title: Iron-ascorbate-mediated lipid peroxidation causes epigenetic changes in the antioxidant defense in intestinal epithelial cells: impact on inflammation.
abstract: BACKGROUND
  The gastrointestinal tract is frequently exposed to noxious stimuli that may cause oxidative stress, inflammation and injury. Intraluminal pro-oxidants from ingested nutrients especially iron salts and ascorbic acid frequently consumed together, can lead to catalytic formation of oxygen-derived free radicals that ultimately overwhelm the cellular antioxidant defense and lead to cell damage.
  
  
  OBJECTIVE
  Since the mechanisms remain sketchy, efforts have been exerted to evaluate the role of epigenetics in modulating components of endogenous enzymatic antioxidants in the intestine. To this end, Caco-2/15 cells were exposed to the iron-ascorbate oxygen radical-generating system.
  
  
  RESULTS
  Fe/Asc induced a significant increase in lipid peroxidation as reflected by the elevated formation of malondialdehyde along with the alteration of antioxidant defense as evidenced by raised superoxide dismutase 2 (SOD2) and diminished glutathione peroxidase (GPx) activities and genes. Consequently, there was an up-regulation of inflammatory processes illustrated by the activation of NF-κB transcription factor, the higher production of interleukin-6 and cycloxygenase-2 as well as the decrease of IκB. Assessment of promoter's methylation revealed decreased levels for SOD2 and increased degree for GPx2. On the other hand, pre-incubation of Caco-2/15 cells with 5-Aza-2'-deoxycytidine, a demethylating agent, or Trolox antioxidant normalized the activities of SOD2 and GPx, reduced lipid peroxidation and prevented inflammation.
  
  
  CONCLUSIONS
  Redox and inflammatory modifications in response to Fe/Asc -mediated lipid peroxidation may implicate epigenetic methylation.
authors.affiliation: Department of Nutrition, Research Centre, CHU-Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Yara
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lavoie
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
authors.forename: Edgard
authors.initials: E
authors.lastname: Delvin
authors.forename: Devendra
authors.initials: D
authors.lastname: Amre
authors.forename: Valerie
authors.initials: V
authors.lastname: Marcil
authors.forename: Ernest
authors.initials: E
authors.lastname: Seidman
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000009:adverse effects*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005609:Free Radicals / Q000009:adverse effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000196:embryology; D007501:Iron / Q000009:adverse effects*; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000235:genetics; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid; D051546:Cyclooxygenase 2; D005609:Free Radicals; D005979:Glutathione Peroxidase; D051550:I-kappa B Kinase; D015850:Interleukin-6; D007501:Iron; D008315:Malondialdehyde; D016328:NF-kappa B; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2