DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Fabrizio Gentile; Alessia Arcaro; Stefania Pizzimenti; Martina Daga; Giovanni Paolo Cetrangolo; Chiara Dianzani; Alessio Lepore; Maria Graf; Paul R. J. Ames; Giuseppina Barrera

doi:10.3934/genet.2017.2.103

AIMS Genetics, Inhaltsverzeichnis

CC BY 4.0 · AIMS Genet 2017; 04(02): 103-137
DOI: 10.3934/genet.2017.2.103

Review

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Fabrizio Gentile

¹Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy

,

Alessia Arcaro

¹Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy

,

Stefania Pizzimenti

²Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

,

Martina Daga

²Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

,

Giovanni Paolo Cetrangolo

¹Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy

,

Chiara Dianzani

³Department of Drug Science and Technology, University of Torino, Torino, Italy

,

Alessio Lepore

⁴Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy

,

Maria Graf

⁴Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy

,

Paul R. J. Ames

⁵CEDOC, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal, and Department of Haematology, Dumfries Royal Infirmary, Dumfries, Scotland, UK

,

Giuseppina Barrera

²Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

› Institutsangaben

Abstract

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process.

The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity.

Keywords

lipid peroxidation - aldehydes - DNA adducts - cancer - inflammation - autoimmunity

Volltext

Referenzen

References
1 Csala M, Kardon T, Legeza B. et al. On the role of 4-hydroxynonenal in health and disease. Biochim Biophys Acta 2015; 1852: 826-838
2 Forman HJ. Redox signaling: An evolution from free radicals to aging. Free Radic Biol Med 2016; 97: 398-407
3 Hammer A, Ferro M, Tillian HM. et al. Effect of oxidative stress by iron on 4-hydroxynonenal formation and proliferative activity in hepatomas of different degrees of differentiation. Free Radic Biol Med 1997; 23: 26-33
4 Canuto RA, Muzio G, Maggiora M. et al. Glutathione-S-transferase, alcohol dehydrogenase and aldehyde reductase activities during diethylnitrosamine-carcinogenesis in rat liver. Cancer Lett 1993; 68: 177-183
5 Barrera G, Pizzimenti S, Dianzani MU. Lipid peroxidation: control of cell proliferation, cell differentiation and cell death. Mol Aspects Med 2008; 29: 1-8
6 Voulgaridou GP, Anestopoulos I, Franco R. et al. DNA damage induced by endogenous aldehydes: Current state of knowledge. Mutat Res 2011; 711: 13-27
7 Esterbauer H, Zollner H. Methods for determination of aldehydic lipid peroxidation products. Free Radic Biol Med 1989; 7: 197-203
8 Frijhoff J, Winyard PG, Zarkovic N. et al. Clinical Relevance of Biomarkers of Oxidative Stress. Antioxid Redox Signal 2015; 23: 1144-1170
9 Spiteller P, Kern W, Reiner J. et al. Aldehydic lipid peroxidation products derived from linoleic acid. Biochim Biophys Acta Mol Cell Biol L 2001; 1531: 188-208
10 GuÉraud F, Atalay M, Bresgen N. et al. Chemistry and biochemistry of lipid peroxidation products. Free Radic Res 2010; 44: 1098-1124
11 Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 1991; 11: 81-128
12 Kawai Y, Takeda S, Terao J. Lipidomic analysis for lipid peroxidation-derived aldehydes using gas chromatography-mass spectrometry. Chem Res Toxicol 2007; 20: 99-107
13 Schauenstein E. Autoxidation of polyunsaturated esters in water: chemical structure and biological activity of the products. J Lipid Res 1967; 8: 417-428
14 Pryor WA, Porter NA. Suggested mechanisms for the production of 4-hydroxy-2-nonenal from the autoxidation of polyunsaturated fatty acids. Free Radic Res Commun 1990; 8: 541-543
15 Benedetti A, Comporti M, Esterbauer H. Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids. Biochim Biophys Acta 1980; 620: 281-296
16 Poli G, Dianzani MU, Cheeseman KH. et al. 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 1985; 227: 629-638
17 Singh M, Kapoor A, Bhatnagar A. Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls. Chem Biol Interact 2015; 234: 261-273
18 Barrera G, Pizzimenti S, Ciamporcero ES. et al. Role of 4-hydroxynonenal-protein adducts in human disease. Antiox Redox Signal 2015; 22: 18
19 Lee SH, Blair IA. Characterization of 4-oxo-2-nonenal as a novel product of lipid peroxidation. Chem Res Toxicol 2000; 13: 698-702
20 Doorn JA, Petersen DR. Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo-2-nonenal. Chem Res Toxicol 2002; 15: 1445-1450
21 Rindgen D, Lee SH, Nakajima M. et al. Formation of a substituted 1,N6-etheno-2″-deoxyadenosine adduct by lipid hydroperoxide-mediated genration of 4-oxo-2-nonenal. Chem Res Toxicol 2000; 13: 846-852
22 Lee SH, Rindgen D, Bible RH. et al. Characterization of 2″-deoxyadenosine adducts derived from 4-oxo-2-nonenal, a novel product of lipid peroxidation. Chem Res Toxicol 2000; 13: 565-574
23 Pollack M, Oe T, Lee SH. et al. Characterization of 2″-deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Chem Res Toxicol 2003; 16: 893-900
24 Maekawa M, Kawai K, Takahashi Y. et al. Identification of 4-oxo-2-hexenal and other direct mutagens formed in model lipid peroxidation reactions as dGuo adducts. Chem Res Toxicol 2005; 19: 130-138
25 Uchida K, Kanematsu M, Sakai K. et al. Protein-bound acrolein: potential markers for oxidative stress. Proc Natl Acad Sci USA 1998; 95: 4882-4887
26 Anderson MM, Hazen SL, Hsu FF. et al. Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha, beta-unsaturated aldehydes by phagocytes at sites of inflammation. J Clin Invest 1997; 99: 424-432
27 Marnett LJ, Hurd HK, Hollstein MC. et al. Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat Res 1985; 148: 25-34
28 Niedernhofer LJ, Daniels JS, Rouzer CA. et al. Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem 2003; 278: 31426-31433
29 Marnett LJ. Oxy radicals, lipid peroxidation and DNA damage. Toxicology 2002; 181-182: 219-222
30 Kadlubar FF, Anderson KE, Haussermann S. et al. Comparison of DNA adduct levels associated with oxidative stress in human pancreas. Mutat Res 1998; 405: 125-133
31 Marnett LJ. Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 1999; 424: 83-95
32 Fink SP, Reddy GR, Marnett LJ. Mutagenicity in Escherichia coli of the major DNA adduct derived from the endogenous mutagen malondialdehyde. Proc Natl Acad Sci USA 1997; 94: 8652-8657
33 Mao H, Schnetz-Boutaud NC, Weisenseel JP. et al. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct. Proc Natl Acad Sci USA 1999; 96: 6615-6620
34 Mao H, Reddy GR, Manett LJ. et al. Solution structure of an oligodeoxynucleotide containing the malondialdehyde deoxyguanosine adduct N2-(3-oxo-1-propenyl)-dG (ring-opened M1G) positioned in a (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene. Biochemistry 1999; 38: 13491-13501
35 Stone MP, Huang H, Brown KL. et al. Chemistry and structural biology of DNA damage and biological consequences. Chem Biodivers 2011; 8: 1571-1615
36 Cohen SM, Garland EM, St John M. et al. Acrolein initiates rat urinary bladder carcinogenesis. Cancer Res 1992; 52: 3577-3581
37 Feng Z, Hu W, Hu Y. et al. Acrolein is a major cigarette-related lung cancer agent: preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl Acad Sci USA 2006; 103: 15404-15409
38 Chung FL, Chen HJ, Nath RG. Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis 1996; 17: 2105-2111
39 Chung FL, Nath RG, Nagao M. et al. Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts. Mutat Res 1999; 424: 71-81
40 Nair U, Bartsch H, Nair J. Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans. Free Radic Biol Med 2007; 43: 1109-1120
41 Zhang S, Villalta PW, Wang M. et al. Detection and quantitation of acrolein-derived 1,N2-propanodeoxyguanosine adducts in human lung by liquid chromatography-electrospray ionization-tandem mass spectrometry. Chem Res Toxicol 2007; 20: 565-571
42 Yang IY, Hossain M, Miller H. et al. Responses to the major acrolein-derived deoxyguanosine adduct in Escherichia coli. J Biol Chem 2001; 276: 9071-9076
43 Yang IY, Johnson F, Grollman AP. et al. Genotoxic mechanism for the major acrolein-derived deoxyguanosine adduct in human cells. Chem Res Toxicol 2002; 15: 160-164
44 de los Santos C, Zaliznyak T, Johnson F. NMR characterization of a DNA duplex containing the major acrolein-derived deoxyguanosine adduct gamma -OH-1,-N2-propano-2″-deoxyguanosine. J Biol Chem 2001; 276: 9077-9082
45 Nair DT, Johnson RE, Prakash L. et al. Protein-template-directed synthesis across an acrolein-derived DNA adduct by yeast Rev1 DNA polymerase. Structure 2008; 16: 239-245
46 Zaliznyak T, Boonala R, Attaluri S. et al. Solution structure of DNA containing alpha-OH-PdG: the mutagenic adduct produced by acrolein. Nucleic Acid Res 2009; 37: 2153-2163
47 Sanchez AM, Minko IG, Kurtz AJ. et al. Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived alpha-HOPdG and gamma-HOPdG regioisomeric deoxyguanosine adducts. Chem Res Toxicol 2003; 16: 1019-1028
48 Chung FL, Nath RG, Ocando J. et al. Deoxyguanosine adducts of t-4-hydroxy-2-nonenal are endogenous DNA lesions in rodents and humans: detection and potential sources. Cancer Res 2000; 60: 1507-1511
49 Cho YJ, Wang H, Kozekov ID. et al. Orientation of the crotonaldehyde-derived N2-[3-oxo-1(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5″-CpG-3″ sequence. Chem Res Toxicol 2006; 19: 1019-1029
50 Brambilla G, Sciaba L, Faggin P. et al. Cytotoxicity, DNA fragmentation and sister-chromatid exchange in Chinese hamster ovary cells exposed to the lipid peroxidation product 4-hydroxynonenal and homologousaldehydes. Mutat Res 1986; 171: 169-176
51 Cajelli E, Ferraris A, Brambilla G. Mutagenicity of 4-hydroxynonenal in V79 Chinese hamster cells. Mutat Res 1987; 190: 169-176
52 Eckl PM, Ortner A, Esterbauer H. Genotoxic properties of 4-hydroxyalkenals and analogous aldehydes. Mutat res 1993; 290: 183-192
53 Eckl P, Esterbauer H. Genotoxic effects of 4-hydroxyalkenals. Adv Biosci 1989; 76: 141-157
54 Karlhuber GM, Bauer HC, Eckl PM. Cytotoxic and genotoxic effects of 4-hydroxynonenal in cerebral endothelial cells. Mutat Res 1997; 381: 209-216
55 Wacker M, Wanek P, Eder E. Detection of q,N2-propano-deoxyguanosine 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 2001; 137: 269-283
56 Douki T, Odin F, Caillat S. et al. Predominance of the 1,N2-propano 2″-deoxyguanosine adduct among 4-hydroxy-2-nonenal-induced DNA lesions. Free Radic Biol Med 2004; 37: 62-70
57 Hu W, Feng Z, Eveleigh J. et al. The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 2002; 23: 1781-1789
58 Huang H, Wang H, Qi N. et al. Rearrangement of the (6S,8R,11S) and (6R,8S,11R) exocyclic 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal to N2-deoxyguanosine cyclic hemiacetal adducts when placed complementary to cytosine in duplex DNA. J Am Chem Soc 2008; 130: 10898-10906
59 Huang H, Wang H, Stephen LloydR. et al. Conformational interconversion of the trans-4-hydroxynonenal-derved (6S,8R,11S) 1,N2-deoxyguanosine adduct when mismatched with deoxyadenosine in DNA. Chem Res Toxicol 2009; 22: 187-200
60 Kozekov ID, Nechev LV, Sanchez A. et al. Interchain cross-linking of DNA mediated by the principal adduct of acrolein. Chem Res Toxicol 2001; 14: 1482-1485
61 Kozekov ID, Nechev LV, Moseley MS. et al. DNA interchain cross-links formed by acrolein and crotonaldehyde. J Am Chem Soc 2003; 125: 50-61
62 Wang H, Kozekov ID, Harris TM. et al. 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 2003; 125: 5687-5700
63 Cho YJ, Kim HY, Huang H. et al. Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5″-CpG-3″ sequence by the acrolein-derived gamma-OH-1,N2-propano-2″-deoxyguanosine DNA adduct. J Am Chem Soc 2005; 127: 17686-17696
64 Cho YJ, Wang H, Kozekov ID. et al. Stereospecific formation of interstrand carbinolamine DNA crosslinks by crotonaldehyde- and acetaldehyde-derived α-C_H3-Γ-OH-1,N2-propano-2″-deoxyguanosine adducts in the 5″-CpG-3″ sequence. Chem Res Toxicol 2006; 19: 195-208
65 Chen HJC, Chung FL. Epoxidation of trans-4-hydroxy-2-nonenal by fatty acid hydroperoxides and hydrogen peroxide. Chem Res Toxicol 1996; 9: 306-312
66 Sodum RS, Chung FL. Stereoselective formation of in vitro nucleic acid adducts by 2,3-epoxy-4-hydroxynonanal. Cancer Res 1991; 51: 137-143
67 Chen HJ, Gonzalez FJ, Shou M. et al. 2,3-epoxy-4-hydroxynonanal, a potential lipid peroxidation product for etheno adduct formation, is not a substrate of human epoxide hydrolase. Carcinogenesis 1998; 19: 939-943
68 Wei X, Yin H. Covalent modification of DNA by Α, Γ-unsaturated aldehydes derived from lipid peroxidation: Recent progress and challenges. Free Radic Res 2015; 49: 905-917
69 Kowalczyk P, CieŚla JM, Komisarski M. et al. Long-chain adducts of trans-4-hydroxy-2-nonenal to DNA bases cause recombination, base substitutions and frameshift mutations in M13 phage. Mutat Res 2004; 550: 33-48
70 Huang H, Kozekov ID, Kozekova A. et al. DNA cross-link induced by trans-4-hydroxynonenal. Environ Mol Mutagen 2010; 51: 625-634
71 Hussain SP, Raja K, Amstad PA. et al. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 2000; 97: 12770-12775
72 Chung FL, Pan J, Choudhury S. et al. Formation of trans-4-hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from ω-3 and ω-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation. Mutat Res 2003; 531: 25-36
73 Winczura A, Czubaty A, Winczura K. et al. Lipid peroxidation product 4-hydroxy-2-nonenal modulates base excision repair in human cells. DNA Repair (Amst) 2014; 22: 1-11
74 Tang MS, Wang HT, Hu Y. et al. Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Mol Nutr Food Res 2011; 55: 1291-1300
75 Munnia A, Amasio ME, Peluso M. Exocyclic malondialdehyde and aromatic DNA adducts in larynx tissues. Free Radic Biol Med 2004; 37: 850-858
76 Peluso M, Munnia A, Risso GG. et al. Breast fine-needle aspiration malondialdehyde deoxyguanosine adduct in breast cancer. Free Radic Res 2011; 45: 477-482
77 Lee SH, Williams MV, DuBois RN. et al. Cyclooxygenase-2-mediated DNA damage. J Biol Chem 2005; 280: 28337-28346
78 Matsuda T, Tao H, Goto M. et al. Lipid peroxidation-induced DNA adducts in human gastric mucosa. Carcinogenesis 2013; 34: 121-127
79 Lee HW, Wang HT, Weng MW. et al. Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget 2014; 5: 3526-3540
80 Parola M, Robino G, Marra F. et al. HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 1998; 102: 1942-1950
81 Ranjan D, Chen C, Johnston TD. et al. Stimulation of Epstein-Barr virus-infected human B cell growth by physiological concentrations of 4-hydroxynonenal. Cell Biochem Funct 2006; 24: 147-152
82 GuÉraud F. 4-Hydroxynonenal metabolites and adducts in pre-carcinogenic conditions and cancer. Free Radic Biol Med 2017; pii: S0891-5849(16)31121-2
83 Wu KC, Cui JY, Klaassen CD. Effect of graded Nrf2 activation on phase-I and -II drug metabolizing enzymes and transporters in mouse liver. PLoS One 2012; e39006
84 Morry J, Ngamcherdtrakul W, Yantasee W. Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. Redox Biol 2017; 11: 240-253
85 PoljŠak B, Fink R. The protective role of antioxidants in the defence against ROS/RNS-mediated environmental pollution. Oxid Med Cell Longev 2014; 2014: 671539
86 Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist 2004; 7: 97-110
87 Young O, Crotty T, O'Connell R. et al. Levels of oxidative damage and lipid peroxidation inthyroidneoplasia. Head and Neck 2010; 32: 750-756
88 Patel BP, Rawal UM, Dave TK. et al. Lipid peroxidation, total antioxidant status, and total thiol levels predict overall survival in patients with oral squamous cell carcinoma. Integrative Cancer Therapies 2007; 6: 365-372
89 Tsao SM, Yin MC, Liu WH. Oxidant stress and B vitamins status in patients with non-small cell lung cancer. Nutr Cancer 2007; 59: 8-13
90 Kumar B, Koul S, Khandrika L. et al. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 2008; 68: 1777-1785
91 Fruehauf JP, Meyskens Jr FL. Reactive oxygen species: a breath of life or death?. Clin Cancer Res 2007; 13: 789-794
92 Barrera G. Oxidative Stress and Lipid Peroxidation Products in Cancer Progression and Therapy. ISRN Oncology 2012; 137289
93 Forman HJ, Fukuto JM, Miller T. et al. The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal. Arch Biochem Biophys 2008; 477: 183-195
94 Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acid 2012
95 Awasthi SS, Singhal YC, Awasthi B. et al. RLIP76 and cancer. Clin Cancer Res 2008; 14: 4372-4377
96 Tjalkens RB, Cook LW, Petersen DR. Formation and export of the glutathione conjugate of 4-hydroxy-2,3-Enonenal(4-HNE) in hepatoma cells. Arch Biochem Biophys 1999; 361: 113-119
97 Gasparovic AC, Milkovic L, Sunjic SB. et al. Cancer growth regulation by 4-hydroxynonenal. Free Radic Biol Med 2017; pii: S0891-5849(17)30039-4
98 Zarkovic N, Ilic Z, Jurin M. et al. Stimulation of HeLa cell growth by physiological concentrations of 4-hydroxynonenal. Cell Biochem. Funct 1993; 11: 279-286
99 Zanetti D, Poli G, Vizio B. et al. 4-hydroxynonenal and transforming growth factor-beta1 expression in colon cancer. Mol Aspects Med 2003; 24: 273-280
100 Cerbone A, Toaldo C, Laurora S. et al. 4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells. Free Radic Biol Med 2007; 42: 1661-1670
101 Barrera G, Muraca R, Pizzimenti S. et al. Inhibition of c-myc expression induced by 4-hydroxynonenal, a product of lipid peroxidation, in the HL-60 human leukemic cell line. Biochem Biophys Res Commun 1994; 203: 553-561
102 Pizzimenti S, Barrera G, Dianzani MU. et al. Inhibition of D1, D2, and A-cyclin expression in HL-60 cells by the lipid peroxydation product 4-hydroxynonenal. Free Radic Biol Med 1999; 26: 1578-1586
103 Pizzimenti S, Briatore F, Laurora S. et al. 4-Hydroxynonenal inhibits telomerase activity and hTERT expression in human leukemic cell lines. Free Radic Biol Med 2006; 40: 1578-1591
104 Albright CD, Klem E, Shah AA. et al. Breast cancer cell-targeted oxidative stress: enhancement of cancer cell uptake of conjugated linoleic acid, activation of p53, and inhibition of proliferation. Exp Mol Pathol 2005; 79: 118-125
105 Sunjic SB, Cipak A, Rabuzin F. et al. The influence of 4-hydroxy-2-nonenal on proliferation, differentiation and apoptosis of human osteosarcoma cells. Biofactors 2005; 24: 141-148
106 Pettazzoni P, Pizzimenti S, Toaldo C. et al. Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells. Free Radic Biol Med 2011; 50: 313-322
107 Chaudhary P, Sharma R, Sahu M. et al. 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 2013; 288: 20532-20546
108 Ji GR, Yu NC, Xue X. et al. 4-Hydroxy-2-nonenal induces apoptosis by inhibiting AKT signaling in human osteosarcoma cells. Scientific World Journal 2014; 2014: 873525
109 Cao ZG, Xu X, Xue YM. et al. Comparison of 4-hydroxynonenal-induced p53-mediated apoptosis in prostate cancer cells LNCaP and DU145. Contemp Oncol (Pozn) 2014; 18: 22-28
110 Bauer G, Zarkovic N. Revealing mechanisms of selective, concentration-dependent potentials of 4-hydroxy-2-nonenal to induce apoptosis in cancer cells through inactivation of membrane-associated catalase. Free Radic Biol Med 2015; 81: 128-144
111 Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014; 740: 364-378
112 Thorn CF, Oshiro C, Marsh S. et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011; 21: 440-446
113 Casares C, RamÍrez-Camacho R, Trinidad A. et al. Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol 2012; 269: 2455-2459
114 Cipak A, Jaganjac M, Tehlivets O. et al. Adaptation to oxidative stress induced by polyunsaturated fatty acids in yeast. Biochim Biophys Acta 2008; 1781: 283-287
115 Awasthi YC, Yang Y, Tiwari NK. et al. Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases. Free Radic Biol Med 2004; 37: 607-619
116 Traverso N, Ricciarelli R, Nitti M. et al. Role of glutathione in cancer progression and chemoresistance. Oxid Med Cell Longev 2013; 2013: 972913
117 Furfaro AL, Traverso N, Domenicotti C. et al. The Nrf2/HO-1 axis in cancer cell growth and chemoresistance. Oxid Med Cell Longev 2016; 2016: 1958174
118 Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?. Nat Rev Drug Discov 2009; 8: 579-591
119 Trachootham D, Zhou Y, Zhang H. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 2006; 10: 241-252
120 Trachootham D, Zhang H, Zhang W. et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood 2008; 112: 1912-1922
121 Zhang H, Trachootham D, Lu W. et al. Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia 2008; 22: 1191-1199
122 Oberley TD, Toyokuni S, Szweda LI. Localization of hydroxyl-nonenal protein adducts in normal human kidney and selected human kidney cancers. Free Radic Biol Med 1999; 27: 695-703
123 Skrzydlewska E, Stankiewicz A, Sulkowska M. et al. Antioxidant status and lipid peroxidation in colorectal cancer. J Toxicol Environ Health 2001; 64: 213-222
124 Juric-Sekhar G, Zarkovic K, Waeg G. et al. Distribution of 4-hydroxynonenal-protein conjugates as a marker of LPO and parameter of malignancy in astrocytic and ependymal tumors of the brain. Tumori 2009; 95: 762-768
125 Karihtala P, Kauppila S, Puistola U. et al. Divergent behaviour of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2 nonenal (HNE) in breast carcinogenesi. Histopathology 2011; 58: 854-862
126 Dianzani MU. 4-Hydroxynonenal from pathology to physiology. Mol Aspects Med 2003; 24: 263-272
127 Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 2003; 42: 318-343
128 Cohen G, Riahi Y, Sasson S. Lipid peroxidation of poly-unsaturated fatty acids in normal and obese adipose tissues. Arch Physiol Biochem 2011; 117: 131-139
129 White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 2002; 283: 413-422
130 Leonarduzzi G, Chiarpotto E, Biasi F. et al. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Mol Nutr Food Res 2005; 49: 1044-1049
131 Arcaro A, Daga M, Cetrangolo GP. et al. Generation of adducts of 4-hydroxy-2-nonenal with heat shock 60 kDa protein 1 in human prolyelocytic HL-60 and monocytic THP-1 cell lines. Oxid Med Cell Longev 2015; 2015: 296146
132 Calderwood SK, Stevenson MA, Murshid A. Heat shock proteins, autoimmunity, and cancer treatment. Autoimmune Dis 2012; 2012: 486069
133 Grundtman C, Kreutmayer SB, Almanzar G. et al. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31: 960-968
134 NÈgre-Salvayre A, Garoby-Salom S. et al. Proatherogenic effects of 4-hydroxynonenal. Free Radic Biol Med 2016; pii: S0891-5849(16)31138-8
135 Gargiulo S, Testa G, Gamba P. et al. Oxysterols and 4-hydroxy-2-nonenal contribute to atherosclerotic plaque destabilization. Free Radic Biol Med 2017; pii: S0891-5849(16)31139-X
136 Li CJ, Nanji AA, Siakotos AN. et al. Acetaldehyde-modified and 4-hydroxynonenal-modified proteins in the livers of rats with alcoholic liver disease. Hepatology 1997; 26: 650-657
137 McKim SE, Uesugi T, Raleigh JA. et al. Chronic intragastric alcohol exposure causes hypoxia and oxidative stress in the rat pancreas. Arch Biochem Biophys 2003; 417: 34-43
138 Turk PW, Laayoun A, Smith SS. et al. DNA adduct 8-hydroxyl-2″-deoxyguanosine (8-hydroxyguanine) affects function of human DNA methyltransferase. Carcinogenesis 1995; 16: 1253-1255
139 Nair J, Godschalk RW, Nair U. et al. Identification of 3,N(4)-etheno-5-methyl-2″-deoxycytidine in human DNA: a new modified nucleoside which may perturb genome methylation. Chem Res Toxicol 2012; 25: 162-169
140 Yara S, Lavoie JC, Beaulieu JF. et al. Iron-ascorbate-mediated lipid peroxidation causes epigenetic changes in the antioxidant defense in intestinal epithelial cells: impact on inflammation. PLoS One 2013; 8: e63456
141 Nair J, Gansauge F, Beger H. et al. Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis. Antioxid Redox Signal 2006; 8: 1003-1010
142 Nair J, Srivatanakul P, Haas C. et al. High urinary excretion of lopid peroxidation-derived DNA damage in patients with cancer-prone liver diseases. Mutat Res 2010; 683: 23-28
143 Pizzimenti S, Ciamporcero E, Daga M. et al. Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Frontiers Physiol 2013; 4: 242
144 Barrera G, Pizzimenti S, Daga M. et al. Aldehydes derived from lipid peroxidation in cancer and autoimmunity. CatalÁ Angel. Lipid Peroxidation: Inhibition, Effects and Mechanisms. New York: Nova Science Publishers, Inc; 2016
145 Weismann D, Binder CJ. The innate immune response to products of phospholipid peroxidation. Biochim Biophysica Acta 2012; 1818: 2465-2475
146 Chou MY, Fogelstrand L, Hartvigsen K. et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 2009; 119: 1335-1349
147 Ohki I, Ishigaki T, Oyama T. et al. Crystal structure of human lectin-like, oxidized low-density lipoprotein receptor 1 ligand binding domain and its ligand recognition mode to OxLDL. Structure 2005; 13: 905-917
148 Nickel T, Schmauss D, Hanssen H. et al. OxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation. Atherosclerosis 2009; 205: 442-450
149 Wuttge DM, Bruzelius M, Stemme S. T-cell recognition of lipid peroxidation products breaks tolerance to self proteins. Immunology 1999; 98: 273-279
150 Scofield RH, Kurien BT, Ganick S. et al. Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading. Free Radic Biol Med 2005; 38: 719-728
151 Kurien BT, Hensley K, Bachmann M. et al. Oxidatively modified autoantigens in autoimmune diseases. Free Radic Biol Med 2006; 41: 549-556
152 Kurien BT, Scofield RH. Autoantibody determination in the diagnosis of systemic lupus erythematosus. Scand J Immunol 2006; 64: 227-235
153 Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in sistemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994; 179: 1317-1330
154 Miranda-CarÚs M-E, Askanase AD, Clancy RM. et al. Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-α by macrophages. J Immunol 2000; 165: 5345-5351
155 Savill J, Dransfield I, Gregory C. et al. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2002; 2: 965-975
156 Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosys of lymphocytes from patients with systemic lupus erythematosus. J Immunol 1994; 152: 3685-3692
157 Georgescu L, Vakkalanka RK, Elkon KB. et al. Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. J Clin Invest 1997; 100: 2622-2633
158 Ren Y, Tang J, Mok MY. et al. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 2003; 48: 2888-2897
159 Zeher M, Szodoray P, Gyimesi E. et al. Correlation of increased susceptibility to apoptosis of CD4⁺ T cells with lymphocyte activation and activity of disease in patients with primary SjÖgren's syndrome. Arthritis Rheum 1999; 42: 1673-1681
160 Espinosa A, Zhou W, Ek M. et al. The SjÖgren's Sydrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J Immunol 2006; 176: 6277-6285
161 Licht R, Dieker JWC, Jacobs CWM. et al. Decreased phagocytosis of apoptotic cells in diseased SLE mice. J Autoimmun 2004; 22: 139-145
162 Pan Z-J, Davis K, Maier S. et al. Neo-epitopes are required for immunogenicity of the La/SS-B nuclear antigen in the context of late apoptotic cells. Clin Experim Immunol 2006; 143: 237-248
163 Kurien T, Porter A, Dorri Y. et al. Degree of modification of Ro60 by the lipid peroxidation by-product 4-hydroxy-2-nonenal may differentially induce SjÖgren's syndrome or sistemic lupus erythematosus in BALB/c mice. Free Radic Biol Med 2011; 50: 1222-1233
164 Khan FMoinuddin, Mir AR. et al. Immunochemical studies on HNE-modified HSA: Anti-HNE-HSA antibodies as a probe for HNE damaged albumin in SLE. Int J Biol Macromol 2016; 86: 145-154
165 Khatoon FMoinuddin, Alam K. et al. Physicochemical and immunological studies on 4-hydroxynonenal modified HSA: Implications of protein damage by lipid peroxidation products in the etiopathogenesis of SLE. Hum Immunol 2012; 73: 1132-1139
166 Chen Q, Esterbauer H, Jurgens H. Studies on epitopes on low-density lipoprotein modified by 4-hydroxynonenal. Biochemical characterization and determination. Biochemical J 1992; 288: 249-254
167 Uchida K, Szweda LI, Chae HZ. et al. Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes. Proc Natl Acad Sci USA 1993; 90: 8742-8746
168 Hashimoto M, Shibata T, Wasada H. et al. Structural basis of protein-bound endogenous aldehydes. Chemical and immunochemical characterization of configurational isomers of a 4-hydroxy-2-nonenal-histidine adduct. J Biol Chem 2003; 278: 5044-5051
169 Akagawa M, Ito S, Toyoda K. et al. Bispecific Abs against modified protein and DNA with oxidized lipids. Proc Natl Acad Sci USA 2006; 103: 6160-6165
170 Toyoda K, Nagae R, Akagawa M. et al. Protein-bound 4-hydroxy-2-nonenal. An endogenous triggering antigen of anti-DNA response. J Biol Chem 2007; 282: 25769-25778
171 Al-Shobaili HA, Al Robaee AA, Alzolibani AA. et al. Antibodies against 4-hydroxy-2-nonenal modified epitopes recognized chromatin and its oxidized forms: role of chromatin, oxidized forms of chromatin and 4-hydroxy-2-nonenal modified epitopes on the etiopathogenesis of SLE. Disease Markers 2012; 33: 19-34
172 Seki S, Kitada T, Yamada T. et al. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver disease. J Hepatol 2002; 37: 56-62
173 Chalasani N, Deeg MA, Crabb DW. Systemic lipid peroxidation and its metabolic and dietary correlates in patients with non-alcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 1497-1502
174 Nobili V, Parola M, Alisi A. et al. Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Molec Med 2010; 26: 471-476
175 Teufel U, Peccerella T, Engelmann G. et al. Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH). Hepatobiliary Surg Nutr 2015; 4: 426-35
176 Ogawa M, Matsuda T, Ogata A. et al. DNA damage in rheumatoid arthritis: an age-dependent increase in the lipid peroxidation-derived DNA adduct, heptanone-etheno-2╙-deoxycytidine. Autoimmune Dis 2013; 2013: 183487
177 Wang G, Pierangeli SS, Papalardo E. et al. Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. Arthritis Rheum 2010; 62: 2064-2072