Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • 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.

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Buettner G. R. (1993) The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch. Biochem. Biophys. 300, 535–543.

    Article  PubMed  CAS  Google Scholar 

  • Cadenas E. and Davies K. J. (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222–230.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Davies M. J. and Truscott R. J. (2001) Photo-oxidation of proteins and its role in cataractogenesis. J. Photochem. Photobiol. B 63, 114–125.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Evan G. and Littlewood T. (1998) A matter of life and cell death. Science 281, 1317–1322.

    Article  PubMed  CAS  Google Scholar 

  • Finkel T. Holbrook N. J. (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hainaut P. and Milner J. (1993) Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Res. 53, 4469–4473.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Janusz, M. and Lisowski J. (1993) Proline-rich polypeptide (PRP)—an immunomodulatory peptide from ovine colostrum. Arch. Immunol. Ther. Exp. 41, 275–279.

    CAS  Google Scholar 

  • Janusz M., Lisowski J., and Franek F. (1974) Isolation and characterization of a proline-rich polypeptide from ovine colostrum. FEBS Lett. 49, 276–279.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Markesbery W. R. (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic. Biol. Med. 23, 137–147.

    Article  Google Scholar 

  • Markesbery W. R. and Carney J. M. (1999) Oxidative alterations in Alzheimer’s disease. Brain Pathol. 9, 133–146.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Mattson M. P. and Furukawa K. (1997) Alzheimer’s disease. Short precursor shortens memory. Nature 387, 457–458.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H., Nakamura K., and Yodoi J. (1997) Redox regulation of cellular activation. Annu. Rev. Immunol. 15, 351–369.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Rusnak F. and Reiter T. (2000) Sensing electrons: protein phosphatase redox regulation. Trends Biochem. Sci. 25, 527–529.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Vaglini F., Pardini C., Viaggi C., and Corsini G. U. (2001) Cytochrome P450 and parkinsonism: protective role of CYP2E1. Funct. Neurol. 16, 107–112.

    PubMed  CAS  Google Scholar 

  • Woods D. B. and Vousden K. H. (2001) Regulation of p53 function. Exp. Cell Res. 264, 56–66.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Zimecki M. and Pierce A. (1984) Immunotropic properties of fractions isolated from human milk. Arch. Immunol. Ther. Exp. 32, 203–209.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, The University of Texas Medical Branch, 77555, Galveston, TX

    Istvan Boldogh, Daniel Liebenthal, T. Kley Hughes, Terry L. Juelich & G. John Stanton

  2. ReGen Therapeutics, Plc, London, England

    Jerzy A. Georgiades & Marian L. Kruzel

Authors
  1. Istvan Boldogh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Liebenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Kley Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terry L. Juelich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jerzy A. Georgiades
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marian L. Kruzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. John Stanton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. John Stanton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boldogh, I., Liebenthal, D., Hughes, T.K. et al. Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. J Mol Neurosci 20, 125–134 (2003). https://doi.org/10.1385/JMN:20:2:125

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:20:2:125

Index Entries

Search

Navigation