School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529000, China.
Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
Free Radic Biol Med. 2024 Oct;223:357-368. doi: 10.1016/j.freeradbiomed.2024.08.006. Epub 2024 Aug 8.
Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aβ) transgenic nematodes by lowering endogenous FA levels and reducing Aβ aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aβ toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.
甲醛（FA）是一种致癌物质，不仅广泛存在于环境中，而且还可以通过代谢过程在体内产生。在生物体中，FA 通过醇脱氢酶 5（ADH5）以依赖谷胱甘肽（GSH）的方式转化为甲酸。体内 FA 的异常积累会导致多种疾病，特别是导致阿尔茨海默病（AD）的认知障碍。在这项研究中，褪黑素衍生物 6a（MD6a）显著改善了暴露于高浓度 FA 的野生型秀丽隐杆线虫的存活和趋化性能。MD6a 通过依赖于 adh-5 的方式增强从 S-羟甲基-GSH 释放共价结合的 GSH，从而降低线虫中的 FA 水平。此外，MD6a 通过降低内源性 FA 水平并以依赖于 adh-5 的方式减少 Aβ 聚集，来保护β-淀粉样蛋白（Aβ）转基因线虫免受线粒体功能障碍和认知障碍。我们的研究结果表明，MD6a 通过 ADH5 解毒 FA，并通过降低秀丽隐杆线虫 AD 模型中的内源性 FA 水平来抵抗 Aβ 毒性。因此，ADH5 可能是 FA 毒性和 AD 的潜在治疗靶标。
