Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.

中文翻译：

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D609 保护视网膜色素上皮作为年龄相关性黄斑变性的潜在疗法。

累积的氧化损伤可能导致不可逆的视网膜色素上皮 (RPE) 细胞死亡，这被认为是干性年龄相关性黄斑变性 (AMD) 的主要原因，导致老年人失明。然而，缺乏针对这种疾病的有效疗法。在这里，我们描述了一个强大的高内涵筛选程序，其中包含 814 种保护性化合物库，发现 D609 强烈保护 RPE 细胞免受碘酸钠 (SI) 诱导的氧化细胞死亡并延长其健康存活率。D609 有效地减弱了过量的活性氧 (ROS) 并防止了由于 RPE 细胞中的氧化应激引起的严重线粒体损失。出奇，D609 的有效抗氧化作用不是通过其自身的还原性实现的，而是主要取决于其增加金属硫蛋白表达的能力。这种水溶性小分子的注射也显示出 SI 诱导的 AMD 小鼠模型中 RPE 层的明确保护作用。这些发现表明，D609 在体外和体内都可以作为 RPE 细胞的新型抗氧化保护剂，并揭示了 D609 的新型抗氧化机制，最终可能在临床上用于治疗 AMD。