Phytochemical activators of Nrf2: a review of therapeutic strategy in diabetes

Abstract

Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D), and altered mitochondrial function and abnormal lipid distribution are closely associated with IR or T2D. Excess oxidative stress-induced mitochondrial damage leads to an imbalance in redox homeostasis, which is considered the major contributor to the progression of diabetes. A key cellular defense mechanism, namely, the nuclear factor-E2 p45-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, plays an essential protective role in combating excess oxidative stress. A series of phytochemicals are reported to improve IR and restore mitochondrial function against excess oxidative stress by activating the Nrf2-ARE signaling pathway to maintain cellular reactive oxygen species (ROS) homeostasis. The present review focuses on key knowledge gaps in the Nrf2-ARE system targeted by phytochemicals and its correlation to diabetes both in the in vitro and in vivo models and recent achievements in human clinical trials to evaluate its efficiency and safety. In addition, we provide an overview of recent research progress in nutrigenomics, precision nutrition and the interactions occurring in gut microbiota associated with the Nrf2-ARE signaling pathway and diabetes chemoprevention by phytochemicals and finally propose a future research strategy for regulating redox and microbiota balance via the Nrf2-ARE pathway. The present review aims to help us comprehensively understand the critical chemopreventive role of the Nrf2-ARE pathway targeted by phytochemicals in diabetes.

Probucol attenuates high glucose-induced Müller cell damage through enhancing the Nrf2/p62 signaling pathway

“…Nrf2 can adjust the expression of antioxidant genes and detoxifying enzymes by reacting with antioxidant components (ARE) (including glutamate cysteine ligase catalytic subunit [GCLC], p62, etc.). GCLC can regulate the synthesis of glutathione and exert antioxidant effects [ 11 ]. Autophagy is another pathway that maintains cell homeostasis in vivo under oxidative stress; excessive ROS production can activate both autophagy and the Nrf2 pathway [ 12 , 13 ].…”