Department of Biotechnology, SRM University, Kattankulathur 603 203, Tamilnadu, India.
SRM Research Institute, SRM University, Kattankulathur 603 203, Tamilnadu, India.
Pharmacol Res. 2015 Jan;91:104-14. doi: 10.1016/j.phrs.2014.10.004. Epub 2014 Oct 29.
The pathogenic processes involving in the development of diabetes range from autoimmune destruction of pancreatic β-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The major contributing factor for excessive β-cell death includes oxidative stress-mediated mitochondrial damage, which creates an imbalance in redox homeostasis. Yet, β-cells have evolved adaptive mechanisms to endure a wide range of stress conditions to safeguard its potential functions. These include 'Nrf2/Keap1' pathway, a key cellular defense mechanism, to combat oxidative stress by regulating phase II detoxifying and antioxidant genes. During diabetes, redox imbalance provokes defective Nrf2-dependent signaling and compromise antioxidant capacity of the pancreas which turnout β-cells to become highly vulnerable against various insults. Hence, identification of small molecule activators of Nrf2/Keap1 pathway remains significant to enhance cellular defense to overcome the burden of oxidative stress related disturbances. This review summarizes the molecular mechanism behind Nrf2 activation and the impact of Nrf2 activators in diabetes and its complications.
涉及糖尿病发展的发病机制从导致胰岛素缺乏的自身免疫性胰腺β细胞破坏到导致胰岛素作用抵抗的异常。导致过多β细胞死亡的主要因素包括氧化应激介导的线粒体损伤，这会导致氧化还原平衡失衡。然而，β细胞已经进化出适应性机制来承受广泛的应激条件，以保护其潜在功能。这些包括“Nrf2/Keap1”途径，这是一种关键的细胞防御机制，通过调节Ⅱ相解毒和抗氧化基因来抵抗氧化应激。在糖尿病中，氧化还原失衡会引发缺陷的 Nrf2 依赖性信号转导，并损害胰腺的抗氧化能力，使β细胞对各种损伤变得高度脆弱。因此，鉴定 Nrf2/Keap1 途径的小分子激活剂对于增强细胞防御以克服与氧化应激相关的紊乱负担仍然具有重要意义。本综述总结了 Nrf2 激活的分子机制以及 Nrf2 激活剂在糖尿病及其并发症中的作用。
