Skip to main content
Log in

An Alternative Pathway Through the Fenton Reaction for the Formation of Advanced Oxidation Protein Products, a New Class of Inflammatory Mediators

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The accumulation of advanced oxidation protein products (AOPPs) has been linked to several pathological conditions, and their levels are formed during oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants produced by myeloperoxidase (MPO). However, it was suggested that the generation of this mediator of inflammation may also occur via an MPO-independent pathway. The aim of this study was to induce the formation of AOPPs in vitro through Fenton reaction and to investigate whether this generation could be counteracted by N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP). The complete Fenton system increased the AOPPs levels and both NAC and FBP were capable of inhibiting the formation of Fenton reaction-induced AOPPs. These data provide a new hypothesis about another pathway of AOPPs formation, as well as report that NAC and FBP may be good candidates to neutralize pro-inflammatory and pro-oxidant effects of AOPPs in several diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Halliwell, B. 2012. Free radicals and antioxidants: updating a personal view. Nutrition Reviews 70: 257–265.

    Article  PubMed  Google Scholar 

  2. Ray, P.D., B.W. Huang, and Y. Tsuji. 2012. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cellular Signalling 24: 981–990.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Sorescu, D., D. Weiss, B. Lassegue, R.E. Clempus, K. Szocs, G.P. Sorescu, L. Valppu, M.T. Quinn, J.D. Lambeth, J.D. Vega, W.R. Taylor, and K.K. Griendling. 2002. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105: 1429–1435.

    Article  CAS  PubMed  Google Scholar 

  4. Brownlee, M. 2001. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820.

    Article  CAS  PubMed  Google Scholar 

  5. Kaneda, H., J. Taguchi, K. Ogasawara, T. Aizawa, and M. Ohno. 2002. Increased level of advanced oxidation protein products in patients with coronary artery disease. Atherosclerosis 162: 221–225.

    Article  CAS  PubMed  Google Scholar 

  6. Kalousova, M., J. Skrha, and T. Zima. 2002. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiological Research 51: 597–604.

    CAS  PubMed  Google Scholar 

  7. Witko-Sarsat, V., M. Friedlander, C. Capeillere-Blandin, T. Nguyen-Khoa, A.T. Nguyen, J. Zingraff, P. Jungers, and B. Descamps-Latscha. 1996. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney International 49: 1304–1313.

    Article  CAS  PubMed  Google Scholar 

  8. Guo, Z.J., H.X. Niu, F.F. Hou, L. Zhang, N. Fu, R. Nagai, X. Lu, B.H. Chen, Y.X. Shan, J.W. Tian, R.H. Nagaraj, D. Xie, and X. Zhang. 2008. Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxidants and Redox Signaling 10: 1699–1712.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou, L.L., W. Cao, C. Xie, J. Tian, Z. Zhou, Q. Zhou, P. Zhu, A. Li, Y. Liu, T. Miyata, F.F. Hou, and J. Nie. 2012. The receptor of advanced glycation end products plays a central role in advanced oxidation protein products-induced podocyte apoptosis. Kidney International 82: 759–770.

    Article  CAS  PubMed  Google Scholar 

  10. Himmelfarb, J., and E. McMonagle. 2001. Albumin is the major plasma protein target of oxidant stress in uremia. Kidney International 60: 358–363.

    Article  CAS  PubMed  Google Scholar 

  11. Mera, K., M. Anraku, K. Kitamura, K. Nakajou, T. Maruyama, and M. Otagiri. 2005. The structure and function of oxidized albumin in hemodialysis patients: Its role in elevated oxidative stress via neutrophil burst. Biochemical and Biophysical Research Communications 334: 1322–1328.

    Article  CAS  PubMed  Google Scholar 

  12. Shi, X.Y., F.F. Hou, H.X. Niu, G. Wang, D. Xie, Z.J. Guo, Z.M. Zhou, F. Yang, J.W. Tian, and X. Zhang. 2008. Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 149: 1829–1839.

    Article  CAS  PubMed  Google Scholar 

  13. Zhou, L.L., F.F. Hou, G.B. Wang, F. Yang, D. Xie, Y.P. Wang, and J.W. Tian. 2009. Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms. Kidney International 76: 1148–1160.

    Article  PubMed  Google Scholar 

  14. Hanasand, M., R. Omdal, K.B. Norheim, L.G. Gøransson, C. Brede, and G. Jonsson. 2012. Improved detection of advanced oxidation protein products in plasma. Clinica Chimica Acta 413: 901–906.

    Article  CAS  Google Scholar 

  15. Capeillère-Blandin, C., V. Gausson, B. Descamps-Latscha, and V. Witko-Sarsat. 2004. Biochemical and spectrophotometric significance of advanced oxidized protein products. Biochimica et Biophysica Acta 1689: 91–102.

    Article  PubMed  Google Scholar 

  16. Capeillère-Blandin, C., V. Gausson, A.T. Nguyen, B. Descamps-Latscha, T. Drüeke, and V. Witko-Sarsat. 2006. Respective role of uraemic toxins and myeloperoxidase in the uraemic state. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association – European Renal Association 21: 1555–1563.

    Article  Google Scholar 

  17. Bochi, G.V., V.D. Torbitz, L.P. Cargnin, M.B. Sangoi, R.C. Santos, P. Gomes, and R.N. Moresco. 2012. Fructose-1,6-bisphosphate and N-acetylcysteine attenuate the formation of advanced oxidation protein products, a new class of inflammatory mediators, in vitro. Inflammation 35: 1786–1792.

    Article  CAS  PubMed  Google Scholar 

  18. Holmes, R.S., and C.J. Masters. 1970. Epigenetic interconversion of the multiple forms of mouse liver catalase. FEBS Letters 11: 45–48.

    Article  CAS  PubMed  Google Scholar 

  19. Witko-Sarsat, V., T. Nguyen Khoa, P. Jungers, T. Drüeke, and B. Descamps-Latscha. 1998. Advanced oxidation protein products: oxidative stress markers and mediators of inflammation in uremia. Advances in nephrology from the Necker Hospital 28: 321–341.

    CAS  PubMed  Google Scholar 

  20. Kalousová, M., J. Skrha, and T. Zima. 2002. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiological Research 51: 597–604.

    PubMed  Google Scholar 

  21. Martín-Gallán, P., A. Carrascosa, M. Gussinyé, and C. Domínguez. 2003. Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications. Free Radical Biology and Medicine 34: 1563–1574.

    Article  PubMed  Google Scholar 

  22. Tabak, O., R. Gelisgen, H. Erman, F. Erdenen, C. Muderrisoglu, H. Aral, and H. Uzun. 2011. Oxidative lipid, protein, and DNA damage as oxidative stress markers in vascular complications of diabetes mellitus. Clinical and Investigative Medicine 34: 163–171.

    Google Scholar 

  23. Chen, S., L. Liu, X. Sun, Y. Liu, and T. Son. 2005. Captopril restores endothelium-dependent relaxation induced by advanced oxidation protein products in rat aorta. Journal of Cardiovascular Pharmacology 46: 803–809.

    Article  CAS  PubMed  Google Scholar 

  24. Drüeke, T., V. Witko-Sarsat, Z. Massy, B. Descamps-Latscha, A.P. Guerin, S.J. Marchais, V. Gausson, and G.M. London. 2002. Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 106: 2212–2217.

    Article  PubMed  Google Scholar 

  25. Anraku, M., K. Kitamura, R. Shintomo, K. Takeuchi, H. Ikeda, J. Nagano, T. Ko, K. Mera, K. Tomita, and M. Otagiri. 2008. Effect of intravenous iron administration frequency on AOPP and inflammatory biomarkers in chronic hemodialysis patients: a pilot study. Clinical Biochemistry 41: 1168–1174.

    Article  CAS  PubMed  Google Scholar 

  26. Halliwell, B. 1978. Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide-generating system. FEBS Letters 96: 238–242.

    Article  CAS  PubMed  Google Scholar 

  27. Rooyakkers, T.M., E.S. Stroes, M.P. Kooistra, E.E. Van Faassen, R.C. Hider, T.J. Rabelink, and J.J. Marx. 2002. Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo. European Journal of Clinical Investigation 32: 9–16.

    Article  CAS  PubMed  Google Scholar 

  28. Tovbin, D., D. Mazor, M. Vorobiov, C. Chaimovitz, and N. Meyerstein. 2002. Induction of protein oxidation by intravenous iron in hemodialysis patients: Role of inflammation. American Journal of Kidney Diseases 40: 1005–1012.

    Article  CAS  PubMed  Google Scholar 

  29. Stępniak, J., A. Lewiński, and M. Karbownik-Lewińska. 2013. Membrane lipids and nuclear DNA are differently susceptive to Fenton reaction substrates in porcine thyroid. Toxicology In Vitro 27: 71–78.

    Article  PubMed  Google Scholar 

  30. Valko, M., C.J. Rhodes, J. Moncol, M. Izakovic, and M. Mazur. 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-Biological Interactions 160: 1–40.

    Article  CAS  PubMed  Google Scholar 

  31. Repka, T., and R.P. Hebbel. 1991. Hydroxyl radical formation by sickle erythrocyte membranes: Role of pathologic iron deposits and cytoplasmic reducing agents. Blood 78: 2753–2758.

    CAS  PubMed  Google Scholar 

  32. Trachootham, D., W. Lu, M.A. Ogasawara, R.D. Nilsa, and P. Huang. 2008. Redox regulation of cell survival. Antioxidants and Redox Signaling 10: 1343–1374.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Pellegrino, P., B. Mallet, S. Delliaux, Y. Jammes, R. Gieu, and O. Schaf. 2011. Zeolites are effective ROS-scavengers in vitro. Biochemical and Biophysical Research Communications 410: 478–483.

    Article  CAS  PubMed  Google Scholar 

  34. Witko-Sarsat, V., V. Gausson, A.T. Nguyen, M. Touam, T. Drüeke, F. Santangelo, and B. Descamps-Latscha. 2003. AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: A potential target for N-acetylcysteine treatment in dialysis patients. Kidney International 64: 82–91.

    Article  CAS  PubMed  Google Scholar 

  35. Aruoma, O.I., B. Halliwell, B.M. Hoey, and J. Butler. 1989. The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biology and Medicine 6: 593–597.

    Article  CAS  PubMed  Google Scholar 

  36. Fishbane, S. 2008. N-Acetylcysteine in the prevention of contrast-induced nephropathy. Clinical Journal of the American Society of Nephrology 3: 281–287.

    Article  CAS  PubMed  Google Scholar 

  37. Holt, S., R. Marley, B. Fernando, D. Harry, R. Anand, D. Goodier, and K. Moore. 1999. Acute cholestasis-induced renal failure: Effects of antioxidants and ligands for the thromboxane A2 receptor. Kidney International 55: 271–277.

    Article  CAS  PubMed  Google Scholar 

  38. Santos, R.C., R.N. Moresco, M.A. Peña Rico, A.R. Susperregui, J.L. Rosa, R. Bartrons, F. Ventura, D.N. Mário, S.H. Alves, E. Tatsch, H. Kober, R.O. de Mello, P. Scherer, H.B. Dias, and J.R. de Oliveira. 2012. Fructose-1,6-bisphosphate reduces the mortality in Candida albicans bloodstream infection and prevents the septic-induced platelet decrease. Inflammation 35: 1256–1261.

    Article  CAS  PubMed  Google Scholar 

  39. de Mello, R.O., A. Lunardelli, E. Caberlon, C.M. de Moraes, R. Christ Vianna Santos, V.L. da Costa, G.V. da Silva, P. da Silva Scherer, L.E. Buaes, D.A. da Silva Melo, M.V. Donadio, F.B. Nunes, and J.R. de Oliveira. 2011. Effect of N-acetylcysteine and fructose-1,6-bisphosphate in the treatment of experimental sepsis. Inflammation 34: 539–550.

    Article  PubMed  Google Scholar 

  40. Alva, N., T. Carbonell, T. Roig, J. Bermúdez, and J. Palomeque. 2011. Fructose 1,6 biphosphate administration to rats prevents metabolic acidosis and oxidative stress induced by deep hypothermia and rewarming. European Journal of Pharmacology 659: 259–264.

    Article  CAS  PubMed  Google Scholar 

  41. Bajić, A., J. Zakrzewska, D. Godjevac, P. Andjus, D.R. Jones, M. Spasić, and I. Spasojević. 2011. Relevance of the ability of fructose 1,6-bis(phosphate) to sequester ferrous but not ferric ions. Carbohydrate Research 346: 416–420.

    Article  PubMed  Google Scholar 

  42. Wei, X.F., Q.G. Zhou, F.F. Hou, B.Y. Liu, and M. Liang. 2009. Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase. American Journal of Physiology. Renal Physiology 296: 427–437.

    Article  Google Scholar 

  43. Zhou, Q.G., M. Zhou, A.J. Lou, D. Xie, and F.F. Hou. 2010. Advanced oxidation protein products induce inflammatory response and insulin resistance in cultured adipocytes via induction of endoplasmic reticulum stress. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology 26: 775–786.

    Article  CAS  Google Scholar 

  44. Cao, W., J. Xu, Z.M. Zhou, G.B. Wang, F.F. Hou, and J. Nie. 2013. Advanced oxidation protein products activate intrarenal renin–angiotensin system via a CD36-mediated, redox-dependent pathway. Antioxidants and Redox Signaling 18: 19–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Valente, A.J., T. Yoshida, R.A. Clark, P. Delafontaine, U. Siebenlist, and B. Chandrasekar. 2013. Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free Radical Biology and Medicine 60: 125–135.

    Article  CAS  PubMed  Google Scholar 

  46. Prousek, J. 2007. Fenton chemistry in biology and medicine. Pure and applied chemistry 79: 2325–2338.

    Article  CAS  Google Scholar 

  47. Repetto, M.G., N.F. Ferrarotti, and A. Boveris. 2010. The involvement of transition metal ions on iron-dependent lipid peroxidation. Archives of Toxicology 84: 255–262.

    Article  CAS  PubMed  Google Scholar 

  48. González, F.B., S. Llesuy, and A. Boveris. 1991. Hydroperoxide-initiated chemiluminescence: Assay for oxidative stress in biopsies of heart, liver and muscle. Free Radical Biology and Medicine 10: 93–100.

    Article  Google Scholar 

  49. Chance, B., H. Sies, and A. Boveris. 1979. Hydroperoxide metabolism in mammalian organs. Physiological Reviews 59: 527–605.

    CAS  PubMed  Google Scholar 

  50. Marsche, G., S. Frank, A. Hrzenjak, M. Holzer, S. Dirnberger, C. Wadsack, H. Scharnagl, T. Stojakovic, A. Heinemann, and K. Oettl. 2009. Plasma-advanced oxidation products are potent high-density lipoprotein receptor antagonists in vivo. Circulation Research 104: 750–757.

    Google Scholar 

Download references

Acknowledgments

This study was supported by grants to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, Brazil). We thank SPi Global Professional Editing Services for writing assistance.

Conflict of interest

There are no conflicts of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rafael Noal Moresco.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bochi, G.V., Torbitz, V.D., Cargnin, L.P. et al. An Alternative Pathway Through the Fenton Reaction for the Formation of Advanced Oxidation Protein Products, a New Class of Inflammatory Mediators. Inflammation 37, 512–521 (2014). https://doi.org/10.1007/s10753-013-9765-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-013-9765-1

KEY WORDS

Navigation