Aldini Giancarlo, Dalle-Donne Isabella, Facino Roberto Maffei, Milzani Aldo, Carini Marina
Institute of Pharmaceutical and Toxicological Chemistry, Faculty of Pharmacy, University of Milan, Viale Abruzzi 42, I-20131, Milan, Italy.
Med Res Rev. 2007 Nov;27(6):817-68. doi: 10.1002/med.20073.
Protein carbonylation induced by reactive carbonyl species (RCS) generated by peroxidation of polyunsaturated fatty acids plays a significant role in the etiology and/or progression of several human diseases, such as cardiovascular (e.g., atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of intermediate RCS, mainly alpha,beta-unsaturated aldehydes, di-aldehydes, and keto-aldehydes, are due to their capacity to react with the nucleophilic sites of proteins, forming advanced lipoxidation end-products (ALEs). Because of the emerging deleterious role of RCS/protein adducts in several human diseases, different potential therapeutic strategies have been developed in the last few years. This review sheds focus on fundamental studies on lipid-derived RCS generation, their biological effects, and their reactivity with proteins, with particular emphasis to 4-hydroxy-trans-2-nonenal (HNE)-, acrolein (ACR)-, malondialdehyde (MDA)-, and glyoxal (GO)-modified proteins. It also discusses the recently developed pharmacological approaches for the management of chronic diseases in which oxidative stress and RCS formation are massively involved. Inhibition of ALE formation, based on carbonyl-sequestering agents, seems to be the most promising pharmacological tool and is reviewed in detail.
多不饱和脂肪酸过氧化产生的反应性羰基化合物（RCS）诱导的蛋白质羰基化在多种人类疾病的病因和/或进展中起重要作用，如心血管疾病（如动脉粥样硬化、糖尿病长期并发症）和神经退行性疾病（如阿尔茨海默病、帕金森病和脑缺血）。中间RCS（主要是α,β-不饱和醛、二醛和酮醛）的大多数生物学效应是由于它们与蛋白质亲核位点反应形成晚期氧化终产物（ALE）的能力。由于RCS/蛋白质加合物在多种人类疾病中日益显现出有害作用，在过去几年中已开发出不同的潜在治疗策略。本综述重点关注脂质衍生的RCS生成、其生物学效应及其与蛋白质反应性的基础研究，特别强调4-羟基反式-2-壬烯醛（HNE）、丙烯醛（ACR）、丙二醛（MDA）和乙二醛（GO）修饰的蛋白质。它还讨论了最近开发的用于治疗大量涉及氧化应激和RCS形成的慢性疾病的药理学方法。基于羰基螯合剂抑制ALE形成似乎是最有前景的药理学工具，并将进行详细综述。
