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Journal of Molecular Neuroscience

, Volume 20, Issue 2, pp 125–134 | Cite as

Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum

  • Istvan Boldogh
  • Daniel Liebenthal
  • T. Kley Hughes
  • Terry L. Juelich
  • Jerzy A. Georgiades
  • Marian L. Kruzel
  • G. John StantonEmail author
Original Article

Abstract

In previous studies we showed that colostrinin (CLN), a complex of proline-rich polypeptides derived from ovine colostrum, induces mitogenic stimulation, as well as a variety of cytokines in human peripheral blood leukocytes, and possesses antioxidant activity in pheochromocytoma (PC12) cells. In this study we investigated the effects of CLN on 4-hydroxynonenal (4HNE)-mediated adduct formation, generation of reactive oxygen species (ROS), glutathione (GSH) metabolism, and the modification of signal transduction cascade that leads to activation of c-Jun N-terminal kinase (JNK) in PC12 cells. Here we demonstrate that CLN (1) reduced the abundance of 4HNE-protein adducts, as shown by fluorescent microscopy and Western blot analysis; (2) reduced intracellular levels of ROS, as shown by a decrease in 2′,7′-dichlorodihydro-fluorescein-mediated fluorescence; (3) inhibited 4HNE-mediated GSH depletion, as determined fluorimetrically; and (4) inhibited 4HNE-induced activation of JNKs. Together, these findings suggest that CLN appears to down-regulate 4HNE-mediated lipid peroxidation and its product-induced signaling that otherwise may lead to pathological changes at the cellular and organ level. These findings also suggest further that CLN could be useful in the treatment of diseases such as Alzheimer’s, as well as those in which ROS are implicated in pathogenesis.

Index Entries

Colostrum colostrinin 4HNE ROS 

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References

  1. Boldogh I., Hughes T. K., Georgiades J. A., and Stanton J. (2000) Antioxidant and nerve differentiating activity of colostrinine and related peptides, in First International Symposium on Colostrinin Georgiades J., ed. Lodz, Poland.Google Scholar
  2. Boldogh I., Hughes T. K., Georgiades J. A., and Stanton J. (2001) Antioxidant and cell-differentiating activity of colostrinin and its component peptides (CCP) in cell culture. Yearbook of Psychogeriatry 4, 57–65.Google Scholar
  3. Brown A. J., Leong S. L., Dean R. T., and Jessup W. (1997) 7-Hydroperoxycholesterol and its products in oxidized low density lipoprotein and human atherosclerotic plaque. J. Lipid Res. 38, 1730–1745.PubMedGoogle Scholar
  4. Bruce-Keller A. J., Li Y. J., Lovell M. A., Kraemer P. J., Gary D. S., Brown R. R., et al. (1998) 4-Hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats. J. Neuropathol. Exp. Neurol. 57, 257–267.PubMedCrossRefGoogle Scholar
  5. Buettner G. R. (1993) The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch. Biochem. Biophys. 300, 535–543.PubMedCrossRefGoogle Scholar
  6. Cadenas E. and Davies K. J. (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222–230.PubMedCrossRefGoogle Scholar
  7. Camandola S., Poli G., and Mattson M. P. (2000) The lipid peroxidation product 4-hydroxy-2,3-nonenal inhibits constitutive and inducible activity of nuclear factor kappa B in neurons. Brain Res. Mol. Brain Res. 85, 53–60.PubMedCrossRefGoogle Scholar
  8. Cheng J. Z., Singhal S. S., Saini M., Singhal J., Piper J. T., Van Kuijk F. J., et al. (1999) Effects of mGST A4 trans-fection on 4-hydroxynonenal-mediated apoptosis and differentiation of K562 human erythroleukemia cells. Arch. Biochem. Biophys. 372, 29–36.PubMedCrossRefGoogle Scholar
  9. Davies M. J. and Truscott R. J. (2001) Photo-oxidation of proteins and its role in cataractogenesis. J. Photochem. Photobiol. B 63, 114–125.PubMedCrossRefGoogle Scholar
  10. Davis W. Jr., Ronai Z., and Tew K. D. (2001) Cellular thiols and reactive oxygen species in drug-induced apoptosis. J. Pharmacol. Exp. Ther. 296, 1–6.PubMedGoogle Scholar
  11. de Zwart L. L., Meerman J. H., Commandeur J. N., and Vermeulen N. P. (1999) Biomarkers of free radical damage applications in experimental animals and in humans. Free Radic. Biol. Med. 26, 202–226.PubMedCrossRefGoogle Scholar
  12. Esterbauer H., Schaur R. J., and Zollner H. (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 11, 81–128.PubMedCrossRefGoogle Scholar
  13. Evan G. and Littlewood T. (1998) A matter of life and cell death. Science 281, 1317–1322.PubMedCrossRefGoogle Scholar
  14. Finkel T. Holbrook N. J. (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247.PubMedCrossRefGoogle Scholar
  15. Friguet B., Bulteau A. L., Chondrogianni N., Conconi M., and Petropoulos I. (2000) Protein degradation by the proteasome and its implications in aging. Ann. NY Acad. Sci. 908, 143–154.PubMedCrossRefGoogle Scholar
  16. Gardner J. L. and Gallagher E. P. (2001) Development of a peptide antibody specific to human glutathione S-transferase alpha 4-4 (hGSTA4-4) reveals preferential localization in human liver mitochondria. Arch. Biochem. Biophys. 390, 19–27.PubMedCrossRefGoogle Scholar
  17. Hainaut P. and Milner J. (1993) Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Res. 53, 4469–4473.PubMedGoogle Scholar
  18. Han S. I., Oh S. Y., Woo S. H., Kim K. H., Kim J. H., Kim H. D., and Kang H. S. (2001) Implication of a small GTPase Rac1 in the activation of c-Jun N-terminal kinase and heat shock factor in response to heat shock. J. Biol. Chem. 276, 1889–1895.PubMedCrossRefGoogle Scholar
  19. Hughes A. L., Gollapudi L., Sladek T. L., and Neet K. E. (2000) Mediation of nerve growth factor-driven cell cycle arrest in PC12 cells by p53. Simultaneous differentiation and proliferation subsequent to p53 functional inactivation. J. Biol. Chem. 275, 37829–37837.PubMedCrossRefGoogle Scholar
  20. Inglot A. D., Gelder F., and Georgiades J. A. (1998) Tumor-associated antigens are cytokine inducers and hypo-reactivity factors to the immune system. Biotherapy 11, 27–37.PubMedCrossRefGoogle Scholar
  21. Janusz, M. and Lisowski J. (1993) Proline-rich polypeptide (PRP)—an immunomodulatory peptide from ovine colostrum. Arch. Immunol. Ther. Exp. 41, 275–279.Google Scholar
  22. Janusz M., Lisowski J., and Franek F. (1974) Isolation and characterization of a proline-rich polypeptide from ovine colostrum. FEBS Lett. 49, 276–279.PubMedCrossRefGoogle Scholar
  23. Janusz M., Staroscik K., Zimecki M., Wieczorek Z., and Lisowski J. (1981) Chemical and physical characterization of a proline-rich polypeptide from sheep colostrum. Biochem. J. 199, 9–15.PubMedGoogle Scholar
  24. Keller J. N., Kindy M. S., Holtsberg F. W., St Clair D. K., Yen H. C., Germeyer A., S., et al. (1998) Mitochondrial managanese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 18, 687–697.PubMedGoogle Scholar
  25. Kong A. N., Yu R., Chen C., Mandlekar S., and Primiano T. (2000) Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch. Pharmacol Res. 23, 1–16.CrossRefGoogle Scholar
  26. Kruman I., Bruce-Keller A. J., Bredesen D., Waeg G., and Mattson M. P. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17, 5089–5100.PubMedGoogle Scholar
  27. Kruzel M., Janusz M., Lisowski J., Fischleigh, R., and Georgiades J. A. (2001) Towards an understanding of biological role of colostrinin peptides. J. Mol. Neurosci. 17, 115–125.CrossRefGoogle Scholar
  28. Lafon-Cazal M., Culcasi M., Gaven F., Pietri S., and Bockaert J. (1993) Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology 32, 1259–1266.PubMedCrossRefGoogle Scholar
  29. LeBel C. P., Ischiropoulos H., and Bondy S. C. (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem. Res. Toxicol. 5, 227–231.PubMedCrossRefGoogle Scholar
  30. Leonarduzzi G., Arkan M. C., Basaga H., Chiarpotto E., Sevanian A., and Poli G. (2000) Lipid oxidation products in cell signaling. Free Radic. Biol. Med. 28, 1370–1378.PubMedCrossRefGoogle Scholar
  31. Lovell M. A., Ehmann W. D., Mattson M. P., and Markesbery W. R. (1997) Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol. Aging 18, 457–461.PubMedCrossRefGoogle Scholar
  32. Markesbery W. R. (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic. Biol. Med. 23, 137–147.CrossRefGoogle Scholar
  33. Markesbery W. R. and Carney J. M. (1999) Oxidative alterations in Alzheimer’s disease. Brain Pathol. 9, 133–146.PubMedCrossRefGoogle Scholar
  34. Markesbery W. R. and Lovell M. A. (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol. Aging 19, 33–36.PubMedCrossRefGoogle Scholar
  35. Mattson M. P. and Furukawa K. (1997) Alzheimer’s disease. Short precursor shortens memory. Nature 387, 457–458.PubMedCrossRefGoogle Scholar
  36. Mecocci P., MacGarvey U., and Beal M. F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751.PubMedCrossRefGoogle Scholar
  37. Montine T. J., Markesbery W. R., Morrow J. D., and Roberts L. J. II (1998) Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease. Ann. Neurol. 44, 410–413.PubMedCrossRefGoogle Scholar
  38. Nakamura H., Nakamura K., and Yodoi J. (1997) Redox regulation of cellular activation. Annu. Rev. Immunol. 15, 351–369.PubMedCrossRefGoogle Scholar
  39. Page S., Fischer C., Baumgartner B., Haas M., Kreusel U., Loidl G., et al. (1999) 4-Hydroxynonenal prevents NF-kappaB activation and tumor necrosis factor expression by inhibiting IkappaB phosphorylation and subsequent proteolysis. J. Biol. Chem. 274, 11611–11618.PubMedCrossRefGoogle Scholar
  40. Parola M., Robino G., Marra F., Pinzani M., Bellomo G., Leonarduzzi G., et al. (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J. Clin. Invest. 102, 1942–1950.PubMedCrossRefGoogle Scholar
  41. Perkins A. J., Hendrie H. C., Callahan C. M., Gao S., Unverzagt F. W., Xu Y., et al. (1999) Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am. J. Epidemiol. 150, 37–44.PubMedGoogle Scholar
  42. Perrig W. J., Perrig P., and Stahelin H. B. (1997) The relation between antioxidants and memory performance in the old and very old. J. Am. Geriatr. Soc. 45, 718–724.PubMedGoogle Scholar
  43. Poli G. and Schaur R. J. (2000) 4-Hydroxynonenal in the pathomechanisms of oxidative stress. International Union of Biochemistry and Molecular Biology Life 50, 315–321.PubMedCrossRefGoogle Scholar
  44. Prasad M. R., Lovell M. A., Yatin M., Dhillon H., and Markesbery W. R. (1998) Regional membrane phospholipid alterations in Alzheimer’s disease. Neurochem. Res. 23, 81–88.PubMedCrossRefGoogle Scholar
  45. Rivas-Arancibia S., Vazquez-Sandoval R., Gonzalez-Kladiano D., Schneider-Rivas S., and Lechuga-Guerrero A. (1998) Effects of ozone exposure in rats on memory and levels of brain and pulmonary superoxide dismutase. Environ. Res. 76, 33–39.PubMedCrossRefGoogle Scholar
  46. Ross J. S., Stagliano N. E., Donovan M. J., Breitbart R. E., and Ginsburg G. S. (2001) Atherosclerosis: a cancer of the blood vessels? Am. J. Clin. Pathol. 116 (Suppl.), S97–107.PubMedGoogle Scholar
  47. Rusnak F. and Reiter T. (2000) Sensing electrons: protein phosphatase redox regulation. Trends Biochem. Sci. 25, 527–529.PubMedCrossRefGoogle Scholar
  48. Sano M., Ernesto C., Thomas R. G., Klauber M. R., Schafer K., Grundman M., (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222.PubMedCrossRefGoogle Scholar
  49. Sayre L. M., Zelasko D. A., Harris P. L., Perry G., Salomon R. G., and Smith M. A. (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J. Neurochem. 68, 2092–2097.PubMedCrossRefGoogle Scholar
  50. Senft A. P., Dalton T. P., and Shertzer H. G. (2000) Determining glutathione and glutathione disulfide using the fluorescence probe o-phthalaldehyde. Anal. Biochem. 280, 80–86.PubMedCrossRefGoogle Scholar
  51. Sinclair A. J., Bayer A. J., Johnston J., Warner C., and Maxwell S. R. (1998) Altered plasma antioxidant status in subjects with Alzheimer’s disease and vascular dementia. Int. J. Geriatr. Psychiatry 13, 840–845.PubMedCrossRefGoogle Scholar
  52. Stanton J., Boldogh I., Georgiades J. A., and Hughes T. K. (2001) Induction of proliferation and cytokines by colostrinin and component proline rich peptides in human peripheral blood leukocytes. Yearbook of Psychogeriatry 4, 67–75.Google Scholar
  53. Uchida K. and Stadtman E. R. (1992) Modification of histidine residues in proteins by reaction with 4-hydroxynonenal. Proc. Natl. Acad. Sci. USA 89, 4544–4548.PubMedCrossRefGoogle Scholar
  54. Vaglini F., Pardini C., Viaggi C., and Corsini G. U. (2001) Cytochrome P450 and parkinsonism: protective role of CYP2E1. Funct. Neurol. 16, 107–112.PubMedGoogle Scholar
  55. Woods D. B. and Vousden K. H. (2001) Regulation of p53 function. Exp. Cell Res. 264, 56–66.PubMedCrossRefGoogle Scholar
  56. Yoritaka A., Hattori N., Uchida K., Tanaka M., Stadtman E. R., and Mizuno Y. (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc. Natl. Acad. Sci. USA 93, 2696–2701.PubMedCrossRefGoogle Scholar
  57. Zimecki M. and Pierce A. (1984) Immunotropic properties of fractions isolated from human milk. Arch. Immunol. Ther. Exp. 32, 203–209.Google Scholar
  58. Zimecki M., Lisowski J., Hraba T., Wieczorek Z., Janusz M., and Staroscik K. (1984a) The effect of a proline-rich polypeptide (PRP) on the humoral immune response. I. Distinct effect of PRP on the T cell properties of mouse glass-nonadherent (NAT) and glass-adherent (GAT) thymocytes in thymectomized mice. Arch. Immunol. Ther. Exp. 32, 191–196.Google Scholar
  59. Zimecki M., Lisowski J., Hraba T., Wieczorek Z., Janusz M., and Staroscik K. (1984b) The effect of a proline-rich polypeptide (PRP) on the humoral immune response. II. PRP induces differentiation of helper cells from glassnonadherent thymocytes (NAT) and suppressor cells from glass-adherent thymocytes (GAT). Arch. Immunol. Ther. Exp. 32, 197–201.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Istvan Boldogh
    • 1
  • Daniel Liebenthal
    • 1
  • T. Kley Hughes
    • 1
  • Terry L. Juelich
    • 1
  • Jerzy A. Georgiades
    • 2
  • Marian L. Kruzel
    • 2
  • G. John Stanton
    • 1
    Email author
  1. 1.Department of Microbiology and ImmunologyThe University of Texas Medical BranchGalveston
  2. 2.ReGen Therapeutics, PlcLondonEngland

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