Novel molecular approaches for improving enzymatic and nonenzymatic detoxification of 4-hydroxynonenal: toward the discovery of a novel class of bioactive compounds.

4-Hydroxy-trans-2-nonenal (HNE), an α,β-unsaturated aldehyde generated endogenously by the radical-mediated peroxidation of ω-6 polyunsaturated fatty acids, is a bioactive molecule acting in several physiopathological mechanisms and most of its activity is due to the covalent modification of biomolecules. Although at low and physiological levels HNE acts as an endogenous signaling molecule, a growing bulk of evidence indicates that at high and toxic concentrations, HNE is involved in the onset and propagation of several human diseases. To get more conclusive evidence of HNE as a pathogenetic factor, a pharmacological tool able to inhibit the HNE-induced cellular response is required. Such compound is currently not available, although several molecular strategies have so far been reported with the aim of inhibiting HNE formation or catalyzing its removal. Although most of these are not selective, such strategies have been found to induce several biological responses and would merit further investigation. In this review the various strategies are reported and discussed together with their limits and potentials.