Signaling by 4-hydroxy-2-nonenal: Exposure protocols, target selectivity and degradation

Abstract

4-hydroxy-2-nonenal (HNE), a major non-saturated aldehyde product of lipid peroxidation, has been extensively studied as a signaling messenger. In these studies a wide range of HNE concentrations have been used, ranging from the unstressed plasma concentration to far beyond what would be found in actual pathophysiological condition. In addition, accumulating evidence suggest that signaling protein modification by HNE is specific with only those proteins with cysteine, histidine, and lysine residues located in certain sequence or environments adducted by HNE. HNE-signaling is further regulated through the turnover of HNE-signaling protein adducts through proteolytic process that involve proteasomes, lysosomes and autophagy. This review discusses the HNE concentrations and exposure modes used in signaling studies, the selectivity of the HNE-adduction site, and the turnover of signaling protein adducts.

Chronic Oxidative Stress Promotes Molecular Changes Associated with Epithelial Mesenchymal Transition, NRF2, and Breast Cancer Stem Cell Phenotype

“…HNE is also recognized as a biomarker of oxidative stress, and as such, is involved in (breast) cancer progression [31][32][33]. In accordance with its role are concentrations found in human plasma, where concentrations ranging from 0.1 µM to 1 µM are considered physiological, while 1 µM to 10 µM are considered as "where pathology begins" [34]. Taken that hereditary mutations in breast cancer, as well as conventional cancer treatment strategies, such as chemo-and radiotherapy, cause increases in ROS, which can, in turn, cause lipid peroxidation and HNE formation, these oxidative processes may affect numerous signaling molecules such as HNE activation of NRF2 transcription factor.…”

4-Hydroxynonenal (HNE) and hepatic injury related to chronic oxidative stress

“…High levels of HNE may influence cellular function and behaviour [17]. The formation of cross-linked HNE-protein adducts might notably affect the cellular senescence process and, thus, contribute to aging [3,17,20]. Studies have shown that the generation of HNE-protein adducts can play important pathogenic roles in age-related neurodegenerative diseases, atherosclerosis and cancer [21][22][23][24].…”

“…HNE is degraded to non-toxic or less toxic compounds which are either metabolised or excreted [17]. The key HNE-degrading enzymes are glutathione S-transferases (GST), alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) [3,17,28]. In rat hepatocytes, more than half of HNE is metabolised to the GSH-HNE intermediate conjugate [17,29].…”

“…NF-kB is sequestered in the cytoplasm of cells and is bound it inhibitor IkB. NF-kB is activated by degradation of inhibitor by HNE and inflammatory cytokines [3]. After liberation, NF-kB translocate to the nucleus binding to DNA and enhances the expression of genes TNF-a, IL-1b, Il-6 and IL-8 and consequently lead to mtDNA damage which results in generation of more reactive oxygen species (ROS), forming a vicious cycle of oxidative stress [37].…”

“…Among the 4-hydroxyalkenals, 4-hydroxy-2-nonenal (HNE) is the most studied compound. Both, physiological and toxic roles of HNE have been reported [1][2][3]. HNE derives from oxidation of membrane n-6polyunsaturated fatty acids (PUFAs), essentially arachidonic acid and linoleic acid, two of the most important fatty acids in membranes.…”