Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum.
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.
Boldogh
Istvan
I
Department of Microbiology and Immunology. The University of Texas Medical Branch, Galveston, TX 77555, USA.
Liebenthal
Daniel
D
Hughes
T Kley
TK
Juelich
Terry L
TL
Georgiades
Jerzy A
JA
Kruzel
Marian L
ML
Stanton
G John
GJ
D000447:Aldehydes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D003126:Colostrum / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D000447:Aldehydes; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C105874:colostrinine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal