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Toxicol Appl Pharmacol. 2015 Oct 15;288(2):161-78. doi: 10.1016/j.taap.2015.07.007. Epub 2015 Jul 14.

Antioxidant potential of CORM-A1 and resveratrol during TNF-α/cycloheximide-induced oxidative stress and apoptosis in murine intestinal epithelial MODE-K cells.

Author information

1
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Belgium. Electronic address: dinesh.babu@ugent.be.
2
Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Belgium.
3
Inflammation Research Center, Molecular Signaling and Cell Death Unit, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Molecular Signaling and Cell Death Unit, Ghent University, Ghent, Belgium.
4
Inserm U955, Equipe 12 and University Paris-Est Créteil, Faculty of Medicine, F-94000 Créteil, France.
5
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Belgium.

Abstract

Targeting excessive production of reactive oxygen species (ROS) could be an effective therapeutic strategy to prevent oxidative stress-associated gastrointestinal inflammation. NADPH oxidase (NOX) and mitochondrial complexes (I and II) are the major sources of ROS production contributing to TNF-α/cycloheximide (CHX)-induced apoptosis in the mouse intestinal epithelial cell line, MODE-K. In the current study, the influence of a polyphenolic compound (resveratrol) and a water-soluble carbon monoxide (CO)-releasing molecule (CORM-A1) on the different sources of TNF-α/CHX-induced ROS production in MODE-K cells was assessed. This was compared with H2O2-, rotenone- or antimycin-A-induced ROS-generating systems. Intracellular total ROS, mitochondrial-derived ROS and mitochondrial superoxide anion (O2(-)) production levels were assessed. Additionally, the influence on TNF-α/CHX-induced changes in mitochondrial membrane potential (Ψm) and mitochondrial function was studied. In basal conditions, CORM-A1 did not affect intracellular total or mitochondrial ROS levels, while resveratrol increased intracellular total ROS but reduced mitochondrial ROS production. TNF-α/CHX- and H2O2-mediated increase in intracellular total ROS production was reduced by both resveratrol and CORM-A1, whereas only resveratrol attenuated the increase in mitochondrial ROS triggered by TNF-α/CHX. CORM-A1 decreased antimycin-A-induced mitochondrial O2(-) production without any influence on TNF-α/CHX- and rotenone-induced mitochondrial O2(-) levels, while resveratrol abolished all three effects. Finally, resveratrol greatly reduced and abolished TNF-α/CHX-induced mitochondrial depolarization and mitochondrial dysfunction, while CORM-A1 only mildly affected these parameters. These data indicate that the cytoprotective effect of resveratrol is predominantly due to mitigation of mitochondrial ROS, while CORM-A1 acts solely on NOX-derived ROS to protect MODE-K cells from TNF-α/CHX-induced cell death. This might explain the more pronounced cytoprotective effect of resveratrol.

KEYWORDS:

CORM-A1; Intestinal epithelial cells; Mitochondria; NADPH oxidase; Resveratrol; TNF-α/CHX

PMID:
26187750
DOI:
10.1016/j.taap.2015.07.007
[Indexed for MEDLINE]

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