibrosis, cell apoptosis and proliferation, Nrf2 expression and transcription were assessed by immunohistochemical staining for the protein level and real-time PCR method for mRNA level. Diabetes increased aortic wall thickness and structural derangement as well as JNK phosphorylation, all of which were attenuated by C66 treatment as JNKi did. Inhibition of JNK phosphorylation by C66 and JNKi also significantly prevented diabetes-induced increases in inflammation, oxidative and nitrative stress, apoptosis, cell proliferation and fibrosis. Furthermore, inhibition of JNK phosphorylation by C66 and JNKi significantly increased aortic Nrf2 expression and transcription function (e.g. increased expression of Nrf2-downstream genes) in normal and diabetic conditions. These results suggest that diabetes-induced pathological changes in the aorta can be protected by C66 via inhibition of JNK function, accompanied by the up-regulation of Nrf2 expression and function.
心血管疾病作为全球主要死因与糖尿病相关。本研究旨在探讨姜黄素类似物C66对糖尿病诱导的主动脉病理变化的保护作用。通过单次腹腔注射链脲佐菌素诱导雄性C57BL/6小鼠患糖尿病。将糖尿病小鼠和年龄匹配的非糖尿病小鼠随机分为溶剂对照组（对照和糖尿病组）、C66组（C66和糖尿病/C66组）或c-Jun氨基末端激酶（JNK）抑制剂组（sp600125，JNKi和糖尿病/JNKi组）。所有三种处理均通过灌胃给予，剂量为5mg/kg，隔天一次，持续3个月。通过免疫组织化学染色评估主动脉炎症、氧化应激、纤维化、细胞凋亡和增殖、Nrf2表达及转录的蛋白水平，通过实时PCR方法评估mRNA水平。糖尿病增加了主动脉壁厚度和结构紊乱以及JNK磷酸化，而C66处理和JNKi处理一样均减弱了这些变化。C66和JNKi对JNK磷酸化的抑制也显著预防了糖尿病诱导的炎症、氧化和硝化应激、细胞凋亡、细胞增殖及纤维化的增加。此外，C66和JNKi对JNK磷酸化的抑制在正常和糖尿病条件下均显著增加了主动脉Nrf2表达及转录功能（如Nrf2下游基因表达增加）。这些结果表明，C66可通过抑制JNK功能，伴随Nrf2表达及功能上调，对糖尿病诱导的主动脉病理变化起到保护作用。
