Lim Julie C, Jiang Lanpeng, Lust Natasha G, Donaldson Paul J
Department Physiology, University of Auckland, Auckland 1023, New Zealand.
Aotearoa New Zealand National Eye Centre, University of Auckland, Auckland 1023, New Zealand.
Antioxidants (Basel). 2024 Oct 1;13(10):1193. doi: 10.3390/antiox13101193.
Oxidative stress plays a major role in the formation of the cataract that is the result of advancing age, diabetes or which follows vitrectomy surgery. Glutathione (GSH) is the principal antioxidant in the lens, and so supplementation with GSH would seem like an intuitive strategy to counteract oxidative stress there. However, the delivery of glutathione to the lens is fraught with difficulties, including the limited bioavailability of GSH caused by its rapid degradation, anatomical barriers of the anterior eye that result in insufficient delivery of GSH to the lens, and intracellular barriers within the lens that limit delivery of GSH to its different regions. Hence, more attention should be focused on alternative methods by which to enhance GSH levels in the lens. In this review, we focus on the following three strategies, which utilize the natural molecular machinery of the lens to enhance GSH and/or antioxidant potential in its different regions: the NRF2 pathway, which regulates the transcription of genes involved in GSH homeostasis; the use of lipid permeable cysteine-based analogues to increase the availability of cysteine for GSH synthesis; and the upregulation of the lens's internal microcirculation system, which is a circulating current of Na ions that drives water transport in the lens and with it the potential delivery of cysteine or GSH. The first two strategies have the potential to restore GSH levels in the epithelium and cortex, while the ability to harness the lens's internal microcirculation system offers the exciting potential to deliver and elevate antioxidant levels in its nucleus. This is an important distinction, as the damage phenotypes for age-related (nuclear) and diabetic (cortical) cataract indicate that antioxidant delivery must be targeted to different regions of the lens in order to alleviate oxidative stress. Given our increasing aging and diabetic populations it has become increasingly important to consider how the natural machinery of the lens can be utilized to restore GSH levels in its different regions and to afford protection from cataract.
氧化应激在因年龄增长、糖尿病或玻璃体切除术后导致的白内障形成过程中起主要作用。谷胱甘肽（GSH）是晶状体中的主要抗氧化剂，因此补充GSH似乎是对抗晶状体氧化应激的直观策略。然而，将谷胱甘肽递送至晶状体充满困难，包括GSH快速降解导致其生物利用度有限、眼前部的解剖学屏障导致GSH向晶状体的递送不足，以及晶状体内的细胞内屏障限制了GSH向其不同区域的递送。因此，应更多关注提高晶状体中GSH水平的替代方法。在本综述中，我们聚焦于以下三种策略，这些策略利用晶状体的天然分子机制来提高其不同区域的GSH和/或抗氧化潜力：NRF2途径，其调节参与GSH稳态的基因转录；使用脂质可渗透的基于半胱氨酸的类似物来增加用于GSH合成的半胱氨酸的可用性；以及上调晶状体的内部微循环系统，这是一种钠离子循环电流，驱动晶状体中的水运输以及随之而来的半胱氨酸或GSH的潜在递送。前两种策略有可能恢复上皮和皮质中的GSH水平，而利用晶状体内部微循环系统的能力提供了在其核内递送和提高抗氧化水平的令人兴奋的潜力。这是一个重要的区别，因为年龄相关性（核性）和糖尿病性（皮质性）白内障的损伤表型表明，抗氧化剂递送必须针对晶状体的不同区域，以减轻氧化应激。鉴于我们不断增长的老年和糖尿病人口，考虑如何利用晶状体的天然机制来恢复其不同区域的GSH水平并提供抗白内障保护变得越来越重要。
