4-Hydroxy-nonenal—A Bioactive Lipid Peroxidation Product

Biomolecules - Tập 5 Số 4 - Trang 2247-2337
R. J. Schaur1, Werner Siems2, Nikolaus Bresgen3, Peter Eckl3
1Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 33a, 8010 Graz, Austria
2Institute for Medical Education, KortexMed GmbH, Hindenburgring 12a, 38667 Bad Harzburg, Germany
3Division of Genetics, Department of Cell Biology, University of Salzburg, Hellbrunnerstasse 34, 5020 Salzburg, Austria

Tóm tắt

This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress.

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Tài liệu tham khảo

Schauenstein, 1963, Ueber die Reaktion von 9,12 Linolsaeureester in Wasser 6. Mitteilung: Chromatographische Untersuchungen ueber die Zusammensetzung des Praeparates LHPO und die Isolierung der einzelnen tumor-wirksamen Hydroperoxid-Komponenten, Chem. Mon., 94, 11, 10.1007/BF00900233

Halliwell, B., and Gutteridge, J. (2007). Free Radicals in Biology and Medicine, Oxford University Press. [4th ed.].

Catala, 2009, Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions, Chem. Phys. Lipids, 157, 1, 10.1016/j.chemphyslip.2008.09.004

Poli, 2008, 4-Hydroxynonenal: A membrane lipid oxidation product of medicinal interest, Med. Res. Rev., 28, 569, 10.1002/med.20117

Schaur, 2003, Basic aspects of the biochemical reactivity of 4-hydroxynonenal, Mol. Asp. Med., 24, 149, 10.1016/S0098-2997(03)00009-8

Dubinina, 2010, Role of 4-hydroxy-trans-2-nonenal in cell functions, Biochem. Moscow, 75, 1069, 10.1134/S0006297910090014

Fritz, 2013, An overview of the chemistry and biology of reactive aldehydes, Free Rad. Biol. Med., 59, 85, 10.1016/j.freeradbiomed.2012.06.025

Zarkovic, 2013, Pathophysiological relevance of aldehydic protein modifications, J. Proteomics, 92, 239, 10.1016/j.jprot.2013.02.004

Perluigi, 2012, 4-hydroxy-2-nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: A toxic combination illuminated by redox proteomics studies, Antioxid. Redox Signal., 17, 1590, 10.1089/ars.2011.4406

Riahi, 2010, Signaling and cytotoxic functions of 4-hydroxyalkenals, Am. J. Physiol. Endocrinol. Metab., 299, E879, 10.1152/ajpendo.00508.2010

Forman, 2010, Reactive oxygen species and α,β-unsaturated aldehydes as second messengers in signal transduction, Oxid. Nitrosative Stress Dis., 1203, 35

Higdon, 2012, Cell signalling by reactive lipid species: New concepts and molecular mechanisms, Biochem. J., 442, 453, 10.1042/BJ20111752

Dwivedi, 2007, Role of 4-hydroxynonenal and its metabolites in signaling, Redox Rep., 12, 4, 10.1179/135100007X162211

Ayala, A., Munoz, M.F., and Argueelles, S. (2014). Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell. Longev.

Spickett, 2013, The lipid peroxidation product 4-hydroxy-2-nonenal: Advances in chemistry and analysis, Redox Biol., 1, 145, 10.1016/j.redox.2013.01.007

LoPachin, 2009, Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: Nucleophilic targets and adduct formation, Chem. Res. Toxicol., 22, 1499, 10.1021/tx900147g

Mattson, 2009, Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders, Exp. Gerontol., 44, 625, 10.1016/j.exger.2009.07.003

Guichardant, 2009, Analysis of biomarkers from lipid peroxidation: A comparative study, Eur. J. Lipid Sci. Technol., 111, 75, 10.1002/ejlt.200800069

Pryor, W.A. (1980). Free Radicals in Biology, Academic Press.

Aikens, 1991, Perhydroxyl radical (HOO.) initiated lipid-peroxidation—The role of fatty-acid hydroperoxides, J. Biol. Chem., 266, 15091, 10.1016/S0021-9258(18)98591-1

Tsunada, 2003, Chronic exposure to subtoxic levels of peroxidized lipids suppresses mucosal cell turnover in rat small intestine and reversal by glutathione, Dig. Dis. Sci., 48, 210, 10.1023/A:1021775524062

Bochkov, 2002, Protective role of phospholipid oxidation products in endotoxin-induced tissue damage, Nature, 419, 77, 10.1038/nature01023

Yin, 2004, Identification of a novel class of endoperoxides from arachidonate autoxidation, J. Biol. Chem., 279, 3766, 10.1074/jbc.M307137200

Poli, 2000, 4-Hydroxynonenal in the pathomechanisms of oxidative stress, Iubmb Life, 50, 315

Pillon, 2010, Quantitative structure-activity relationship for 4-hydroxy-2-alkenal induced cytotoxicity in L6 muscle cells, Chem. Biol. Interact., 188, 171, 10.1016/j.cbi.2010.06.015

Vazdar, 2012, Behavior of 4-hydroxynonenal in phospholipid membranes, J. Phys. Chem. B, 116, 6411, 10.1021/jp3044219

Dabrowski, 2010, Stereoselective Effects of 4-hydroxynonenal in cultured mouse hepatocytes, Chem. Res. Toxicol., 23, 1601, 10.1021/tx100190k

Hiratsuka, 2001, (S)-preferential cytotoxicity of 4-hydroxy-2(E)-nonenal enantiomers in rat Clone 9 cells, Toxicology, 164, 199

Gueraud, 2005, Enantioselective metabolism of (R)- and (S)-4-hydroxy-2-nonenal in rat, Biofactors, 24, 97, 10.1002/biof.5520240111

Sadhukhan, 2014, Glutathionylated 4-hydroxy-2-(E)-alkenal enantiomers in rat organs and their contributions toward the disposal of 4-hydroxy-2-(E)-nonenal in rat liver, Free Rad. Biol. Med., 70, 78, 10.1016/j.freeradbiomed.2014.02.008

Wakita, 2009, Stereochemical configuration of 4-hydroxy-2-nonenal-cysteine adducts and their stereoselective formation in a redox-regulated protein, J. Biol. Chem., 284, 28810, 10.1074/jbc.M109.019927

Komisarski, 2009, Practical highly enantioselective synthesis of (R)- and (S)-(E)-4-hydroxynon-2-enal, Acta Biochim. Polonica, 56, 189, 10.18388/abp.2009_2532

Yadav, U.C.S., and Ramana, K.V. (2013). Regulation of NF-kappaB-induced inflammatory signaling by lipid peroxidation-derived aldehydes. Oxid. Med. Cell. Longevity.

Singh, 2009, Fat accumulation in Caenorhabditis elegans triggered by the electrophilic lipid peroxidation product 4-Hydroxynonenal (4-HNE), Aging, 1, 68, 10.18632/aging.100005

Singh, 2008, Role of the electrophilic lipid peroxidation product 4-hydroxynonenal in the development and maintenance of obesity in mice, Biochemistry, 47, 3900, 10.1021/bi702124u

Schneider, C., and Brash, A.R. (2013). Monomeric and dimeric routes to formation of 4-hydroxynonenal during lipid peroxidation. Abstr. Papers Am. Chem. Soc., 246, Abstract 41-AGFD.

Long, 2010, Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: Make some room HNE, Free Rad. Biol. Med., 49, 1, 10.1016/j.freeradbiomed.2010.03.015

Wang, 2013, Cyclooxygenase-2 generates the endogenous mutagen trans-4-hydroxy-2-nonenal in Enterococcus faecalis-infected macrophages, Cancer Prev. Res., 6, 206, 10.1158/1940-6207.CAPR-12-0350

Kang, 2011, Hepatotoxicity and nephrotoxicity produced by 4-hydroxy-2-nonenal (4-HNE) following 4-week oral administration to sprague-dawley rats, J. Toxicol. Environ. Health Part A, 74, 779, 10.1080/15287394.2011.567952

Zhang, 2010, 4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway, J. Mol. Cell. Cardiol., 49, 576, 10.1016/j.yjmcc.2010.05.011

Mannervik, 2012, Five decades with glutathione and the GSTome, J. Biol. Chem., 287, 6072, 10.1074/jbc.X112.342675

Balogh, 2011, Interactions of glutathione transferases with 4-hydroxynonenal, Drug Metab. Rev., 43, 165, 10.3109/03602532.2011.558092

Rudd, 2011, Enhanced glutathione depletion, protein adduct formation, and cytotoxicity following exposure to 4-hydroxy-2-nonenal (HNE) in cells expressing human multidrug resistance protein-1 (MRP1) together with human glutathione S-transferase-M1 (GSTM1), Chem. Biol. Interact., 194, 113, 10.1016/j.cbi.2011.08.012

Shireman, 2010, Glutathione transferase A4-4 resists adduction by 4-hydroxynonenal, Arch. Biochem. Biophys., 504, 182, 10.1016/j.abb.2010.09.005

Zhou, 1999, Ability of carnosine and other skeletal muscle components to quench unsaturated aldehydic lipid oxidation products, J. Agric. Food Chem., 47, 51, 10.1021/jf980780j

Shearn, 2013, Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis, Free Rad. Biol. Med., 65, 680, 10.1016/j.freeradbiomed.2013.07.011

Zhu, 2009, Natural polyphenols as direct trapping agents of lipid peroxidation-derived acrolein and 4-hydroxy-trans-2-nonenal, Chem. Res. Toxicol., 22, 1721, 10.1021/tx900221s

Stevens, J.F., Sowell, J.D., and Frei, B. Ascorbic Acid Conjugates. (US20090104705A1), US Patent.

Aldini, G., Yeum, K.J., Niki, E., and Russell, R.M. (2010). Biomarkers for Antioxidative Defense and Oxidative Damage, Blackwell Publishing.

Wakita, 2011, A method for detection of 4-hydroxy-2-nonenal adducts in proteins, Free Radic. Biol. Med., 51, 1, 10.1016/j.freeradbiomed.2011.02.037

Zhang, 2011, Relating protein adduction to gene expression changes: A systems approach, Mol. Biosyst., 7, 2118, 10.1039/c1mb05014a

Dick, 2001, Antioxidative function and substrate specificity of NAD(P)H-dependent alkenal/one oxidoreductase—A new role for leukotriene B-4 12-hydroxydehydrogenase/15-oxoprostaglandin 13-reductase, J. Biol. Chem., 276, 40803, 10.1074/jbc.M105487200

Chen, 1996, Epoxidation of trans-4-hydroxy-2-nonenal by fatty acid hydroperoxides and hydrogen peroxide, Chem. Res. Toxicol., 9, 306, 10.1021/tx9501389

Perry, 2013, Neurofilaments are the major neuronal target of hydroxynonenal-mediated protein cross-links, Free Radic. Res., 47, 507, 10.3109/10715762.2013.794265

Singh, 2013, Phenelzine mitochondrial functional preservation and neuroprotection after traumatic brain injury related to scavenging of the lipid peroxidation-derived aldehyde 4-hydroxy-2-nonenal, J. Cerebral Blood Flow Metab., 33, 593, 10.1038/jcbfm.2012.211

Fournet, 2013, α,β-Acetylenic amino thiolester inhibitors of aldehyde dehydrogenases 1&3: Suppressors of apoptogenic aldehyde oxidation and activators of apoptosis, Curr. Med. Chem., 20, 527

Guo, 2013, ALDH2 protects against stroke by clearing 4-HNE, Cell Res., 23, 915, 10.1038/cr.2013.69

Ma, 2011, Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: Role of autophagy paradox and toxic aldehyde, Eur. Heart J., 32, 1025, 10.1093/eurheartj/ehq253

Muzio, 2012, Aldehyde dehydrogenases and cell proliferation, Free Radic. Biol. Med., 52, 735, 10.1016/j.freeradbiomed.2011.11.033

Townsend, 2001, Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells, Chem. Biol. Interact., 130–132, 261, 10.1016/S0009-2797(00)00270-2

Black, 2012, Molecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal, Free Radic. Biol. Med., 52, 1937, 10.1016/j.freeradbiomed.2012.02.050

2012, Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts, Chem. Res. Toxicol., 25, 722, 10.1021/tx2005184

Murakami, 2009, Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde, Neurobiol. Aging, 30, 325, 10.1016/j.neurobiolaging.2007.07.002

Srivastava, 2009, Aldose reductase protects against early atherosclerotic lesion formation in apolipoprotein e-null mice, Circ. Res., 105, 793, 10.1161/CIRCRESAHA.109.200568

Keith, 2009, Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts, Chem. Biol. Interact., 178, 242, 10.1016/j.cbi.2008.10.055

Li, 2012, Human aldo-keto reductase AKR7A2 protects against the cytotoxicity and mutagenicity of reactive aldehydes and lowers intracellular reactive oxygen species in hamster V79-4 cells, Chem. Biol. Interact., 195, 25, 10.1016/j.cbi.2011.09.007

Jung, K.-A., and Kwak, M.-K. (2013). Enhanced 4-hydroxynonenal resistance in KEAP1 silenced human colon cancer cells. Oxid. Med. Cell. Longevity.

Lyon, 2013, Aldo-keto reductases mediate constitutive and inducible protection against aldehyde toxicity in human neuroblastoma SH-SY5Y cells, Neurochem. Int., 62, 113, 10.1016/j.neuint.2012.10.007

Zhong, 2009, Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels, Biochem. Biophys. Res. Commun., 387, 245, 10.1016/j.bbrc.2009.06.123

Martin, 2009, Role of human aldo-keto-reductase AKR1B10 in the protection against toxic aldehydes, Chem. Biol. Interact., 178, 145, 10.1016/j.cbi.2008.10.021

Endo, 2010, Properties and tissue distribution of a novel aldo-keto reductase encoding in a rat gene (Akr1b10), Arch. Biochem. Biophys., 503, 230, 10.1016/j.abb.2010.08.010

Matsunaga, 2011, Protective effect of rat aldo-keto reductase (AKR1C15) on endothelial cell damage elicited by 4-hydroxy-2-nonenal, Chem. Biol. Interact., 191, 364, 10.1016/j.cbi.2010.12.018

Marchette, 2010, Retinol dehydrogenase 12 detoxifies 4-hydroxynonenal in photoreceptor cells, Free Radic. Biol. Med., 48, 16, 10.1016/j.freeradbiomed.2009.08.005

Amunom, 2011, Cytochromes p450 catalyze the reduction of α,β-unsaturated aldehydes, Chem. Res. Toxicol., 24, 1223, 10.1021/tx200080b

Zhang, 2009, Catabolism of 4-hydroxyacids and 4-hydroxynonenal via 4-hydroxy-4-phosphoacyl-CoAs, J. Biol. Chem., 284, 33521, 10.1074/jbc.M109.055665

Berthiaume, J.M., Li, Q., Sadhukhan, S., Henry, F., Tochtrop, G.P., Brunengraber, H., and Zhang, G. (2013). Catabolism of 4-hydroxy-2(E)-nonenal (HNE) via omega oxidation in perfused rat livers. FASEB J., 27, Abstract No. 794.15.

Subramaniam, 1997, The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins, J. Neurochem., 69, 1161, 10.1046/j.1471-4159.1997.69031161.x

Chen, 1994, Alterations in mitochondrial-membrane fluidity by lipid-peroxidation products, Free Radic. Biol. Med., 17, 411, 10.1016/0891-5849(94)90167-8

Barrier, 1999, Origin of 4-hydroxynonenal incubation-induced inhibition of dopamine transporter and Na+/K+ adenosine triphosphate in rat striatal synaptosomes, Neurosci. Lett., 277, 91, 10.1016/S0304-3940(99)00652-7

Liu, 2013, RNA-seq data analysis at the gene and CDS levels provides a comprehensive view of transcriptome responses induced by 4-hydroxynonenal, Mol. Biosyst., 9, 3036, 10.1039/c3mb70114j

Schreier, 2010, Hydrogen sulfide scavenges the cytotoxic lipid oxidation product 4-HNE, Neurotox. Res., 17, 249, 10.1007/s12640-009-9099-9

Siems, 2003, Intracellular metabolism of 4-hydroxynonenal, Mol. Asp. Med., 24, 167, 10.1016/S0098-2997(03)00011-6

Vila, 2008, Identification of protein targets of 4-hydroxynonenal using click chemistry for ex vivo biotinylation of azido and alkynyl derivatives, Chem. Res. Toxicol., 21, 432, 10.1021/tx700347w

Tallman, K.A., Vila, A., Porter, N.A., and Marnett, L.J. (2009). Measuring electrophile stress. Curr. Protoc. Toxicol., 11–17.

Chavez, 2010, Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: Protein carbonylation is diminished by ascorbic acid, Chem. Res. Toxicol., 23, 37, 10.1021/tx9002462

Codreanu, 2009, Global analysis of protein damage by the lipid electrophile 4-hydroxy-2-nonenal, Mol. Cell. Proteomics, 8, 670, 10.1074/mcp.M800070-MCP200

Petersen, D.R., Carbone, D., and Doorn, J. (2006, January 16–18). Hepatocellular targets of 4-hydroxy-2-nonenal modification. Proceedings of the 3rd International Meeting of the HNE-Club, Genova, Italy. Abstract No. 6.

Hussain, 2006, Modifications of proteins by 4-hydroxy-2-nonenal in the ventilatory muscles of rats, Am. J. Physiol. Lung Cell. Mol. Physiol., 290, L996, 10.1152/ajplung.00337.2005

Jung, 2005, Distribution of oxidized and HNE-modified proteins in U87 cells, Biofactors, 24, 165, 10.1002/biof.5520240120

Carbone, 2005, Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease, J. Pharmacol. Exp. Ther., 315, 8, 10.1124/jpet.105.088088

Carbone, 2004, Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal, Chem. Res. Toxicol., 17, 1459, 10.1021/tx049838g

Legards, J.F., and des Rosiers, C. (2006, January 16–18). Assay of 4-hydroxynonenal (HNE) adducts with various polyaminoacids (PAA) using gas chromatography-mass spectrometry (GCMS). Proceedings of the 3rd International Meeting of the HNE-Club, Genova, Italy.

Doorn, 2003, Covalent adduction of nucleophilic amino acids by 4-hydroxynonenal and 4-oxononenal, Chem. Biol. Interact., 143, 93, 10.1016/S0009-2797(02)00178-3

Isom, 2004, Modification of cytochrome c by 4-hydroxy-2-nonenal: Evidence for histidine, lysine, and arginine-aldehyde adducts, J. Am. Soc. Mass Spectrom., 15, 1136, 10.1016/j.jasms.2004.03.013

Liu, 2003, Mass spectroscopic characterization of protein modification by 4-Hydroxy-2-(E)-nonenal and 4-Oxo-2-(E)-nonenal, Chem. Res. Toxicol., 16, 901, 10.1021/tx0300030

Aldini, 2005, Covalent modification of actin by 4-hydroxy-trans-2-nonenal (HNE): LC-ESI-MS/MS evidence for Cys374 Michael adduction, J. Mass Spectrom., 40, 946, 10.1002/jms.872

Bennaars-Eiden, A., Higgins, L.A., Hertzel, A.V., Kapphahn, R.J., Ferrington, D., and Bernlohr, D.A. (2003). Covalent modification of epithelial fatty acid binding protein by 4-hydroxynonenal in vitro and in vivo: Evidence for a role in antioxidant biology. FASEB J., 17, Abstract No. 845.847.

Carbone, 2005, Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase, Chem. Res. Toxicol., 18, 1324, 10.1021/tx050078z

Asselin, 2006, Circulating 4-hydroxynonenal-protein thioether adducts assessed by gas chromatography-mass spectrometry are increased with disease progression and aging in spontaneously hypertensive rats, Free Radic. Biol. Med., 41, 97, 10.1016/j.freeradbiomed.2006.03.011

Moreau, 2005, Reversal by aminoguanidine of the age-related increase in glycoxidation and lipoxidation in the cardiovascular system of Fischer 344 rats, Biochem. Pharmacol., 69, 29, 10.1016/j.bcp.2004.09.006

Kim, 2006, Proteomic analysis of nitrated and 4-hydroxy-2-nonenal-modified serum proteins during aging, J. Gerontol. Ser. A Biol. Sci. Med. Sci., 61, 332, 10.1093/gerona/61.4.332

Petersen, 2004, Reactions of 4-hydroxynonenal with proteins and cellular targets, Free Radic. Biol.Med., 37, 937, 10.1016/j.freeradbiomed.2004.06.012

Renner, 2005, Formation of 4-hydroxy-2-nonenal protein adducts in the ischemic rat heart after transplantation, J. Heart Lung Transpl., 24, 730, 10.1016/j.healun.2004.02.021

Galligan, 2012, Protein carbonylation in a murine model for early alcoholic liver disease, Chem. Res. Toxicol., 25, 1012, 10.1021/tx300002q

Aoyama, 2006, Aging and oxidative stress in progressive supranuclear palsy, Eur. J. Neurol., 13, 89, 10.1111/j.1468-1331.2006.01139.x

Grune, T. (, 2006). HNE-modified proteins: Formation, distribution and fate. Proceedings of the 3rd International Meeting of the HNE-Club, Genova, Italy. Abstract No. 17.

Carbone, 2004, 4-hydroxynonenal regulates 26S proteasomal degradation of alcohol dehydrogenase, Free Radic. Biol. Med., 37, 1430, 10.1016/j.freeradbiomed.2004.07.016

Okada, 1999, 4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress—Identification of proteasomes as target molecules, J. Biol. Chem., 274, 23787, 10.1074/jbc.274.34.23787

Hyun, 2002, Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: A mechanism contributing to neurodegeneration?, J. Neurochem., 83, 360, 10.1046/j.1471-4159.2002.01125.x

Li, 2005, The effect of ethanol-induced CYP2E1 on proteasome activity: The role of 4-hydroxynonenal, Exp. Mol. Pathol., 78, 109, 10.1016/j.yexmp.2004.10.005

Kessova, 2005, The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells, J. Pharmacol. Exp. Ther., 315, 304, 10.1124/jpet.105.088047

Ferrington, 2004, Catalytic site-specific inhibition of the 20S proteasome by 4-hydroxynonenal, FEBS Lett., 578, 217, 10.1016/j.febslet.2004.11.003

Tsuchiya, 2005, Degradation of glyceraldehyde-3-phosphate dehydrogenase triggered by 4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal, Arch. Biochem. Biophys., 438, 217, 10.1016/j.abb.2005.04.015

Xu, 1999, Independent synthesis, solution behavior, and studies on the mechanism of formation of a primary amine-derived fluorophore representing cross-linking of proteins by (E)-4-hydroxy-2-nonenal, J. Org. Chem., 64, 5732, 10.1021/jo982523j

Zarkovic, 2009, Protein-aldehydic adducts as biomarkers of oxidative stress, lipid peroxidation and oxidative homeostasis, Free Radic. Res., 43, 33

Wang, 2013, Oxidative protein modification of soluble N-ethylmaleimide-sensitive factor attachment protein receptors, FASEB J., 27, 890

Gallagher, 2006, Several glutathione S-transferase isozymes that protect against oxidative injury are expressed in human liver mitochondria, Biochem. Pharmacol., 71, 1619, 10.1016/j.bcp.2006.02.018

Alary, 2003, Identification of intermediate pathways of 4-hydroxynonenal metabolism in the rat, Chem. Res.Toxicol., 16, 320, 10.1021/tx025671k

Lucas, 2002, Effect of glutathione augmentation on lipid peroxidation after spinal cord injury, J. Neurotrauma, 19, 763, 10.1089/08977150260139138

Yang, 2003, Lipid peroxidation and cell cycle signaling: 4-Hydroxynonenal, a key molecule in stress mediated signaling, Acta Biochim. Polonica, 50, 319, 10.18388/abp.2003_3689

Patrick, 2005, Depletion of 4-hydroxynonenal in hGSTA4-transfected HLE B-3 cells results in profound changes in gene expression, Biochem. Biophys. Res. Commun., 334, 425, 10.1016/j.bbrc.2005.06.099

Dwivedi, 2006, The course of CCl4 induced hepatotoxicity is altered in mGSTA4-4 null (−/−) mice, Toxicology, 218, 58, 10.1016/j.tox.2005.10.012

Engle, 2004, Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: Generation and analysis of mGSTA4 null mouse, Toxicol. Appl. Pharmacol., 194, 296, 10.1016/j.taap.2003.10.001

Knoll, 2005, Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is associated with cellular levels of glutathione and the modulation of glutathione S-transferase A4 expression by butyrate, Toxicol. Sci., 86, 27, 10.1093/toxsci/kfi171

Srivastava, 2010, Synthesis, quantification, characterization, and signaling properties of glutathionyl conjugates of enals, Methods Enzymol., 474, 297, 10.1016/S0076-6879(10)74018-0

Frohnert, 2014, Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation, Diabetes, 63, 89, 10.2337/db13-0777

Spite, 2009, Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress, Br. J. Pharmacol., 158, 1062, 10.1111/j.1476-5381.2009.00234.x

Aldini, 2005, Carnosine and related dipeptides as quenchers of reactive carbonyl species: From structural studies to therapeutic perspectives, Biofactors, 24, 77, 10.1002/biof.5520240109

Aldini, 2002, Carnosine is a quencher of 4-hydroxy-nonenal: Through what mechanism of reaction?, Biochem. Biophys. Res. Commun., 298, 699, 10.1016/S0006-291X(02)02545-7

Barski, 2013, Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein e-null mice, Arterioscler. Thromb. Vasc. Biol., 33, 1162, 10.1161/ATVBAHA.112.300572

Wang, 2012, Shotgun lipidomics analysis of 4-hydroxyalkenal species directly from lipid extracts after one-step in situ derivatization, Anal. Chem., 84, 4580, 10.1021/ac300695p

Guiotto, 2005, Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldehyde scavenger histidyl-containing analogues of carnosine, J. Med. Chem., 48, 6156, 10.1021/jm050507q

Guiotto, 2005, Carnosine and carnosine-related antioxidants: A review, Curr. Med. Chem., 12, 2293, 10.2174/0929867054864796

Vistoli, 2009, Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species, Chemmedchem, 4, 967, 10.1002/cmdc.200800433

Bertinaria, 2011, Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents, J. Med. Chem., 54, 611, 10.1021/jm101394n

Sugano, 2013, Different anti-oxidant effects of thioredoxin 1 and thioredoxin 2 in retinal epithelial cells, Cell Struct. Funct., 38, 81, 10.1247/csf.12025

Zhang, 2014, Glutaredoxin 2 reduces both thioredoxin 2 and thioredoxin 1 and protects cells from apoptosis induced by auranofin and 4-hydroxynonenal, Antioxid. Redox Signal., 21, 669, 10.1089/ars.2013.5499

Tang, 2011, A mass spectrometric analysis of 4-hydroxy-2-(E)-nonenal modification of cytochrome c, J. Mass Spectrom., 46, 290, 10.1002/jms.1890

Gardner, 2001, Effect of 4-hydroxy-2(E)-nonenal on soybean lipoxygenase-1, Lipids, 36, 623, 10.1007/s11745-001-0766-9

Uchida, 1993, Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase—A possible involvement of intramolecular and intermolecular cross-linking reaction, J. Biol. Chem., 268, 6388, 10.1016/S0021-9258(18)53264-6

Ishii, 2003, Molecular basis of enzyme inactivation by an endogenous electrophile 4-hydroxy-2-nonenal: Identification of modification sites in glyceraldehyde-3-phosphate dehydrogenase, Biochemistry, 42, 3474, 10.1021/bi027172o

Ploemen, 1997, Interactions of α,β-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1, Chem. Biol. Interact., 108, 67, 10.1016/S0009-2797(97)00096-3

Flohe, 1999, 4-Hydroxynonenal inhibits glutathione peroxidase: Protection by glutathione, Free Radic. Biol. Med., 26, 1383, 10.1016/S0891-5849(98)00335-9

Korotchkina, 2001, Protection by thiols of the mitochondrial complexes from 4-hydroxy-2-nonenal, Free Radic. Biol. Med., 30, 992, 10.1016/S0891-5849(01)00491-9

Vilardo, 1998, Site-specific inactivation of aldose reductase by 4-hydroxynonenal, Arch. Biochem. Biophys., 350, 245, 10.1006/abbi.1997.0488

Yu, 2004, Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase—Modulation of selenoproteins by lipoxygenase enzymes, J. Biol. Chem., 279, 28028, 10.1074/jbc.M313939200

Fang, 2006, Inhibition of thioredoxin and thioredoxin reductase by 4-hydroxy-2-nonenal in vitro and in vivo, J. Am. Chem. Soc., 128, 1879, 10.1021/ja057358l

Chen, 2005, 4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2, J. Biol. Chem., 280, 41921, 10.1074/jbc.M508556200

Chen, 2006, Adaptive response induced by lipid peroxidation products in cell cultures, FEBS Lett., 580, 479, 10.1016/j.febslet.2005.12.045

Morquette, 2006, Production of lipid peroxidation products in osteoarthritic tissues—New evidence linking 4-hydroxynonenal to cartilage degradation, Arthritis Rheum., 54, 271, 10.1002/art.21559

Ramanathan, 2014, Covalent binding of 4-hydroxy-2-nonenal to lactate dehydrogenase decreases NADH formation and metmyoglobin reducing activity, J. Agric. Food Chem., 62, 2112, 10.1021/jf404900y

Schlisser, 2010, Teratogen-induced oxidative stress targets glyceraldehyde-3-phosphate dehydrogenase in the organogenesis stage mouse embryo, Toxicol. Sci., 118, 686, 10.1093/toxsci/kfq287

Markesbery, 1999, Oxidative alterations in Alzheimer’s disease, Brain Pathol., 9, 133, 10.1111/j.1750-3639.1999.tb00215.x

Butterfield, 2002, Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: Potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress1,2, Free Radic. Biol. Med., 32, 1050, 10.1016/S0891-5849(02)00794-3

Markesbery, 1998, Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease, Neurobiol. Aging, 19, 33, 10.1016/S0197-4580(98)00009-8

Sultana, 2004, Oxidatively modified GST and MRP1 in Alzheimer’s disease brain: Implications for accumulation of reactive lipid peroxidation products, Neurochem. Res., 29, 2215, 10.1007/s11064-004-7028-0

Huang, 2012, Anti-oxidative stress regulator NF-E2-related factor 2 mediates the adaptive induction of antioxidant and detoxifying enzymes by lipid peroxidation metabolite 4-hydroxynonenal, Cell Biosci., 2, 1, 10.1186/2045-3701-2-40

Balogh, 2010, Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal, Biochemistry, 49, 1541, 10.1021/bi902038u

Calamaras, 2012, Post-translational modification of serine/threonine kinase LKB1 via adduction of the reactive lipid species 4-hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity, J. Biol. Chem., 287, 42400, 10.1074/jbc.M112.385831

Shearn, 2014, Identification of 5' AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol, J. Biol. Chem., 289, 15449, 10.1074/jbc.M113.543942

Wang, 2014, A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles, Nat. Methods, 11, 79, 10.1038/nmeth.2759

Shearn, 2011, Modification of Akt2 by 4-hydroxynonenal inhibits insulin-dependent Akt signaling in HepG2 cells, Biochemistry, 50, 3984, 10.1021/bi200029w

MacDonald, 2013, Identification of ATP synthase as a lipid peroxide protein adduct in pancreatic islets from humans with and without type 2 Diabetes mellitus, J. Clin. Endocrinol. Metab., 98, E727, 10.1210/jc.2012-4203

Guo, 2011, Protein targets for carbonylation by 4-hydroxy-2-nonenal in rat liver mitochondria, J. Proteomics, 74, 2370, 10.1016/j.jprot.2011.07.009

Shearn, 2011, Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition by 4-hydroxynonenal leads to increased Akt activation in hepatocytes, Mol. Pharmacol., 79, 941, 10.1124/mol.110.069534

Fang, 2013, Temporally controlled targeting of 4-hydroxynonenal to specific proteins in living cells, J. Am. Chem. Soc., 135, 14496, 10.1021/ja405400k

Los, 2008, HatoTag: A novel protein labeling technology for cell imaging and protein analysis, ACS Chem. Biol., 3, 373, 10.1021/cb800025k

Fritz, 2011, 4-hydroxynonenal inhibits SIRT3 via thiol-specific modification, Chem. Res. Toxicol., 24, 651, 10.1021/tx100355a

Krohne, 2010, Lipid peroxidation products reduce lysosomal protease activities in human retinal pigment epithelial cells via two different mechanisms of action, Exp. Eye Res., 90, 261, 10.1016/j.exer.2009.10.014

Wang, 2003, Oxidized neprilysin in aging and Alzheimer’s disease brains, Biochem. Biophys. Res. Commun., 310, 236, 10.1016/j.bbrc.2003.09.003

Wang, 2009, Effects of HNE-modification induced by A beta on neprilysin expression and activity in SH-SY5Y cells, J. Neurochem., 108, 1072, 10.1111/j.1471-4159.2008.05855.x

Wang, 2010, N-Acetylcysteine prevents 4-hydroxynonenal—And amyloid-β-induced modification and inactivation of neprilysin in SH-SY5Y cells, J. Alzheimers Dis., 19, 179, 10.3233/JAD-2010-1226

Liu, 2013, Carbonylation of mitochondrial aconitase with 4-hydroxy-2-(E)-nonenal: Localization and relative reactivity of addition sites, Biochim. Biophys. Acta Proteins Proteomics, 1834, 1144, 10.1016/j.bbapap.2013.03.005

Zhao, 2014, Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment, Free Radic. Biol. Med., 72, 55, 10.1016/j.freeradbiomed.2014.03.001

Gentile, 2009, Exposure of HL-60 human leukaemic cells to 4-hydroxynonenal promotes the formation of adduct(s) with alpha-enolase devoid of plasminogen binding activity, Biochem. J., 422, 285, 10.1042/BJ20090564

Reed, 2009, Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD, Brain Res., 1274, 66, 10.1016/j.brainres.2009.04.009

Muller, 2013, Protein disulfide isomerase modification and inhibition contribute to ER stress and apoptosis induced by oxidized low density lipoproteins, Antioxid. Redox Signal., 18, 731, 10.1089/ars.2012.4577

Aluise, 2013, Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles, Chem. Res. Toxicol., 26, 270, 10.1021/tx300449g

Tanito, 2006, Identification of 4-hydroxynonenal-modified retinal proteins induced by photooxidative stress prior to retinal degeneration, Free Radic. Biol. Med., 41, 1847, 10.1016/j.freeradbiomed.2006.09.012

Toyokuni, 2000, Serum 4-hydroxy-2-nonenal-modified albumin is elevated in patients with type 2 Diabetes Mellitus, Antioxid. Redox Signal., 2, 681, 10.1089/ars.2000.2.4-681

Aldini, 2006, Mass spectrometric characterization of covalent modification of human serum albumin by 4-hydroxy-trans-2-nonenal, J. Mass Spectrom., 41, 1149, 10.1002/jms.1067

Liu, 2012, The reactivity of human serum albumin towards trans-4-hydroxy-2-nonenal, J. Mass Spectrom., 47, 411, 10.1002/jms.2037

Khatoon, 2012, Physicochemical and immunological studies on 4-hydroxynonenal modified HSA: Implications of protein damage by lipid peroxidation products in the etiopathogenesis of SLE, Hum. Immunol., 73, 1132, 10.1016/j.humimm.2012.08.011

Xiang, 2013, Oxidative stress-induced posttranslational modifications of human hemoglobin in erythrocytes, Arch. Biochem. Biophys., 529, 34, 10.1016/j.abb.2012.11.002

Naveena, 2010, Detection of 4-hydroxy-2-nonenal adducts of turkey and chicken myoglobins using mass spectrometry, Food Chem., 122, 836, 10.1016/j.foodchem.2010.02.062

Smathers, 2012, Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics, PLoS ONE, 7, e38459, 10.1371/journal.pone.0038459

Hellberg, 2010, X-ray crystallographic analysis of adipocyte fatty acid binding protein (aP2) modified with 4-hydroxy-2-nonenal, Protein Sci., 19, 1480, 10.1002/pro.427

Stewart, 2009, Lipid aldehyde-mediated cross-linking of apolipoprotein B-100 inhibits secretion from HepG2 cells, Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1791, 772, 10.1016/j.bbalip.2009.04.004

Shao, 2010, Modifying apolipoprotein A–I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway, J. Biol. Chem., 285, 18473, 10.1074/jbc.M110.118182

Zhu, 2009, Mass spectrometric characterization of protein modification by the products of nonenzymatic oxidation of linoleic acid, Chem. Res. Toxicol., 22, 1386, 10.1021/tx9000072

Ou, 2002, In vivo assessment of lipid peroxidation products associated with age-related neurodegenerative diseases, Exp. Neurol., 175, 363, 10.1006/exnr.2002.7923

Mattson, 2003, Neuronal and glial calcium signaling in Alzheimer’s disease, Cell Calcium, 34, 385, 10.1016/S0143-4160(03)00128-3

Pedersen, 1998, Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients, Ann. Neurol., 44, 819, 10.1002/ana.410440518

Lovell, 2012, 4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures, J. Alzheimers Dis., 32, 139, 10.3233/JAD-2012-120409

Maroteaux, 1988, Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal, J. Neurosci., 8, 2804, 10.1523/JNEUROSCI.08-08-02804.1988

Cabin, 2002, Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein, J. Neurosci., 22, 8797, 10.1523/JNEUROSCI.22-20-08797.2002

Murphy, 2000, Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons, J. Neurosci., 20, 3214, 10.1523/JNEUROSCI.20-09-03214.2000

Lotharius, 2002, Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson’s disease, Hum. Mol. Genet., 11, 2395, 10.1093/hmg/11.20.2395

Jomova, 2010, Metals, oxidative stress and neurodegenerative disorders, Mol. Cell. Biochem., 345, 91, 10.1007/s11010-010-0563-x

Xiang, 2013, Oxidative stress-induced posttranslational modifications of alpha-synuclein: Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity, Mol. Cell. Neurosci., 54, 71, 10.1016/j.mcn.2013.01.004

Bae, 2013, Lipid peroxidation product 4-hydroxy-2-nonenal promotes seeding-capable oligomer formation and cell-to-cell transfer of a-synuclein, Antioxid. Redox Signal., 18, 770, 10.1089/ars.2011.4429

Nasstrom, 2011, The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties, Free Radic. Biol. Med., 50, 428, 10.1016/j.freeradbiomed.2010.11.027

Shibata, 2010, Involvement of 4-hydroxy-2-nonenal accumulation in multiple system atrophy, Acta Histochem. Cytochem., 43, 69, 10.1267/ahc.10005

Chardonnet, 2011, Inhibition by 4-hydroxynonenal (HNE) of Ca2+ transport by SERCA1a: Low concentrations of HNE open protein-mediated leaks in the membrane, Free Radic. Biol. Med., 50, 323, 10.1016/j.freeradbiomed.2010.11.017

Gunthorpe, 2002, The diversity in the vanilloid (TRPV) receptor family of ion channels, Trends Pharmacol. Sci., 23, 183, 10.1016/S0165-6147(02)01999-5

Kishimoto, 2011, Oxidative stress-induced posttranslational modification of TRPV1 expressed in esophageal epithelial cells, Am. J. Physiol. Gastrointest. Liver Physiol., 301, G230, 10.1152/ajpgi.00436.2009

Vindis, 2006, Desensitization of platelet-derived growth factor receptor-beta by oxidized lipids in vascular cells and atherosclerotic lesions—Prevention by Aldehyde Scavengers, Circ. Res., 98, 785, 10.1161/01.RES.0000216288.93234.c3

Shimozu, 2012, Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1, Biochem. J., 442, 171, 10.1042/BJ20111029

Kim, 2009, Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization, Chem. Biol. Interact., 182, 59, 10.1016/j.cbi.2009.07.009

Liu, 2005, Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations, Free Radic. Biol. Med., 38, 746, 10.1016/j.freeradbiomed.2004.11.005

Hernandez, 2004, Quinones facilitate the self-assembly of the phosphorylated tubulin binding region of tau into fibrillar polymers, Biochemistry, 43, 2888, 10.1021/bi035345j

Mendez, 2012, Differential carbonylation of cytoskeletal proteins in blood group O erythrocytes: Potential role in protection against severe malaria, Infect. Genet. Evol., 12, 1780, 10.1016/j.meegid.2012.06.013

Arashiki, 2010, The covalent modification of spectrin in red cell membranes by the lipid peroxidation product 4-hydroxy-2-nonenal, Biochem. Biophys. Res. Commun., 391, 1543, 10.1016/j.bbrc.2009.12.121

Mendez, 2010, Combined proteomic approaches for the identification of specific amino acid residues modified by 4-hydroxy-2-nonenal under physiological conditions, J. Proteome Res., 9, 5770, 10.1021/pr100555v

Yamashima, 2012, Hsp70.1 and related lysosomal factors for necrotic neuronal death, J. Neurochem., 120, 477, 10.1111/j.1471-4159.2011.07596.x

Perluigi, 2005, Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis, Free Radic. Biol. Med., 38, 960, 10.1016/j.freeradbiomed.2004.12.021

Sahara, 2010, Calpain-mediated Hsp70.1 cleavage in hippocampal CA1 neuronal death, Biochem. Biophys. Res. Commun., 393, 806, 10.1016/j.bbrc.2010.02.087

Connor, 2011, Protein-selective capture to analyze electrophile adduction of Hsp90 by 4-hydroxynonenal, Chem. Res. Toxicol., 24, 1275, 10.1021/tx200157t

Smathers, 2011, Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease, Chem. Biol. Interact., 192, 107, 10.1016/j.cbi.2011.02.021

Jacobs, 2010, Systems analysis of protein modification and cellular responses induced by electrophile stress, Acc. Chem. Res., 43, 673, 10.1021/ar900286y

Galligan, 2014, Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: Functional independence of ATPase activity and chaperone function, Free Radic. Biol. Med., 73, 411, 10.1016/j.freeradbiomed.2014.06.002

Brand, M.D., Buckingham, J.A., Esteves, T.C., Green, K., Lambert, A.J., Miwa, S., Murphy, M.P., Pakay, J.L., Talbot, D.A., and Echtay, K.S. (2004). Mitochondrial superoxide and aging: Uncoupling-protein activity and superoxide production. Free Radic., 203–213.

Esteves, 2005, The reactions catalysed by the mitochondrial uncoupling proteins UCP2 and UCP3, Biochim. Biophys. Acta Bioenerget., 1709, 35, 10.1016/j.bbabio.2005.06.002

Smith, 2004, Activation and function of mitochondrial uncoupling protein in plants, J. Biol. Chem., 279, 51944, 10.1074/jbc.M408920200

Echtay, 2003, A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling, EMBO J., 22, 4103, 10.1093/emboj/cdg412

Echtay, 2005, Hydroxynonenal and uncoupling proteins: A model for protection against oxidative damage, Biofactors, 24, 119, 10.1002/biof.5520240114

Malingriaux, 2013, Fatty acids are key in 4-hydroxy-2-nonenal-mediated activation of uncoupling proteins 1 and 2, PLoS ONE, 8, e77786, 10.1371/journal.pone.0077786

Jarmuszkiewicz, 2013, Hydroxynonenal-stimulated activity of the uncoupling protein in Acanthamoeba castellanii mitochondria under phosphorylating conditions, Biol. Chem., 394, 649, 10.1515/hsz-2012-0326

Aguirre, 2010, GDP and carboxyatractylate inhibit 4-hydroxynonenal-activated proton conductance to differing degrees in mitochondria from skeletal muscle and heart, Biochim. Biophys. Acta Bioenerget., 1797, 1716, 10.1016/j.bbabio.2010.06.009

Jin, 2013, Oxidatively modified proteins as plasma biomarkers in breast cancer, Cancer Biomarkers, 13, 193, 10.3233/CBM-130349

Pillon, 2011, Structural and functional changes in human insulin induced by the lipid peroxidation byproducts 4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal, Chem. Res.Toxicol., 24, 752, 10.1021/tx200084d

Lee, 2010, Mass spectrometric characterization of modifications to angiotensin II by lipid peroxidation products, 4-oxo-2(E)-nonenal and 4-hydroxy-2(E)-nonenal, Chem. Res. Toxicol., 23, 1771, 10.1021/tx100228q

El-Bikai, R., Welman, M., Margaron, Y., Cote, J.-F., Macqueen, L., Buschmann, M.D., Fahmi, H., Shi, Q., Maghni, K., and Fernandes, J.C. (2010). Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: Implication in osteoarthritis pathogenesis. Arthritis Res. Ther., 12.

Alzolibani, 2013, 4-Hydroxy-2-nonenal modified histone-H2A: A possible antigenic stimulus for systemic lupus erythematosus autoantibodies, Cell. Immunol., 284, 154, 10.1016/j.cellimm.2013.07.011

Guichardant, 1998, Covalent modifications of aminophospholipids by 4-hydroxynonenal, Free Radic. Biol. Med., 25, 1049, 10.1016/S0891-5849(98)00149-X

Guo, 2012, Identification of novel bioactive aldehyde-modified phosphatidylethanolamines formed by lipid peroxidation, Free Radic. Biol. Med., 53, 1226, 10.1016/j.freeradbiomed.2012.07.077

Sowell, 2004, Vitamin C conjugates of genotoxic lipid peroxidation products: Structural characterization and detection in human plasma, Proc. Natl. Acad. Sci. USA, 101, 17964, 10.1073/pnas.0408433102

Sowell, 2007, Vitamin C conjugates of genotoxic lipid peroxidation products: Structural characterization and detection in human plasma, Proc. Natl. Acad. Sci. USA, 104, 14543, 10.1073/pnas.0706514104

Miranda, 2009, Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells, Chem. Res. Toxicol., 22, 863, 10.1021/tx900042u

Amarnath, 2004, Pyridoxamine: An extremely potent scavenger of 1,4-dicarbonyls, Chem. Res. Toxicol., 17, 410, 10.1021/tx0300535

Hardas, 2013, Oxidative modification of lipoic acid by HNE in Alzheimer disease brain, Redox Biol., 1, 80, 10.1016/j.redox.2013.01.002

Voulgaridou, 2011, DNA damage induced by endogenous aldehydes: Current state of knowledge, Mutat. Res. Fund. Mol. Mech. Mutagen., 711, 13, 10.1016/j.mrfmmm.2011.03.006

Minko, 2009, Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal, Chem. Res. Toxicol., 22, 759, 10.1021/tx9000489

Eckl, 1993, Genotoxic properties of 4-hydroxyalkenals and analogous aldehydes, Mutat. Res. Fund. Mol. Mech. Mutagen., 290, 183, 10.1016/0027-5107(93)90158-C

Karlhuber, 1997, Cytotoxic and genotoxic effects of 4-hydroxynonenal in cerebral endothelial cells, Mutat. Res. Fund. Mol. Mech. Mutagen., 381, 209, 10.1016/S0027-5107(97)00170-X

Wang, 2003, Site-specific synthesis and reactivity of oligonucleotides containing stereochemically defined 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal, J. Am. Chem. Soc., 125, 5687, 10.1021/ja0288800

Wacker, 2001, Detection of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal after gavage of trans-4-hydroxy-2-nonenal or induction of lipid peroxidation with carbon tetrachloride in F344 rats, Chem. Biol. Interact., 137, 269, 10.1016/S0009-2797(01)00259-9

Kozekov, 2010, Formation of deoxyguanosine cross-links from calf thymus DNA treated with acrolein and 4-hydroxy-2-nonenal, Chem. Res. Toxicol., 23, 1701, 10.1021/tx100179g

Huang, 2010, DNA Cross-link induced by trans-4-Hydroxynonenal, Environ. Mol. Mutagen., 51, 625, 10.1002/em.20599

Huang, 2011, Formation of a N2-dG:N2-dG carbinolamine DNA cross-link by the trans-4-Hydroxynonenal-derived (6S,8R,11S) 1,N2-dG adduct, J. Am. Chem. Soc., 133, 16101, 10.1021/ja205145q

Choudhury, 2013, Repair kinetics of acrolein- and (E)-4-hydroxy-2-nonenal-derived DNA adducts in human colon cell extracts, Mutat. Res. Fund. Mol. Mech. Mutagen., 751, 15, 10.1016/j.mrfmmm.2013.09.004

Choudhury, 2004, Repair kinetics of trans-4-hydroxynonenal-induced cyclic 1,N2-propanodeoxyguanine DNA adducts by human cell nuclear extracts, Biochemistry, 43, 7514, 10.1021/bi049877r

Winczura, 2012, Damage of DNA and proteins by major lipid peroxidation products in genome stability, Free Radic. Res., 46, 442, 10.3109/10715762.2012.658516

Janowska, 2009, Nucleotide excision repair and recombination are engaged in repair of trans-4-hydroxy-2-nonenal adducts to DNA bases in Escherichia coli, Int. J. Biol. Sci., 5, 611, 10.7150/ijbs.5.611

Banerjee, 2012, Replication bypass of the trans-4-Hydroxynonenal-derived (6S,8R,11S)-1,N2-deoxyguanosine DNA adduct by the Sulfolobus solfataricus DNA polymerase IV, Chem. Res. Toxicol., 25, 422, 10.1021/tx200460j

Janowska, 2012, Role of damage-specific DNA polymerases in M13 phage mutagenesis induced by a major lipid peroxidation product trans-4-hydroxy-2-nonenal, Mutat. Res. Fund. Mol. Mech. Mutagen., 729, 41, 10.1016/j.mrfmmm.2011.09.006

Chen, 1998, 2,3-Epoxy-4-hydroxynonanal, a potential lipid peroxidation product for etheno adduct formation, is not a substrate of human epoxide hydrolase, Carcinogenesis, 19, 939, 10.1093/carcin/19.5.939

Lee, 2005, 4-Hydroperoxy-2-nonenal-induced formation of 1,N2-etheno-2'-deoxyguanosine adducts, Chem. Res. Toxicol., 18, 780, 10.1021/tx0497088

Wang, 2009, Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease, Hepatology, 50, 453, 10.1002/hep.22978

Nair, 2010, High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases, Mutat. Res. Fund. Mol. Mech. Mutagen., 683, 23, 10.1016/j.mrfmmm.2009.10.002

Grune, 1997, Evaluation of purine nucleotide loss, lipid peroxidation and ultrastructural alterations in post-hypoxic hepatocytes, J. Physiol. Lond., 498, 511, 10.1113/jphysiol.1997.sp021877

Grune, 1995, Postanoxic formation of aldehydic lipid-peroxidation products in human renal tubular cells, Free Radic. Biol. Med., 18, 21, 10.1016/0891-5849(94)E0093-X

Blasig, 1995, 4-hydroxynonenal, a novel indicator of lipid-peroxidation for reperfusion injury of the myocardium, Am. J. Physiol. Heart Circ. Physiol., 269, H14, 10.1152/ajpheart.1995.269.1.H14

Grune, 1994, Metabolism of 4-hydroxynonenal, a cytotoxic lipid-peroxidation product, in ehrlich mouse ascites-cells at different proliferation stages, Cancer Res., 54, 5231

Blasig, 1994, Formation of 4-hydroxyalkenals by the reperfusion-injured rat-heart, Cell. Biochem. Mol. Asp. Reperfus. Injury, 723, 462

Siems, 1995, 4-hydroxynonenal formation during ischemia and reperfusion of rat small-intestine, Life Sci., 57, 785, 10.1016/0024-3205(95)02006-5

Poli, 1985, Separation and characterization of the aldehydic products of lipid-peroxidation stimulated by carbon-tetrachloride or adp iron in isolated rat hepatocytes and rat-liver microsomal suspensions, Biochem. J., 227, 629, 10.1042/bj2270629

Shao, 2006, Oxidative stress in head trauma in aging, Free Radic. Biol. Med., 41, 77, 10.1016/j.freeradbiomed.2006.03.007

Williams, 2006, Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease, Neurobiol. Aging, 27, 1094, 10.1016/j.neurobiolaging.2005.06.004

Auge, 2010, Pathological aspects of lipid peroxidation, Free Radic. Res., 44, 1125, 10.3109/10715762.2010.498478

Grune, 1993, Accumulation of aldehydic lipid peroxidation products during postanoxic reoxygenation of isolated rat hepatocytes, Free Radic. Biol. Med., 15, 125, 10.1016/0891-5849(93)90051-U

Schwarzer, 1996, Increased levels of 4-hydroxynonenal in human monocytes fed with malarial pigment hemozoin—A possible clue for hemozoin toxicity, FEBS Lett., 388, 119, 10.1016/0014-5793(96)00523-6

Gil, 2006, Age-associated analysis of oxidative stress parameters in human plasma and erythrocytes, Free Radic. Res., 40, 495, 10.1080/10715760600592962

Selley, 1989, Determination of the lipid-peroxidation product trans-4-hydroxy-2-nonenal in biological samples by high-performance liquid-chromatography and combined capillary column gas chromatography negative-ion chemical ionization mass-spectrometry, J. Chromatogr. Biomed. Appl., 488, 329, 10.1016/S0378-4347(00)82957-6

Schmidt, 1996, Increased levels of lipid peroxidation products malondialdehyde and 4-hydroxynonenal after perinatal hypoxia, Pediatr. Res., 40, 15, 10.1203/00006450-199607000-00003

Michel, 1997, Increased lipid peroxidation in children with autoimmune diseases, Acta Paediatr., 86, 609, 10.1111/j.1651-2227.1997.tb08943.x

Uchida, 1995, Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies, Arch. Biochem. Biophys., 324, 241, 10.1006/abbi.1995.0036

Yoritaka, 1996, Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease, Proc. Natl. Acad. Sci. USA, 93, 2696, 10.1073/pnas.93.7.2696

Okamoto, 1994, Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma, Int. J. Cancer, 58, 825, 10.1002/ijc.2910580613

Ando, 1997, Oxidative stress is found in amyloid deposits in systemic amyloidosis, Biochem. Biophys. Res. Commun., 232, 497, 10.1006/bbrc.1996.5997

Butterfield, 2006, Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment, Neurosci. Lett., 397, 170, 10.1016/j.neulet.2005.12.017

Morikawa, 1997, Increased mitochondrial damage by lipid peroxidation in trophoblast cells of preeclamptic placentas, Biochem. Mol. Biol. Int., 41, 767

Hamilton, 1998, Potential involvement of 4-hydroxynonenal in the response of human lung cells to ozone, Am. J. Physiol. Lung Cell. Mol. Physiol., 274, L8, 10.1152/ajplung.1998.274.1.L8

Liu, 2006, Detection and quantification of endogenous cyclic DNA adducts derived from trans-4-hydroxy-2-nonenal in human brain tissue by isotope dilution capillary liquid chromatography nanoelectrospray tandem mass spectrometry, Chem. Res. Toxicol., 19, 710, 10.1021/tx0502903

Surh, 2005, Estimation of daily exposure to 4-hydroxy-2-alkenals in Korean foods containing n-3 and n-6 polyunsaturated fatty acids, Food Addit. Contam., 22, 701, 10.1080/02652030500164359

Ito, 2003, Protective effect of S-allyl-L-cysteine, a garlic compound, on amyloid beta-protein-induced cell death in nerve growth factor-differentiated PC12 cells, Neurosci. Res., 46, 119, 10.1016/S0168-0102(03)00037-3

Glei, 2006, Both wheat (Triticum aestivum) bran arabinoxylans and gut flora-mediated fermentation products protect human colon cells from genotoxic activities of 4-hydroxynonenal and hydrogen peroxide, J. Agric. Food Chem., 54, 2088, 10.1021/jf052768e

Loguercio, 2005, Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases, J. Clin. Gastroenterol., 39, 540, 10.1097/01.mcg.0000165671.25272.0f

Chowdhury, 2002, Lipid peroxidation in rat brain is increased by simulated weightlessness and decreased by a soy-protein diet, Ann. Clin. Lab. Sci., 32, 188

Skrzydlewska, 2002, Protective effect of green tea against lipid peroxidation in the rat liver, blood serum and the brain, Phytomedicine, 9, 232, 10.1078/0944-7113-00119

Leiphon, 2007, Inhibition of aldehyde detoxification in CNS mitochondria by fungicides, Neurotoxicology, 28, 143, 10.1016/j.neuro.2006.08.008

Ullrich, 1994, Identification of metabolic pathways of the lipid-peroxidation product 4-hydroxynonenal by mitochondria isolated from rat-kidney cortex, FEBS Lett., 352, 84, 10.1016/0014-5793(94)00922-8

Siems, 1997, Metabolic fate of 4-hydroxynonenal in hepatocytes: 1,4-dihydroxynonene is not the main product, J. Lipid Res., 38, 612, 10.1016/S0022-2275(20)37269-2

Siems, 1998, High capacity of secondary antioxidative pathways in thymocytes: Rapid detoxification of 4-hydroxynonenal, Int. J. Thymol., 6, 518

Ullrich, 1997, Intracellular metabolism of 4-hydroxynonenal in primary cultures of rabbit synovial fibroblasts, Free Radic. Biol. Med., 22, 1153, 10.1016/S0891-5849(96)00496-0

Grune, 1997, Identification of metabolic pathways of the lipid peroxidation product 4-hydroxynonenal in in situ perfused rat kidney, J. Lipid Res., 38, 1660, 10.1016/S0022-2275(20)37184-4

Grune, 1991, Identification of metabolic pathways of the lipid-peroxidation product 4-hydroxynonenal by enterocytes of rat small-intestine, Biochem. Int., 25, 963

Petras, 1995, 4-hydroxynonenal is degraded to mercapturic acid conjugate in rat-kidney, Free Radic. Biol. Med., 19, 685, 10.1016/0891-5849(95)00060-B

Kinter, 1996, Glutathione consumption and glutathione peroxidase inactivation in fibroblast cell lines by 4-hydroxy-2-nonenal, Free Radic. Biol. Med., 21, 457, 10.1016/0891-5849(96)00128-1

Esterbauer, 1985, Metabolism of the lipid-peroxidation product 4-hydroxynonenal by isolated hepatocytes and by liver cytosolic fractions, Biochem. J., 228, 363, 10.1042/bj2280363

Fauler, G. (1987). Investigations on the Metabolism of 4-Hydroxy-Alkenals. [Ph.D. Thesis, University of Graz].

Siems, 1990, Metabolic pathways of lipid peroxidation product 4-hydroxynonenal in hepatocytes quantitative assessment of an antioxidative defense system, Free Radic. Biol. Med., 9, 110, 10.1016/0891-5849(90)90564-Y

1991, Biological effects of aldehydes with particular attention to hydroxynonenal and malondialdehyde, Membrane Lipid Peroxidation, Volume 3, 141

Esterbauer, 1991, Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes, Free Radic. Biol. Med., 11, 81, 10.1016/0891-5849(91)90192-6

Poli, G., Albano, E., and Dianzani, M.U. (1993). Free Radicals: From Basic Science to Medicine, Birkhäuser Verlag.

Siems, 1992, Qualitative and quantitative-determination of metabolites of the lipid-peroxidation product 4-hydroxynonenal from hepatocytes, enterocytes and tumor-cells, Fresenius J. Anal. Chem., 343, 75, 10.1007/BF00332017

Canuto, 1993, Effects of aldehyde products of lipid peroxidation on the activity of aldehyde metabolizing enzymes in hepatomas, Adv. Exp. Med. Biol., 328, 17, 10.1007/978-1-4615-2904-0_3

Canuto, 1993, Ability of different hepatoma-cells to metabolize 4-hydroxynonenal, Cell Biochem. Funct., 11, 79, 10.1002/cbf.290110202

Ferro, 1988, Metabolism of 4-hydroxynonenal by the rat hepatoma-cell line MH1C1, Cell Biochem. Funct., 6, 245, 10.1002/cbf.290060405

Weiner, H., Wermuth, M.B., and Crabb, D.W. (1990, January 12–15). Metabolism of 4 hydroxynonenal in hepatoma cell lines. Advances in Experimental Medicine and Biology, Vol. 284. Enzymology and Molecular Biology of Carbonyl Metabolism 3, Proceedings of the Fifth International Workshop, West Lafayette, IN, USA.

Srivastava, 2001, Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells, Atherosclerosis, 158, 339, 10.1016/S0021-9150(01)00454-3

Srivastava, 1998, Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart, J. Biol. Chem., 273, 10893, 10.1074/jbc.273.18.10893

Spitz, 1990, Cytotoxicity and metabolism of 4-hydroxy-2-nonenal and 2-nonenal in H2O2-resistant cell-lines—Do aldehydic by-products of lipid-peroxidation contribute to oxidative stress, Biochem. J., 267, 453, 10.1042/bj2670453

Meyer, 2004, Metabohom of 4-hydroxy-trans-2-nonenal by central nervous system mitochondria is dependent on age and NAD(+) availability, Chem. Res. Toxicol., 17, 1272, 10.1021/tx049843k

Canuto, 1989, Oxidative-metabolism of 4-hydroxy-2,3-nonenal during diethyl-nitrosamine-induced carcinogenesis in rat-liver, Cancer Lett., 46, 7, 10.1016/0304-3835(89)90208-5

Chen, 1996, Detoxification of reactive aldehydes in mitochondria: Effects of age and dietary restriction, Aging Clin. Exp. Res., 8, 334, 10.1007/BF03339590

Honzatko, 2005, Enantioselective metabolism of trans-4-hydroxy-2-nonenal by brain mitochondria, Free Radic. Biol. Med., 39, 913, 10.1016/j.freeradbiomed.2005.05.010

Alary, 2003, Fate of 4-hydroxynonenal in vivo: Disposition and metabolic pathways, Mol. Asp. Med., 24, 177, 10.1016/S0098-2997(03)00012-8

Alary, 1995, Mercapturic acid conjugates as urinary end metabolites of the lipid-peroxidation product 4-hydroxy-2-nonenal in the rat, Chem. Res. Toxicol., 8, 34, 10.1021/tx00043a004

Winter, 1987, Distribution of trans-4-hydroxy-2-hexenal and tandem mass-spectrometric detection of its urinary mercapturic acid in the rat, Drug Metab. Dispos., 15, 608

Alin, 1985, 4-hydroxyalk-2-enals are substrates for glutathione transferase, FEBS Lett., 179, 267, 10.1016/0014-5793(85)80532-9

Danielson, 1987, Structure-activity-relationships of 4-hydroxyalkenals in the conjugation catalyzed by mammalian glutathione transferases, Biochem. J., 247, 707, 10.1042/bj2470707

Mitchell, 1987, The oxidation of α,β-unsaturated aldehydic products of lipid-peroxidation by rat-liver aldehyde dehydrogenases, Toxicol. Appl. Pharmacol., 87, 403, 10.1016/0041-008X(87)90245-6

Mitchell, 1991, Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase mediated acetaldehyde oxidation by trans-4-hydroxy-2-nonenal, Hepatology, 13, 728

Hartley, 1995, The hepatocellular metabolism of 4-hydroxynonenal by alcohol-dehydrogenase, aldehyde dehydrogenase, and glutathione-S-transferase, Arch. Biochem. Biophys., 316, 197, 10.1006/abbi.1995.1028

Singhal, 1994, Several closely-related glutathione-S-transferase isozymes catalyzing conjugation of 4-hydroxynonenal are differentially expressed in human tissues, Arch. Biochem. Biophys., 311, 242, 10.1006/abbi.1994.1233

Berhane, 1994, Detoxication of base propenals and other α,β-unsaturated aldehyde products of radical reactions and lipid-peroxidation by human glutathione transferases, Proc. Natl. Acad. Sci. USA, 91, 1480, 10.1073/pnas.91.4.1480

Fukuda, 1997, Cellular response to the redox active lipid peroxidation products: Induction of glutathione S-transferase P by 4-hydroxy-2-nonenal, Biochem. Biophys. Res. Commun., 236, 505, 10.1006/bbrc.1997.6585

Yang, 2004, Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: Possible role in human atherosclerosis, Atherosclerosis, 173, 211, 10.1016/j.atherosclerosis.2003.12.023

Cao, 2003, The role of chemically induced glutathione and glutathione S-transferase in protecting against 4-hydroxy-2-nonenal-mediated cytotoxicity in vascular smooth muscle cells, Cardiovas. Toxicol., 3, 165, 10.1385/CT:3:2:165

Kaiserova, 2006, Redox activation of aldose reductase in the ischemic heart, J. Biol. Chem., 281, 15110, 10.1074/jbc.M600837200

Kolb, 1995, Substrate specificity of human aldose reductase: Identification of 4-hydroxynonenal as an endogenous substrate, Biochim. Biophys. Acta, 1249, 117, 10.1016/0167-4838(95)00021-L

Srivastava, 1984, Aldose and aldehyde reductases in human-tissues, Biochim. Biophys. Acta, 800, 220, 10.1016/0304-4165(84)90399-4

He, 1998, Reduction of 4-hydroxynonenal and 4-hydroxyhexenal by retinal aldose reductase, Biochem. Biophys. Res. Commun., 247, 719, 10.1006/bbrc.1998.8845

Srivastava, 2011, Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders, Chem. Biol. Interact., 191, 330, 10.1016/j.cbi.2011.02.023

Koh, 2000, Aldehyde reductase gene expression by lipid peroxidation end products, MDA and HNE, Free Radic. Res., 33, 739, 10.1080/10715760000301261

Hoehn, 2013, Protein oxidation in aging and the removal of oxidized proteins, J. Proteomics, 92, 132, 10.1016/j.jprot.2013.01.004

Grune, 1997, Breakdown of oxidized proteins as a part of secondary antioxidant defenses in mammalian cells, Biofactors, 6, 165, 10.1002/biof.5520060210

Grune, 1997, Degradation of oxidized proteins in mammalian cells, FASEB J., 11, 526, 10.1096/fasebj.11.7.9212076

Laurent, 2000, Metabolism of 4-hydroxynonenal, a cytotoxic product of lipid peroxidation, in rat precision-cut liver slices, Toxicol. Lett., 114, 203, 10.1016/S0378-4274(99)00301-X

Alary, 1998, Identification of novel urinary metabolites of the lipid peroxidation product 4-hydroxy-2-nonenal in rats, Chem. Res. Toxicol., 11, 1368, 10.1021/tx980068g

Li, 2013, 4-Hydroxy-2(E)-nonenal (HNE) catabolism and formation of HNE adducts are modulated by beta oxidation of fatty acids in the isolated rat heart, Free Rad. Biol. Med., 58, 35, 10.1016/j.freeradbiomed.2013.01.005

Kubatova, 2006, Astrocytic biotransformation of trans-4-hydroxy-2-nonenal is dose-dependent, Chem. Res. Toxicol., 19, 844, 10.1021/tx0600393

Alary, 1998, 1,4-dihydroxynonene mercapturic acid, the major end metabolite of exogenous 4-hydroxy-2-nonenal, is a physiological component of rat and human urine, Chem. Res. Toxicol., 11, 130, 10.1021/tx970139w

Laurent, 1999, Analysis in the rat of 4-hydroxynonenal metabolites excreted in bile: Evidence of enterohepatic circulation of these byproducts of lipid peroxidation, Chem. Res. Toxicol., 12, 887, 10.1021/tx9900425

Ji, 2002, Multidrug resistance-associated protein2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal, Free Rad. Biol. Med., 33, 370, 10.1016/S0891-5849(02)00906-1

Esterbauer, 1976, Reaction of cysteine with α,β-unsaturated aldehydes, Tetrahedron, 32, 285, 10.1016/0040-4020(76)87015-9

Grune, 1997, Increased levels of 4-hydroxynonenal modified proteins in plasma of children with autoimmune diseases, Free Rad. Biol. Med., 23, 357, 10.1016/S0891-5849(96)00586-2

Peiro, 2005, Dihydroxynonene mercapturic acid, a urinary metabolite of 4-hydroxynonenal, as a biomarker of lipid peroxidation, Biofactors, 24, 89, 10.1002/biof.5520240110

Volkel, 2006, Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer’s disease, Neurochem. Int., 48, 679, 10.1016/j.neuint.2005.12.003

Ramana, 2006, Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE)—Role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth, J. Biol. Chem., 281, 17652, 10.1074/jbc.M600270200

Ramana, 2006, Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition, Circulation, 114, 1838, 10.1161/CIRCULATIONAHA.106.630830

Srivastava, 2006, Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells, Diabetes, 55, 901, 10.2337/diabetes.55.04.06.db05-0932

Tammali, 2006, Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colon cancer cells, Cancer Res., 66, 9705, 10.1158/0008-5472.CAN-06-2105

Ronis, 2005, Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition, Free Rad. Biol. Med., 39, 619, 10.1016/j.freeradbiomed.2005.04.011

Arakawa, 2006, N-acetylcysteine selectively protects cerebellar granule cells from 4-hydroxynonenal-induced cell death, Neurosci. Res., 55, 255, 10.1016/j.neures.2006.03.008

Zheng, 2005, Calorie restriction delays lipid oxidative damage in Drosophila melanogaster, Aging Cell, 4, 209, 10.1111/j.1474-9726.2005.00159.x

Lee, 2004, Suppression of apoptosis by calorie restriction in aged kidney, Exp. Gerontol., 39, 1361, 10.1016/j.exger.2004.06.015

Zainal, 2000, Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle, FASEB J., 14, 1825, 10.1096/fj.99-0881com

Shoeb, 2014, 4-Hydroxynonenal in the pathogenesis and progression of human diseases, Curr. Med. Chem., 21, 230, 10.2174/09298673113209990181