Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA; email:
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:291-308. doi: 10.1146/annurev-pharmtox-031620-035348. Epub 2020 Sep 30.
Oxidative injury due to elevated levels of reactive oxygen species is implicated in cardiovascular diseases, Alzheimer's disease, lung and liver diseases, and many cancers. Antioxidant therapies have generally been ineffective at treating these diseases, potentially due to ineffective doses but also due to interference with critical host defense and signaling processes. Therefore, alternative strategies to prevent oxidative injury are needed. Elevated levels of reactive oxygen species induce lipid peroxidation, generating reactive lipid dicarbonyls. These lipid oxidation products may be the most salient mediators of oxidative injury, as they cause cellular and organ dysfunction by adducting to proteins, lipids, and DNA. Small-molecule compounds have been developed in the past decade to selectively and effectively scavenge these reactive lipid dicarbonyls. This review outlines evidence supporting the role of lipid dicarbonyls in disease pathogenesis, as well as preclinical data supporting the efficacy of novel dicarbonyl scavengers in treating or preventing disease.
活性氧水平升高导致的氧化损伤与心血管疾病、阿尔茨海默病、肺部和肝脏疾病以及许多癌症有关。抗氧化疗法在治疗这些疾病方面通常效果不佳，这可能是由于剂量无效，但也可能是由于干扰了关键的宿主防御和信号转导过程。因此，需要预防氧化损伤的替代策略。活性氧水平升高会诱导脂质过氧化，产生活性脂质二羰基化合物。这些脂质氧化产物可能是氧化损伤的最显著介质，因为它们通过与蛋白质、脂质和 DNA 加合而导致细胞和器官功能障碍。在过去十年中，已经开发出了一些小分子化合物来选择性和有效地清除这些活性脂质二羰基化合物。这篇综述概述了支持脂质二羰基化合物在疾病发病机制中的作用的证据，以及支持新型二羰基化合物清除剂在治疗或预防疾病方面的有效性的临床前数据。
