Differential neurogenic effects of casein-derived opioid peptides on neuronal stem cells: implications for redox-based epigenetic changes.
Food-derived peptides, such as β-casomorphin BCM7, have potential to cross the gastrointestinal tract and blood-brain barrier and are associated with neurological disorders and neurodevelopmental disorders. We previously established a novel mechanism through which BCM7 affects the antioxidant levels in neuronal cells leading to inflammatory consequences. In the current study, we elucidated the effects of casein-derived peptides on neuronal development by using the neurogenesis of neural stem cells (NSCs) as an experimental model. First, the transient changes in intracellular thiol metabolites during NSC differentiation (neurogenesis) were investigated. Next, the neurogenic effects of food-derived opioid peptides were measured, along with changes in intracellular thiol metabolites, redox status and global DNA methylation levels. We observed that the neurogenesis of NSCs was promoted by human BCM7 to a greater extent, followed by A2-derived BCM9 in contrast to bovine BCM7, which induced increased astrocyte formation. The effect was most apparent when human BCM7 was administered for 1day starting on 3days postplating, consistent with immunocytochemistry. Furthermore, neurogenic changes regulated by bovine BCM7 and morphine were associated with an increase in the glutathione/glutathione disulfide ratio and a decrease in the S-adenosylmethionine/S-adenosylhomocysteine ratio, indicative of changes in the redox and the methylation states. Finally, bovine BCM7 and morphine decreased DNA methylation in differentiating NSCs. In conclusion, these results suggest that food-derived opioid peptides and morphine regulated neurogenesis and differentiation of NSCs through changes in the redox state and epigenetic regulation.
Department of Pharmaceutical Sciences, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, USA. Electronic address: mtrivedi@nova.edu.
Malav
M
Trivedi
Department of Pharmaceutical Sciences, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, USA.
Yiting
Y
Zhang
Department of Biology, Fischer School of Medicine, Florida Atlantic University, Jupiter Campus, FL, USA.
Miguel
M
Lopez-Toledano
The A2 Milk Company, Sydney, Australia.
Andrew
A
Clarke
Department of Pharmaceutical Sciences, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, USA.
Richard
R
Deth
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002364:Caseins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D004723:Endorphins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009020:Morphine / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D018847:Opioid Peptides / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012435:S-Adenosylhomocysteine / Q000737:chemistry / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism
D000701:Analgesics, Opioid; D002364:Caseins; D004723:Endorphins; D018847:Opioid Peptides; D010446:Peptide Fragments; C041128:beta-casomorphin 7; D009020:Morphine; C021968:beta-casomorphins; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D005978:Glutathione
Casein-derived opioid peptides; Epigenetic regulation; Neurogenesis; Neuronal stem cells; Redox state