nadph oxidase 2-derived reactive oxygen species mediate ffas-induced dysfunction and apoptosis of β-cells via jnk, p38 mapk and p53 pathwaysnadph氧化酶2-derived活性氧调解ffas-induced障碍通过物和细胞凋亡β-cells,p38 mapk和p53通路.pdfVIP

NADPH Oxidase 2-Derived Reactive Oxygen Species Mediate FFAs-Induced Dysfunction and Apoptosis of b- Cells via JNK, p38 MAPK and p53 Pathways 1,2. 3. 2 3 2 2 Huiping Yuan , Xiaoyong Zhang , Xiuqing Huang , Yonggang Lu , Weiqing Tang , Yong Man , Shu 2 1 2,3 Wang , Jianzhong Xi *, Jian Li * 1 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China, 2 Peking University Fifth School of Clinical Medicine, Beijing Hospital, Beijing, China, 3 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Abstract Dysfunction of b-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as ‘diabesity’, is associated with elevated plasma free fatty acids (FFAs). Oxidative stress has been implicated in the pathogenesis of FFA-induced b-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS) and FFA-induced b-cell dysfunction and apoptosis are less clear. In the present study, we test the hypothesis that NOX2-derived ROS may play a critical role in dysfunction and apoptosis of b-cells induced by FFA. Our results show that palmitate and oleate (0.5 mmol/L, 48 h) induced JNK activation and AKT inhibition which resulted in decreased phosphorylation of FOXO1 following nuclear localization and the nucleocytoplasmic translocation of PDX-1, leading to the reducing of insulin and ultimately dysfunction of pancreatic NIT-1 cells. We also found that palmitate and oleate stimulated apoptosis of NIT-1 cells through p38MAPK, p53 and NF-kB pathway. More interestingly, our