title: Antioxidative stress effect of phosphoserine dimers is mediated via activation of the Nrf2 signaling pathway.
abstract: METHODS
  Phosphoserine-containing peptides have been shown to exert antioxidative stress effects, by lowering lipid peroxidation, increasing intracellular glutathione, and increasing the expression of antioxidant enzymes in human intestinal epithelial cells. However, the role of phosphoserine residues in antioxidative stress activity, and their mechanism of action, remains unknown.
  
  
  RESULTS
  The antioxidative stress activity of phosphoserine and phosphoserine peptides was examined using an in vitro model of hydrogen peroxide (H2 O2 )-induced oxidative stress in Caco-2 cells. Phosphoserine dimers (2PS) reduced IL-8 secretion in H2 O2 -treated Caco-2 cells, and reduced H2 O2 -induced expression of genes involved in inflammation and generation of reactive oxygen species (ROS), including chemokine (C-C motif) ligand 5 (CCL5), lactoperoxidase (LPO), myeloperoxidase (MPO), neutrophil cytosolic factor 1/2 (NCF1/2), and nitric oxide synthase 2A (NOS2), and upregulated metallothionein 3 (MT3), peroxiredoxin 3 (PRDX3), and surfactant, pulmonary-associated protein D (SFTPD), which are involved in protection against oxidative stress and activation of the Nrf2 signaling pathway. At the protein level, 2PS reduced H2 O2 -induced phosphorylation of the ERK1/2 and JNK MAPKs, and increased Nrf2 expression. Moreover, the ability of 2PS to reduce H2 O2 -induced IL-8 secretion, a marker of inflammation and oxidative stress, was abrogated in Nrf2 knockdown cells.
  
  
  CONCLUSIONS
  These results suggest that 2PS reduce H2 O2 -induced oxidative stress via the Nrf2 signaling pathway, and reveal a potential mechanism for the antioxidative stress activity of phosphoserine-containing peptides.
authors.affiliation: Department of Food Science, University of Guelph, Guelph, ON, Canada.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mine
authors.forename: Denise
authors.initials: D
authors.lastname: Young
authors.forename: Chengbo
authors.initials: C
authors.lastname: Yang
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D018938:Caco-2 Cells; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000378:metabolism; D007784:Lactoperoxidase / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation; D000090023:Metallothionein 3; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D061105:Peroxiredoxin III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; C483024:CCL5 protein, human; C508606:CXCL8 protein, human; D018946:Chemokine CCL5; D016209:Interleukin-8; D000090023:Metallothionein 3; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009419:Nerve Tissue Proteins; D011108:Polymers; D017382:Reactive Oxygen Species; D010768:Phosphoserine; D006861:Hydrogen Peroxide; D007784:Lactoperoxidase; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D009195:Peroxidase; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; C527764:NCF2 protein, human; C060505:neutrophil cytosolic factor 1
keywords: Cell signaling pathway; Hydrogen peroxide; Nrf2; Oxidative stress; Phosphopeptides