Antioxidant System and Endoplasmic Reticulum Stress in Cataracts.

The primary underlying contributor for cataract, a leading cause of vision impairment and blindness worldwide, is oxidative stress. Oxidative stress triggers protein damage, cell apoptosis, and subsequent cataract formation. The nuclear factor-erythroid 2-related factor 2 (Nrf2) serves as a principal redox transcriptional factor in the lens, offering a line of defense against oxidative stress. In response to oxidative challenges, Nrf2 dissociates from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), moves to the nucleus, and binds to the antioxidant response element (ARE) to activate the Nrf2-dependent antioxidant system. In parallel, oxidative stress also induces endoplasmic reticulum stress (ERS). Reactive oxygen species (ROS), generated during oxidative stress, can directly damage proteins, causing them to misfold. Initially, the unfolded protein response (UPR) activates to mitigate excessive misfolded proteins. Yet, under persistent or severe stress, the failure to rectify protein misfolding leads to an accumulation of these aberrant proteins, pushing the UPR towards an apoptotic pathway, further contributing to cataractogenesis. Importantly, there is a dynamic interaction between the Nrf2 antioxidant system and the ERS/UPR mechanism in the lens. This interplay, where ERS/UPR can modulate Nrf2 expression and vice versa, holds potential therapeutic implications for cataract prevention and treatment. This review explores the intricate crosstalk between these systems, aiming to illuminate strategies for future advancements in cataract prevention and intervention. The Nrf2-dependent antioxidant system communicates and cross-talks with the ERS/UPR pathway. Both mechanisms are proposed to play pivotal roles in the onset of cataract formation.

A grape-supplemented diet prevented ultraviolet (UV) radiation-induced cataract by regulating Nrf2 and XIAP pathways.

The purpose of this study is to investigate if grape consumption, in the form of grape powder (GP), could protect against ultraviolet (UV)-induced cataract. Mice were fed with the regular diet, sugar placebo diet, or a grape diet (regular diet supplemented with 5%, 10%, and 15% GP) for 3 months. The mice were then exposed to UV radiation to induce cataract. The results showed that the GP diet dose-dependently inhibited UV-induced cataract and preserved glutathione pools. Interestingly, UV-induced Nrf2 activation was abolished in the groups on the GP diet, suggesting GP consumption may improve redox homeostasis in the lens, making Nrf2 activation unnecessary. For molecular target prediction, a total of 471 proteins regulated by GP were identified using Agilent Literature Search (ALS) software. Among these targets, the X-linked inhibitor of apoptosis (XIAP) was correlated with all of the main active ingredients of GP, including resveratrol, catechin, quercetin, and anthocyanins. Our data confirmed that GP prevented UV-induced suppression of XIAP, indicating that XIAP might be one of the critical molecular targets of GP. In conclusion, this study demonstrated that GP protected the lens from UV-induced cataract development in mice. The protective effects of GP may be attributed to its ability to improve redox homeostasis and activate the XIAP-mediated antiapoptotic pathway.