College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
Cell Mol Neurobiol. 2023 Nov;43(8):4041-4058. doi: 10.1007/s10571-023-01427-4. Epub 2023 Oct 24.
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.
白内障是全球范围内导致视力损害和失明的主要原因，其主要潜在病因是氧化应激。氧化应激会引发蛋白质损伤、细胞凋亡，进而导致白内障的形成。核因子-红细胞 2 相关因子 2（Nrf2）作为晶状体中的主要氧化还原转录因子，为抵御氧化应激提供了一道防线。在应对氧化应激挑战时，Nrf2 与抑制剂 Kelch 样 ECH 相关蛋白 1（Keap1）分离，转移到细胞核，并与抗氧化反应元件（ARE）结合，激活 Nrf2 依赖性抗氧化系统。与此同时，氧化应激也会诱导内质网应激（ERS）。氧化应激过程中产生的活性氧（ROS）可以直接损伤蛋白质，导致其错误折叠。最初，未折叠蛋白反应（UPR）会激活以减轻过多的错误折叠蛋白。然而，在持续或严重的应激下，错误折叠蛋白无法得到纠正会导致这些异常蛋白的积累，促使 UPR 向凋亡途径发展，进一步促进白内障的发生。重要的是，Nrf2 抗氧化系统和 ERS/UPR 机制在晶状体中存在动态相互作用。这种相互作用中，ERS/UPR 可以调节 Nrf2 的表达，反之亦然，这为白内障的预防和治疗提供了潜在的治疗意义。本综述探讨了这些系统之间的复杂相互作用，旨在阐明未来在白内障预防和干预方面取得进展的策略。Nrf2 依赖性抗氧化系统与 ERS/UPR 途径相互沟通和交流。这两种机制都被认为在白内障形成的起始中发挥着关键作用。
