Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls.
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.
Aldini
Giancarlo
G
Institute of Pharmaceutical and Toxicological Chemistry, Faculty of Pharmacy, University of Milan, Viale Abruzzi 42, I-20131, Milan, Italy. giancarlo.aldini@unimi.it
Dalle-Donne
Isabella
I
Facino
Roberto Maffei
RM
Milzani
Aldo
A
Carini
Marina
M
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D005609:Free Radicals / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008658:Inactivation, Metabolic; D015227:Lipid Peroxidation / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects*
D000447:Aldehydes; D005609:Free Radicals