Iron-Ascorbate-Mediated Lipid Peroxidation Causes Epigenetic Changes in the Antioxidant Defense in Intestinal Epithelial Cells: Impact on Inflammation

Abstract

IntroductionThe 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.HypothesisSince 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.ResultsFe/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.ConclusionRedox and inflammatory modifications in response to Fe/Asc -mediated lipid peroxidation may implicate epigenetic methylation.

The investigation of anti-inflammatory activity of volatile oil of Angelica sinensis by plasma metabolomics approach

“…Ascorbate is a powerful water-soluble antioxidant [40] and could also inhibit the activation of myelo-peroxidase/H2O2/ halide system in the leukocytes, thus improving leukocyte movement [41,42]. In our study, the level of D-glucuronic acid in Model group increased compared with that in Control group, indicating that the body was stimulated to release more ascorbate to inhibit inflammatory reaction.…”

CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response

“…Of note, the iron dose used in the current study was moderate and comparable with normal iron concentrations in biological systems such as the gastrointestinal tract (2). We used Fe/Asc extensively as a strong oxygen radical-generating system in our previous studies (4,9,11,12,65,73). The data presented herein using MIN6 cells clearly indicate that the Fe/Asc system functions as a producer of lipid peroxidation, because the addition of the antioxidant Trolox simultaneously prevents the occurrence of lipid peroxidation and improves the cellular processes and functions.…”

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework

“…On the other hand, such relations are known for other toxicants, such as iron-ascorbate in human epithelial colorectal adenocarcinoma cells, where induced DNA methylation effects were related to altered antioxidative physiology, which could be restored by 5-aza. [35]. Regarding neurobehavior, prenatal, low concentration exposure to bisphenol A affected Dnmt1 and Gad67 expression in rat basolateral amygdala, leading to long term anxiety-like behavior [36].…”