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Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

  • Chemical and Molecular Toxicology (J Bolton, Section Editor)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

The purpose of this review is to summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease.

Recent Findings

The newly developed 2-aminomethylphenol class of scavengers shows great promise in preclinical trials for a number of diverse conditions including neurodegenerative diseases and cardiovascular disease. In addition, new studies with the thiol-based and imidazole-based scavengers have found new applications outside of adjunctive therapy for chemotherapeutics.

Summary

Reactive oxygen species (ROS) generated by cells and tissues not only act as signaling molecules and as cytotoxic agents to defend against pathogens but ROS also cause collateral damage to vital cellular components. The polyunsaturated fatty acyl chains of phospholipids in cell membranes are particularly vulnerable to damaging peroxidation by ROS. Evidence suggests that the breakdown of these peroxidized lipids to reactive carbonyls species plays a critical role in many chronic diseases. Antioxidants that abrogate ROS-induced formation of reactive carbonyl species also abrogate normal ROS signaling and thus exert both beneficial and adverse functional effects. The use of scavengers of reactive dicarbonyl species represents an alternative therapeutic strategy to potentially mitigate the adverse effects of ROS without abrogating normal signaling by ROS. In this review, we focus on three classes of reactive carbonyl species scavengers: thiol-based scavengers (2-mercaptoethanesulfonate and amifostine), imidazole-based scavengers (carnosine and its analogs), and 2-aminomethylphenol-based scavengers (pyridoxamine, 2-hydroxybenzylamine, and 5′-O-pentyl-pyridoxamine) that are either undergoing preclinical studies, advancing to clinical trials, or are already in clinical use.

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Abbreviations

ACR:

Acrolein

AngII:

Angiotensin II

BSA:

Bovine serum albumin

CEL:

N-carboxy-ethyl-lysine

CML:

N-carboxy-methyl-lysine

FDP:

Nɛ-(3-formyl-3,4-dehydropiperidino)

HNE:

4-Hydroxynonenal

2-HOBA:

2-Hydroxybenzylamine or salicylamine

HO•− :

Hydroxyl radical

IsoLG:

Isolevuglandin

MDA:

Malondialdehyde

MESNA:

2-Mercaptoethanesulfonate

MG-H1:

5-Methylimidazol-4-one

MGO:

Methylglycoxal

ONE:

4-Oxo-2-nonenal

PE:

Phosphatidylethanolamine

PM:

Pyridoxamine

PPM:

5′-O-pentyl-pyridoxamine

PUFA:

Polyunsaturated fatty acids

RAGE:

Receptor for Advanced Glycation Endproducts

STZ:

Streptozotocin

TBARS:

Thiobarbituric acid reactive substances

TNF:

Tumor necrosis factor

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2004;24(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  2. Freedman BI, Wuerth J-P, Cartwright K, Bain RP, Dippe S, Hershon K, et al. Design and baseline characteristics for the aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II). Control Clin Trials. 1999;20(5):493–510. doi:10.1016/S0197-2456(99)00024-0.

    Article  CAS  PubMed  Google Scholar 

  3. Brown BE, Mahroof FM, Cook NL, van Reyk DM, Davies MJ. Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins. Diabetologia. 2006;49(4):775–83. doi:10.1007/s00125-006-0137-3.

    Article  CAS  PubMed  Google Scholar 

  4. Liu W, Porter NA, Schneider C, Brash AR, Yin H. Formation of 4-hydroxynonenal from cardiolipin oxidation: intramolecular peroxyl radical addition and decomposition. Free Radic Biol Med. 2011;50(1):166–78. doi:10.1016/j.freeradbiomed.2010.10.709.

    Article  CAS  PubMed  Google Scholar 

  5. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128.

    Article  CAS  PubMed  Google Scholar 

  6. Uchida K, Stadtman ER. Modification of histidine residues in proteins by reaction with 4-hydroxynonenal. Proc Natl Acad Sci U S A. 1992;89(10):4544–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sayre LM, Arora PK, Iyer RS, Salomon RG. Pyrrole formation from 4-hydroxynonenal and primary amines. Chem Res Toxicol. 1993;6(1):19–22.

    Article  CAS  PubMed  Google Scholar 

  8. Brame CJ, Salomon RG, Morrow JD, Roberts 2nd LJ. Identification of extremely reactive gamma-ketoaldehydes (isolevuglandins) as products of the isoprostane pathway and characterization of their lysyl protein adducts. J Biol Chem. 1999;274(19):13139–46.

    Article  CAS  PubMed  Google Scholar 

  9. Zhao J, Chen J, Zhu H, Xiong YL. Mass spectrometric evidence of malonaldehyde and 4-hydroxynonenal adductions to radical-scavenging soy peptides. J Agric Food Chem. 2012;60(38):9727–36. doi:10.1021/jf3026277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guichardant M, Taibi-Tronche P, Fay LB, Lagarde M. Covalent modifications of aminophospholipids by 4-hydroxynonenal. Free Radic Biol Med. 1998;25(9):1049–56.

    Article  CAS  PubMed  Google Scholar 

  11. Linhart KB, Glassen K, Peccerella T, Waldherr R, Linhart H, Bartsch H, et al. The generation of carcinogenic etheno-DNA adducts in the liver of patients with nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr. 2015;4(2):117–23. doi:10.3978/j.issn.2304-3881.2015.01.14.

    PubMed  PubMed Central  Google Scholar 

  12. Itakura K, Osawa T, Uchida K. Structure of a fluorescent compound formed from 4-hydroxy-2-nonenal and N(alpha)-hippuryllysine: a model for fluorophores derived from protein modifications by lipid peroxidation. J Org Chem. 1998;63(1):185–7.

    Article  CAS  PubMed  Google Scholar 

  13. Liu Y, Xu G, Sayre LM. Carnosine inhibits (E)-4-hydroxy-2-nonenal-induced protein cross-linking: structural characterization of Carnosine–HNE adducts. Chem Res Toxicol. 2003;16(12):1589–97. doi:10.1021/tx034160a.

    Article  CAS  PubMed  Google Scholar 

  14. Marchette LD, Wang H, Li F, Babizhayev MA, Kasus-Jacobi A. Carcinine has 4-hydroxynonenal scavenging property and neuroprotective effect in mouse retina. Invest Ophthalmol Vis Sci. 2012;53(7):3572–83. doi:10.1167/iovs.11-9042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Menini S, Iacobini C, Ricci C, Scipioni A, Fantauzzi CB, Giaccari A, et al. D-carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br J Pharmacol. 2012;166(4):1344–56. doi:10.1111/j.1476-5381.2012.01834.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Davies SS, Brantley EJ, Voziyan PA, Amarnath V, Zagol-Ikapitte I, Boutaud O, et al. Pyridoxamine analogues scavenge lipid-derived gamma-ketoaldehydes and protect against H2O2-mediated cytotoxicity. Biochemistry. 2006;45(51):15756–67. doi:10.1021/bi061860g.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. • Amarnath V, Amarnath K. Scavenging 4-oxo-2-nonenal. Chem Res Toxicol. 2015;28(10):1888–90. doi:10.1021/acs.chemrestox.5b00301. Describes novel pathway by which 2-aminomethylphenols react with ONE

    Article  CAS  PubMed  Google Scholar 

  18. • Vidal N, Cavaille JP, Graziani F, Robin M, Ouari O, Pietri S, et al. High throughput assay for evaluation of reactive carbonyl scavenging capacity. Redox Biol. 2014;2:590–8. doi:10.1016/j.redox.2014.01.016. Method of rapidly assessing lipid dicarbonyl reactivities and scavengers by use of fluorescent labeling

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang WH, Liu J, Xu G, Yuan Q, Sayre LM. Model studies on protein side chain modification by 4-oxo-2-nonenal. Chem Res Toxicol. 2003;16(4):512–23. doi:10.1021/tx020105a.

    Article  CAS  PubMed  Google Scholar 

  20. Galligan JJ, Rose KL, Beavers WN, Hill S, Tallman KA, Tansey WP, et al. Stable histone adduction by 4-oxo-2-nonenal: a potential link between oxidative stress and epigenetics. J Am Chem Soc. 2014;136(34):11864–6. doi:10.1021/ja503604t.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stevens JF, Maier CS. Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. Mol Nutr Food Res. 2008;52(1):7–25. doi:10.1002/mnfr.200700412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang Y, Yang Y, Trent MB, He N, Lick SD, Zimniak P, et al. Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis. Atherosclerosis. 2004;173(2):211–21. doi:10.1016/j.atherosclerosis.2003.12.023.

    Article  CAS  PubMed  Google Scholar 

  23. Kehrer JP, Biswal SS. The molecular effects of acrolein. Toxicol Sci. 2000;57(1):6–15. doi:10.1093/toxsci/57.1.6.

    Article  CAS  PubMed  Google Scholar 

  24. Zemski Berry KA, Murphy RC. Characterization of acrolein-glycerophosphoethanolamine lipid adducts using electrospray mass spectrometry. Chem Res Toxicol. 2007;20(9):1342–51. doi:10.1021/tx700102n.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Uchida K, Kanematsu M, Sakai K, Matsuda T, Hattori N, Mizuno Y, et al. Protein-bound acrolein: potential markers for oxidative stress. Proc Natl Acad Sci U S A. 1998;95(9):4882–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McCall MR, Tang JY, Bielicki JK, Forte TM. Inhibition of lecithin-cholesterol acyltransferase and modification of HDL apolipoproteins by aldehydes. Arterioscler Thromb Vasc Biol. 1995;15(10):1599–606. doi:10.1161/01.atv.15.10.1599.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Q, Sun Z, Jiang Y, Chen F, Wang M. Acrolein scavengers: reactivity, mechanism and impact on health. Mol Nutr Food Res. 2011;55(9):1375–90. doi:10.1002/mnfr.201100149.

    Article  CAS  PubMed  Google Scholar 

  28. Bispo VS, de Arruda Campos IP, Di Mascio P, Medeiros MHG. Structural elucidation of a carnosine-acrolein adduct and its quantification in human urine samples. Scientific Reports. 2016;6:19348. doi:10.1038/srep19348. http://www.nature.com/articles/srep19348#supplementary-information

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Salomon RG, Miller DB. Levuglandins: isolation, characterization, and total synthesis of new secoprostanoid products from prostaglandin endoperoxides. Adv Prostaglandin Thromboxane Leukot Res. 1985;15:323–6.

    CAS  PubMed  Google Scholar 

  30. Salomon RG, Jirousek MR, Ghosh S, Sharma RB. Prostaglandin endoperoxides 21. Covalent binding of levuglandin E2 with proteins. Prostaglandins. 1987;34(5):643–56.

    Article  CAS  PubMed  Google Scholar 

  31. Salomon RG, Subbanagounder G, Singh U, O’Neil J, Hoff HF. Oxidation of low-density lipoproteins produces levuglandin-protein adducts. Chem Res Toxicol. 1997;10(7):750–9. doi:10.1021/tx970016b.

    Article  CAS  PubMed  Google Scholar 

  32. Boutaud O, Brame CJ, Salomon RG, Roberts 2nd LJ, Oates JA. Characterization of the lysyl adducts formed from prostaglandin H2 via the levuglandin pathway. Biochemistry. 1999;38(29):9389–96. doi:10.1021/bi990470+.

    Article  CAS  PubMed  Google Scholar 

  33. Zagol-Ikapitte I, Bernoud-Hubac N, Amarnath V, Roberts 2nd LJ, Boutaud O, Oates JA. Characterization of bis(levuglandinyl) urea derivatives as products of the reaction between prostaglandin H2 and arginine. Biochemistry. 2004;43(18):5503–10. doi:10.1021/bi049842r.

    Article  CAS  PubMed  Google Scholar 

  34. Carrier EJ, Amarnath V, Oates JA, Boutaud O. Characterization of covalent adducts of nucleosides and DNA formed by reaction with levuglandin. Biochemistry. 2009;48(45):10775–81. doi:10.1021/bi9015132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. DiFranco E, Subbanagounder G, Kim S, Murthi K, Taneda S, Monnier VM, et al. Formation and stability of pyrrole adducts in the reaction of levuglandin E2 with proteins. Chem Res Toxicol. 1995;8(1):61–7.

    Article  CAS  PubMed  Google Scholar 

  36. • Bi W, Jang GF, Zhang L, Crabb JW, Laird J, Linetsky M, et al. Molecular structures of isolevuglandin-protein cross-links. Chem Res Toxicol. 2016;29(10):1628–40. doi:10.1021/acs.chemrestox.6b00141. Determination of the IsoLG crosslink structures and their dependence on protein sequence and other factors

    Article  CAS  PubMed  Google Scholar 

  37. Guo L, Chen Z, Cox BE, Amarnath V, Epand RF, Epand RM, et al. Phosphatidylethanolamines modified by gamma-ketoaldehyde (gammaKA) induce endoplasmic reticulum stress and endothelial activation. J Biol Chem. 2011;286(20):18170–80. doi:10.1074/jbc.M110.213470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. • Guo L, Chen Z, Amarnath V, Yancey PG, Van Lenten BJ, Savage JR, et al. Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts. Antioxid Redox Signal. 2015;22(18):1633–45. doi:10.1089/ars.2014.6078. Identifies IsoLG-PE as a mediator of macrophage activation via the RAGE receptor, and therefore a likely target of RCS scavenging

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. •• Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, et al. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest. 2014;124(10):4642–56. doi:10.1172/JCI74084. Revealed a novel mechanisms by which IsoLG generation of neo-epitopes mediated hypertension and that 2-aminomethylphenols blocked development of hypertension

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. • Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KR, Xiao L, et al. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest. 2016;126(4):1607. doi:10.1172/JCI87425. Pre-clinical study demonstrating that generation of IsoLG by NADPH oxidase contributes to aortic stiffening and hypertension and that 2-hydroxybenzylamine prevents this

    Article  Google Scholar 

  41. Nakajima T, Davies SS, Matafonova E, Potet F, Amarnath V, Tallman KA, et al. Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation. J Mol Cell Cardiol. 2010;48(2):352–9. doi:10.1016/j.yjmcc.2009.11.016.

    Article  CAS  PubMed  Google Scholar 

  42. Boyden PA, Davies SS, Viswanathan PC, Amarnath V, Balser JR, Roberts 2nd LJ. Potential role of isoketals formed via the isoprostane pathway of lipid peroxidation in ischemic arrhythmias. J Cardiovasc Pharmacol. 2007;50(5):480–6. doi:10.1097/FJC.0b013e31815a0564.

    Article  CAS  PubMed  Google Scholar 

  43. Fukuda K, Davies SS, Nakajima T, Ong BH, Kupershmidt S, Fessel J, et al. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circ Res. 2005;97(12):1262–9. doi:10.1161/01.RES.0000195844.31466.e9.

    Article  CAS  PubMed  Google Scholar 

  44. • Sidorova TN, Yermalitskaya LV, Mace LC, Wells KS, Boutaud O, Prinsen JK, et al. Reactive gamma-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells. J Mol Cell Cardiol. 2015;79:295–302. doi:10.1016/j.yjmcc.2014.11.013. Demonstration of 4-ketoaldehydes promoting the formation of preamyloid oligomers and the protective effects of 2-hydroxybenzylamine

    Article  CAS  PubMed  Google Scholar 

  45. Davies SS, Amarnath V, Montine KS, Bernoud-Hubac N, Boutaud O, Montine TJ, et al. Effects of reactive gamma-ketoaldehydes formed by the isoprostane pathway (isoketals) and cyclooxygenase pathway (levuglandins) on proteasome function. FASEB J. 2002;16(7):715–7. doi:10.1096/fj.01-0696fje.

    CAS  PubMed  Google Scholar 

  46. Foreman D, Levison BS, Miller DB, Salomon RG. Anhydrolevuglandin D2 inhibits the uterotonic activity of prostaglandins F2 alpha and D2. Prostaglandins. 1988;35(1):115–22.

    Article  CAS  PubMed  Google Scholar 

  47. Pryor WA, Stanley JP. Letter: a suggested mechanism for the production of malonaldehyde during the autoxidation of polyunsaturated fatty acids. Nonenzymatic production of prostaglandin endoperoxides during autoxidation. J Org Chem. 1975;40(24):3615–7.

    Article  CAS  PubMed  Google Scholar 

  48. Chio KS, Tappel AL. Synthesis and characterization of the fluorescent products derived from malonaldehyde and amino acids. Biochemistry. 1969;8(7):2821–6.

    Article  CAS  PubMed  Google Scholar 

  49. Marnett LJ. Chemistry and biology of DNA damage by malondialdehyde. IARC Sci Publ. 1999;150:17–27.

    CAS  Google Scholar 

  50. Shuck SC, Wauchope OR, Rose KL, Kingsley PJ, Rouzer CA, Shell SM, et al. Protein modification by adenine propenal. Chem Res Toxicol. 2014;27(10):1732–42. doi:10.1021/tx500218g.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zagol-Ikapite I, Sosa IR, Oram D, Judd A, Amarnath K, Amarnath V, et al. Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers. J Lipid Res. 2015;56(11):2196–205. doi:10.1194/jlr.P063271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li X, Yang S, Lv X, Sun H, Weng J, Liang Y, et al. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats. J Gynecol Oncol. 2013;24(2):177–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Kabasakal L, Şehirli AÖ, Çetinel Ş, Cikler E, Gedik N, Şener G. Mesna (2-mercaptoethane sulfonate) prevents ischemia/reperfusion induced renal oxidative damage in rats. Life Sci. 2004;75(19):2329–40. doi:10.1016/j.lfs.2004.04.029.

    Article  CAS  PubMed  Google Scholar 

  54. Aydin AF, Kusku-Kiraz Z, Dogru-Abbasoglu S, Uysal M. Effect of carnosine treatment on oxidative stress in serum, apoB-containing lipoproteins fraction and erythrocytes of aged rats. Pharmacol Rep. 2010;62(4):733–9.

    Article  CAS  PubMed  Google Scholar 

  55. Nagasawa T, Yonekura T, Nishizawa N, Kitts DD. In vitro and in vivo inhibition of muscle lipid and protein oxidation by carnosine. Mol Cell Biochem. 2001;225(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  56. • Rabbani N, Xue M, Thornalley PJ. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments. Clin Sci. 2016;130(19):1677–96. doi:10.1042/cs20160025. Excellent review describing the formation, metabolism, and consequences of dicarbonyl stress in various diseases and emerging dicarbonyl-targeting therapeutics.

    Article  PubMed  Google Scholar 

  57. Allaman I, Bélanger M, Magistretti PJ. Methylglyoxal, the dark side of glycolysis. Front Neurosci. 2015;9:23. doi:10.3389/fnins.2015.00023.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lo TW, Westwood ME, McLellan AC, Selwood T, Thornalley PJ. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. J Biol Chem. 1994;269(51):32299–305.

    CAS  PubMed  Google Scholar 

  59. Ahmed MU, Brinkmann Frye E, Degenhardt TP, Thorpe SR, Baynes JW. N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins. Biochem J. 1997;324(Pt 2):565–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brinkmann E, Wells-Knecht KJ, Thorpe SR, Baynes JW. Characterization of an imidazolium compound formed by reaction of methylglyoxal and N-alpha-hippuryllysine. J Chem Soc Perkin Trans. 1995;22:2817–8.

    Article  Google Scholar 

  61. Rabbani N, Xue M, Thornalley PJ. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconj J. 2016;33:513–25. doi:10.1007/s10719-016-9705-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998;248(1):28–32. doi:10.1006/bbrc.1998.8806.

    Article  CAS  PubMed  Google Scholar 

  63. Nagaraj RH, Sarkar P, Mally A, Biemel KM, Lederer MO, Padayatti PS. Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal. Arch Biochem Biophys. 2002;402(1):110–9. doi:10.1016/S0003-9861(02)00067-X.

    Article  CAS  PubMed  Google Scholar 

  64. Fuchs P, Loeseken C, Schubert JK, Miekisch W. Breath gas aldehydes as biomarkers of lung cancer. Int J Cancer. 2010;126(11):2663–70. doi:10.1002/ijc.24970.

    CAS  PubMed  Google Scholar 

  65. Alhamdani MSS, Al-Kassir AHAM, Jaleel NA, Hmood AM, Ali HM. Elevated levels of alkanals, alkenals and 4-HO-alkenals in plasma of hemodialysis patients. Am J Nephrol. 2006;26(3):299–303.

    Article  CAS  PubMed  Google Scholar 

  66. Corradi M, Pignatti P, Manini P, Andreoli R, Goldoni M, Poppa M, et al. Comparison between exhaled and sputum oxidative stress biomarkers in chronic airway inflammation. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2004;24(6):1011–7. doi:10.1183/09031936.04.00002404.

    Article  CAS  Google Scholar 

  67. Jalali M, Zare Sakhvidi MJ, Bahrami A, Berijani N, Mahjub H. Oxidative stress biomarkers in exhaled breath of workers exposed to crystalline silica dust by SPME-GC-MS. J Res Health Sci. 2016;16(3):153–61.

    PubMed  Google Scholar 

  68. Zhou S, Decker EA. Ability of amino acids, dipeptides, polyamines, and sulfhydryls to quench hexanal, a saturated aldehydic lipid oxidation product. J Agric Food Chem. 1999;47(5):1932–6.

    Article  CAS  PubMed  Google Scholar 

  69. Townsend AJ, Leone-Kabler S, Haynes RL, Wu Y, Szweda L, Bunting KD. Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Chem Biol Interact. 2001;130–132:261–73. doi:10.1016/S0009-2797(00)00270-2.

    Article  PubMed  Google Scholar 

  70. Tacka KA, Dabrowiak JC, Goodisman J, Souid A-K. Kinetic analysis of the reactions of 4-hydroperoxycyclophosphamide and acrolein with glutathione, mesna, and WR-1065. Drug Metab Dispos. 2002;30(8):875–82. doi:10.1124/dmd.30.8.875.

    Article  CAS  PubMed  Google Scholar 

  71. Brock N, Pohl J. The development of mesna for regional detoxification. Cancer Treat Rev. 1983;10(Suppl A):33–43.

    Article  PubMed  Google Scholar 

  72. Sakurai M, Saijo N, Shinkai T, Eguchi K, Sasaki Y, Tamura T, et al. The protective effect of 2-mercapto-ethane sulfonate (MESNA) on hemorrhagic cystitis induced by high-dose ifosfamide treatment tested by a randomized crossover trial. Jpn J Clin Oncol. 1986;16(2):153–6.

    Article  CAS  PubMed  Google Scholar 

  73. Fukuoka M, Negoro S, Masuda N, Furuse K, Kawahara M, Kodama N, et al. Placebo-controlled double-blind comparative study on the preventive efficacy of mesna against ifosfamide-induced urinary disorders. J Cancer Res Clin Oncol. 1991;117(5):473–8.

    Article  CAS  PubMed  Google Scholar 

  74. Vose JM, Reed EC, Pippert GC, Anderson JR, Bierman PJ, Kessinger A, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol. 1993;11(7):1306–10.

    Article  CAS  PubMed  Google Scholar 

  75. Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, et al. 2-mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med. 2011;50(11):1630–8. doi:10.1016/j.freeradbiomed.2011.03.009.

    Article  CAS  PubMed  Google Scholar 

  76. •• Hayslip J, Dressler EV, Weiss H, Taylor TJ, Chambers M, Noel T, et al. Plasma TNF-α and soluble TNF receptor levels after doxorubicin with or without co-administration of mesna—a randomized, cross-over clinical study. PLoS One. 2015;10(4):e0124988. doi:10.1371/journal.pone.0124988. First clinical demonstration of MESNA inhibiting inflammation when co-administered with redox-active chemotherapeutic doxorubicin.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Ludwig U, Riedel MK, Backes M, Imhof A, Muche R, Keller F. MESNA (sodium 2-mercaptoethanesulfonate) for prevention of contrast medium-induced nephrotoxicity - controlled trial. Clin Nephrol. 2011;75(4):302–8.

    Article  CAS  PubMed  Google Scholar 

  78. Amirshahrokhi K, Khalili A-R. Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol. Int Immunopharmacol. 2016;34:183–8. doi:10.1016/j.intimp.2016.03.006.

    Article  CAS  PubMed  Google Scholar 

  79. Triantafyllidis I, Poutahidis T, Taitzoglou I, Kesisoglou I, Lazaridis C, Botsios D. Treatment with mesna and n-3 polyunsaturated fatty acids ameliorates experimental ulcerative colitis in rats. Int J Exp Pathol. 2015;96(6):433–43. doi:10.1111/iep.12163.

    Article  CAS  PubMed  Google Scholar 

  80. Arai T, Koyama R, Yuasa M, Kitamura D, Mizuta R. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose. Biomed Res. 2014;35(6):389–95. doi:10.2220/biomedres.35.389.

    Article  CAS  PubMed  Google Scholar 

  81. Yilmaz ER, Kertmen H, Gürer B, Kanat MA, Arikok AT, Ergüder BI, et al. The protective effect of 2-mercaptoethane sulfonate (MESNA) against traumatic brain injury in rats. Acta Neurochir. 2013;155(1):141–9. doi:10.1007/s00701-012-1501-3.

    Article  PubMed  Google Scholar 

  82. Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-Spectrum Radioprotector. Oncologist. 2007;12(6):738–47. doi:10.1634/theoncologist.12-6-738.

    Article  CAS  PubMed  Google Scholar 

  83. Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS One. 2014;9(5):e95968. doi:10.1371/journal.pone.0095968.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Kheradmand A, Nayebi AM, Jorjani M, Khalifeh S, Haddadi R. Effects of WR1065 on 6-hydroxydopamine-induced motor imbalance: possible involvement of oxidative stress and inflammatory cytokines. Neurosci Lett. 2016;627:7–12. doi:10.1016/j.neulet.2016.05.040.

    Article  CAS  PubMed  Google Scholar 

  85. Chronidou F, Apostolakis E, Papapostolou I, Grintzalis K, Georgiou CD, Koletsis EN, et al. Beneficial effect of the oxygen free radical scavenger amifostine (WR-2721) on spinal cord ischemia/reperfusion injury in rabbits. J Cardiothorac Surg. 2009;4(1):1–12. doi:10.1186/1749-8090-4-50.

    Article  Google Scholar 

  86. Quinn PJ, Boldyrev AA, Formazuyk VE. Carnosine: its properties, functions and potential therapeutic applications. Mol Asp Med. 1992;13(5):379–444.

    Article  CAS  Google Scholar 

  87. Aerts L, Van Assche FA. Low taurine, gamma-aminobutyric acid and carnosine levels in plasma of diabetic pregnant rats: consequences for the offspring. J Perinat Med. 2001;29(1):81–4. doi:10.1515/JPM.2001.012.

    Article  CAS  PubMed  Google Scholar 

  88. Gualano B, Everaert I, Stegen S, Artioli GG, Taes Y, Roschel H, et al. Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients. Amino Acids. 2012;43(1):21–4. doi:10.1007/s00726-011-1165-y.

    Article  CAS  PubMed  Google Scholar 

  89. Fonteh AN, Harrington RJ, Tsai A, Liao P, Harrington MG. Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects. Amino Acids. 2007;32(2):213–24. doi:10.1007/s00726-006-0409-8.

    Article  CAS  PubMed  Google Scholar 

  90. Harris RC, Wise JA, Price KA, Kim HJ, Kim CK, Sale C. Determinants of muscle carnosine content. Amino Acids. 2012;43(1):5–12. doi:10.1007/s00726-012-1233-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Everaert I, Mooyaart A, Baguet A, Zutinic A, Baelde H, Achten E, et al. Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans. Amino Acids. 2011;40(4):1221–9. doi:10.1007/s00726-010-0749-2.

    Article  CAS  PubMed  Google Scholar 

  92. Hipkiss AR. Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res. 2009;57:87–154. doi:10.1016/S1043-4526(09)57003-9.

    Article  CAS  PubMed  Google Scholar 

  93. • Colzani M, De Maddis D, Casali G, Carini M, Vistoli G, Aldini G. Reactivity, selectivity, and reaction mechanisms of aminoguanidine, hydralazine, pyridoxamine, and carnosine as sequestering agents of reactive carbonyl species: a comparative study. ChemMedChem. 2016; doi:10.1002/cmdc.201500552. Systematic analyses of four carbonyl scavengers in their abilities to quench HNE, MDA, MGO and glyoxal which offers insight into improving scavenger design.

    PubMed  Google Scholar 

  94. Orioli M, Aldini G, Benfatto MC, Facino RM, Carini M. HNE Michael adducts to histidine and histidine-containing peptides as biomarkers of lipid-derived carbonyl stress in urines: LC-MS/MS profiling in Zucker obese rats. Anal Chem. 2007;79(23):9174–84. doi:10.1021/ac7016184.

    Article  CAS  PubMed  Google Scholar 

  95. • Regazzoni L, de Courten B, Garzon D, Altomare A, Marinello C, Jakubova M, et al. A carnosine intervention study in overweight human volunteers: bioavailability and reactive carbonyl species sequestering effect. Sci Rep. 2016;6:27224. doi:10.1038/srep27224. Interventional study with carnosine that shows urinary excretion of carnosine-acrolein adducts depends on individual diversity of carnosine intake, metabolism, and basal RCS production.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Peters V, Schmitt CP, Zschocke J, Gross ML, Brismar K, Forsberg E. Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids. 2012;42(6):2411–6. doi:10.1007/s00726-011-1046-4.

    Article  CAS  PubMed  Google Scholar 

  97. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol. 2005;513(1–2):145–50. doi:10.1016/j.ejphar.2005.02.010.

    Article  CAS  PubMed  Google Scholar 

  98. Peters V, Riedl E, Braunagel M, Hoger S, Hauske S, Pfister F, et al. Carnosine treatment in combination with ACE inhibition in diabetic rats. Regul Pept. 2014;194-195:36–40. doi:10.1016/j.regpep.2014.09.005.

    Article  CAS  PubMed  Google Scholar 

  99. Yan H, Guo Y, Zhang J, Ding Z, Ha W, Harding JJ. Effect of carnosine, aminoguanidine, and aspirin drops on the prevention of cataracts in diabetic rats. Mol Vis. 2008;14:2282–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, et al. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2013;33(6):1162–70. doi:10.1161/ATVBAHA.112.300572.

    Article  CAS  PubMed  Google Scholar 

  101. • Menini S, Iacobini C, Ricci C, Blasetti Fantauzzi C, Pugliese G. Protection from diabetes-induced atherosclerosis and renal disease by D-carnosine-octylester: effects of early vs late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia. 2015;58(4):845–53. doi:10.1007/s00125-014-3467-6. Valuable pre-clinical study showing carnosine both inhibits early AGE formation and protects mice from diabetes-induced vascular and renal disease.

    Article  CAS  PubMed  Google Scholar 

  102. Menini S, Iacobini C, Ricci C, Scipioni A, Blasetti Fantauzzi C, Giaccari A, et al. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br J Pharmacol. 2012;166(4):1344–56. doi:10.1111/j.1476-5381.2012.01834.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Min J, Senut MC, Rajanikant K, Greenberg E, Bandagi R, Zemke D, et al. Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia. J Neurosci Res. 2008;86(13):2984–91. doi:10.1002/jnr.21744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang X, Song L, Cheng X, Yang Y, Luan B, Jia L, et al. Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model. Eur J Pharmacol. 2011;667(1–3):202–7. doi:10.1016/j.ejphar.2011.06.003.

    CAS  PubMed  Google Scholar 

  105. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, et al. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke. 2013;44(1):205–12. doi:10.1161/STROKEAHA.112.673954.

    Article  CAS  PubMed  Google Scholar 

  106. • Davis CK, Laud PJ, Bahor Z, Rajanikant GK, Majid A. Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke. J Cereb Blood Flow Metab. 2016; doi:10.1177/0271678X16658302. Systematic review of effects of carnosine administration in animal models of ischemic stroke.

    PubMed Central  Google Scholar 

  107. Zhang ZY, Sun BL, Yang MF, Li DW, Fang J, Zhang S. Carnosine attenuates early brain injury through its antioxidative and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model. Cell Mol Neurobiol. 2015;35(2):147–57. doi:10.1007/s10571-014-0106-1.

    Article  PubMed  CAS  Google Scholar 

  108. Zieba R, Wagrowska-Danilewicz M. Influence of carnosine on the cardiotoxicity of doxorubicin in rabbits. Pol J Pharmacol. 2003;55(6):1079–87.

    CAS  PubMed  Google Scholar 

  109. • de Courten B, Jakubova M, de Courten MP, Kukurova IJ, Vallova S, Krumpolec P, et al. Effects of carnosine supplementation on glucose metabolism: pilot clinical trial. Obesity. 2016;24(5):1027–34. doi:10.1002/oby.21434. Interventional pilot study showing that carnosine supplementation improved insulin sensitivity and glucose handling in obese and overweight individuals.

    Article  PubMed  CAS  Google Scholar 

  110. Lombardi C, Carubelli V, Lazzarini V, Vizzardi E, Bordonali T, Ciccarese C, et al. Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition. 2015;31(1):72–8. doi:10.1016/j.nut.2014.04.021.

    Article  CAS  PubMed  Google Scholar 

  111. Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova N, et al. Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson’s disease: a pilot study. Rejuvenation Res. 2008;11(4):821–7. doi:10.1089/rej.2008.0716.

    Article  CAS  PubMed  Google Scholar 

  112. Cornelli U. Treatment of Alzheimer’s disease with a cholinesterase inhibitor combined with antioxidants. Neurodegener Dis. 2010;7(1–3):193–202. doi:10.1159/000295663.

    Article  CAS  PubMed  Google Scholar 

  113. Babizhayev MA, Yermakova VN, Sakina NL, Evstigneeva RP, Rozhkova EA, Zheltukhina GA. N alpha-acetylcarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant. Clin Chim Acta. 1996;254(1):1–21.

    Article  CAS  PubMed  Google Scholar 

  114. Babizhayev MA, Micans P, Guiotto A, Kasus-Jacobi A. N-acetylcarnosine lubricant eyedrops possess all-in-one universal antioxidant protective effects of L-carnosine in aqueous and lipid membrane environments, aldehyde scavenging, and transglycation activities inherent to cataracts: a clinical study of the new vision-saving drug N-acetylcarnosine eyedrop therapy in a database population of over 50,500 patients. Am J Ther. 2009;16(6):517–33. doi:10.1097/MJT.0b013e318195e327.

    Article  PubMed  Google Scholar 

  115. Sakae K, Agata T, Kamide R, Yanagisawa H. Effects of L-carnosine and its zinc complex (Polaprezinc) on pressure ulcer healing. Nutr Clin Pract. 2013;28(5):609–16. doi:10.1177/0884533613493333.

    Article  PubMed  Google Scholar 

  116. Baraniuk JN, El-Amin S, Corey R, Rayhan R, Timbol C. Carnosine treatment for gulf war illness: a randomized controlled trial. Glob J Health Sci. 2013;5(3):69–81. doi:10.5539/gjhs.v5n3p69.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Sullivan D, Peterson R, Mujer C, Gad S. A 7-day intravenous toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats. Human & Experimental Toxicology. 2016; doi:10.1177/0960327116661023.

    Google Scholar 

  118. Amarnath V, Amarnath K, Amarnath K, Davies S, Roberts 2nd LJ. Pyridoxamine: an extremely potent scavenger of 1,4-dicarbonyls. Chem Res Toxicol. 2004;17(3):410–5.

    Article  CAS  PubMed  Google Scholar 

  119. Zagol-Ikapitte I, Amarnath V, Bala M, Roberts 2nd LJ, Oates JA, Boutaud O. Characterization of scavengers of gamma-ketoaldehydes that do not inhibit prostaglandin biosynthesis. Chem Res Toxicol. 2010;23(1):240–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chipinda I, Mbiya W, Adigun RA, Morakinyo MK, Law BF, Simoyi RH, et al. Pyridoxylamine reactivity kinetics as an amine based nucleophile for screening electrophilic dermal sensitizers. Toxicology. 2014;315:102–9. doi:10.1016/j.tox.2013.11.009.

    Article  CAS  PubMed  Google Scholar 

  121. Degenhardt TP, Alderson NL, Arrington DD, Beattie RJ, Basgen JM, Steffes MW, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 2002;61(3):939–50. doi:10.1046/j.1523-1755.2002.00207.x.

    Article  CAS  PubMed  Google Scholar 

  122. Tanimoto M, Gohda T, Kaneko S, Hagiwara S, Murakoshi M, Aoki T, et al. Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice. Metabolism. 2007;56(2):160–7. doi:10.1016/j.metabol.2006.08.026.

    Article  CAS  PubMed  Google Scholar 

  123. Liu R, Zhong Y, Li X, Chen H, Jim B, Zhou M-M, et al. Role of transcription factor acetylation in diabetic kidney disease. Diabetes. 2014;63(7):2440–53. doi:10.2337/db13-1810.

    Article  PubMed  PubMed Central  Google Scholar 

  124. • Maessen DE, Brouwers O, Gaens KH, Wouters K, Cleutjens JP, Janssen BJ, et al. Delayed intervention with pyridoxamine improves metabolic function and prevents adipose tissue inflammation and insulin resistance in high-fat diet-induced obese mice. Diabetes. 2016;65(4):956–66. doi:10.2337/db15-1390. Provocative pre-clinical study reporting that PM protects against high fat induced body weight gain.

    Article  CAS  PubMed  Google Scholar 

  125. • Skrypnyk NI, Voziyan P, Yang H, de Caestecker CR, Theberge M-C, Drouin M, et al. Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury. Am J Physiol Ren Physiol. 2016;311(2):F268–F77. doi:10.1152/ajprenal.00056.2016. First pre-clinical report of PM reducing short and long term injury and improving renal function after ischemia-reperfusion acute kidney injury.

    Article  CAS  Google Scholar 

  126. Mastrocola R, Nigro D, Chiazza F, Medana C, Dal Bello F, Boccuzzi G, et al. Fructose-derived advanced glycation end-products drive lipogenesis and skeletal muscle reprogramming via SREBP-1c dysregulation in mice. Free Radic Biol Med. 2016;91:224–35. doi:10.1016/j.freeradbiomed.2015.12.022.

    Article  CAS  PubMed  Google Scholar 

  127. Watson AMD, Soro-Paavonen A, Sheehy K, Li J, Calkin AC, Koitka A, et al. Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice. Diabetologia. 2011;54(3):681–9. doi:10.1007/s00125-010-2000-9.

    Article  CAS  PubMed  Google Scholar 

  128. Cao W, Chen J, Chen Y, Chen S, Chen X, Huang H, et al. Advanced glycation end products induced immune maturation of dendritic cells controls heart failure through NF-κB signaling pathway. Arch Biochem Biophys. 2015;580:112–20. doi:10.1016/j.abb.2015.07.003.

    Article  CAS  PubMed  Google Scholar 

  129. • Brodeur MR, Bouvet C, Bouchard S, Moreau S, Leblond J, de Blois D, et al. Reduction of advanced-glycation end products levels and inhibition of RAGE signaling decreases rat vascular calcification induced by diabetes. PLoS One. 2014;9(1):e85922. doi:10.1371/journal.pone.0085922. Pre-clinical study with PM showing efficacy to reduce diabetes-induced calcification in arteries in rats.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Wang C-H, Wu E-T, Wu M-S, Tsai M-S, Ko Y-H, Chang R-W, et al. Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation. Exp Physiol. 2014;99(11):1488–98. doi:10.1113/expphysiol.2014.082008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Charvet CD, Saadane A, Wang M, Salomon RG, Brunengraber H, Turko IV, et al. Pretreatment with pyridoxamine mitigates isolevuglandin-associated retinal effects in mice exposed to bright light. J Biol Chem. 2013;288(41):29267–80. doi:10.1074/jbc.M113.498832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Dong Z, Iwata D, Kitaichi N, Takeuchi M, Sato M, Endo N, et al. Amelioration of experimental autoimmune uveoretinitis by inhibition of glyceraldehyde-derived advanced glycation end-product formation. J Leukoc Biol. 2014;96(6):1077–85. doi:10.1189/jlb.3A0513-288RRR.

    Article  PubMed  CAS  Google Scholar 

  133. Thotala D, Chetyrkin S, Hudson B, Hallahan D, Voziyan P, Yazlovitskaya E. Pyridoxamine protects intestinal epithelium from ionizing radiation-induced apoptosis. Free Radic Biol Med. 2009;47(6):779–85. doi:10.1016/j.freeradbiomed.2009.06.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yazlovitskaya EM, Voziyan PA, Manavalan T, Yarbrough WG, Ivanova AV. Cellular oxidative stress response mediates radiosensitivity in Fus1-deficient mice. Cell Death Dis. 2015;6:e1652. doi:10.1038/cddis.2014.593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol. 2007;27(6):605–14.

    Article  CAS  PubMed  Google Scholar 

  136. Lewis EJ, Greene T, Spitalewiz S, Blumenthal S, Berl T, Hunsicker LG, et al. Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):131–6. doi:10.1681/asn.2011030272.

    Article  CAS  PubMed  Google Scholar 

  137. Zagol-Ikapitte I, Matafonova E, Amarnath V, Bodine CL, Boutaud O, Tirona RG, et al. Determination of the pharmacokinetics and oral bioavailability of salicylamine, a potent γ-ketoaldehyde scavenger, by LC/MS/MS. Pharmaceutics. 2010;2(1):18–29. doi:10.3390/pharmaceutics2010018.

    Article  CAS  PubMed Central  Google Scholar 

  138. Davies SS, Bodine C, Matafonova E, Pantazides BG, Bernoud-Hubac N, Harrison FE, et al. Treatment with a gamma-ketoaldehyde scavenger prevents working memory deficits in hApoE4 mice. J Alzheimers Dis. 2011;27(1):49–59. doi:10.3233/JAD-2011-102118.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. • Pearson JN, Warren E, Liang L-P, Roberts Ii LJ, Patel M. Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis. Neurobiol Dis. 2017;98:88–99. doi:10.1016/j.nbd.2016.11.011. Preclinical study showing 2-hydroxybenzylamine reduces IsoLG adducts and blocks seizure-associated memory impairment.

    Article  CAS  PubMed  Google Scholar 

  140. • Nguyen TT, Caito SW, Zackert WE, West JD, Zhu S, Aschner M, et al. Scavengers of reactive gamma-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. Aging (Albany NY). 2016;8(8):1759–80. doi:10.18632/aging.101011. Provocative study showing 2-hydroxybenzylamine prolongs lifespans of C. elegans.

  141. Lambert C, Li J, Jonscher K, Yang TC, Reigan P, Quintana M, et al. Acrolein inhibits cytokine gene expression by alkylating cysteine and arginine residues in the NF-kappaB1 DNA binding domain. J Biol Chem. 2007;282(27):19666–75. doi:10.1074/jbc.M611527200.

    Article  CAS  PubMed  Google Scholar 

  142. Oe T, Lee SH, Silva Elipe MV, Arison BH, Blair IA. A novel lipid hydroperoxide-derived modification to arginine. Chem Res Toxicol. 2003;16(12):1598–605. doi:10.1021/tx034178l.

    Article  CAS  PubMed  Google Scholar 

  143. Lee SH, Rindgen D, Bible Jr RH, Hajdu E, Blair IA. Characterization of 2′-deoxyadenosine adducts derived from 4-oxo-2-nonenal, a novel product of lipid peroxidation. Chem Res Toxicol. 2000;13(7):565–74.

    Article  CAS  PubMed  Google Scholar 

  144. Rindgen D, Nakajima M, Wehrli S, Xu K, Blair IA. Covalent modifications to 2′-deoxyguanosine by 4-oxo-2-nonenal, a novel product of lipid peroxidation. Chem Res Toxicol. 1999;12(12):1195–204.

    Article  CAS  PubMed  Google Scholar 

  145. Brinkmann E, Wells-Knecht KJ, Thorpe SR, Baynes JW. Characterization of an imidazolium compound formed by reaction of methylglyoxal and Nα-hippuryllysine. J Chem Soc Perkin Trans. 1995;1:2. doi:10.1039/P19950002817.

    Google Scholar 

  146. Frischmann M, Bidmon C, Angerer J, Pischetsrieder M. Identification of DNA adducts of methylglyoxal. Chem Res Toxicol. 2005;18(10):1586–92. doi:10.1021/tx0501278.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Venkataraman Amarnath for his review of the manuscript and helpful suggestions. Dr. Davies and Zhang received funding from the National Heart, Lung, and Blood Institute grant HL116263-01A1.

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  1. Department of Pharmacology and Division of Clinical Pharmacology, Vanderbilt University, 556 Robinson Research Building, 2220 Pierce Avenue, Nashville, TN, 37232-6602, USA

    Sean S. Davies & Linda S. Zhang

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Correspondence to Sean S. Davies.

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Dr. Davies is co-inventor on U.S. patent #7705054 for use of 2-aminomethylphenols as isolevuglandin scavengers for disorders involving oxidative injury.

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All reported studies/experiments with human and animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines.

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Davies, S.S., Zhang, L.S. Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases. Curr Pharmacol Rep 3, 51–67 (2017). https://doi.org/10.1007/s40495-017-0081-6

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