Amelioration of Oxidative Stress in Caco-2 Cells Treated with Pro-inflammatory Proteins by Chlorogenic Acid Isomers via Activation of the Nrf2–Keap1–ARE-Signaling Pathway
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Abstract
Understanding the potential effects of chlorogenic acid (CGA) isomers on the intestinal
epithelium is important because coffee intake exposes consumers to the six major CGA
isomers: 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), 5-caffeoylquinic
acid (5-CQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA),
and 4,5-dicaffeoylquinic acid (4,5-diCQA). The present study determined the relative
effects of CGA isomers on the antioxidant status of inflamed Caco-2 intestinal cells
by investigating the oxidative-stress-responsive pathway and nuclear-factor-erythroid-derived-2-like
2 (Nrf2) signaling. Differentiated Caco-2 cells were challenged with the inflammatory
mediators PMA and IFNγ, as a model of intestinal inflammation in vitro. Significant
redox ( p < 0.05) responses to these mediators were assessed by indirect measurement
of induced generation of reactive oxygen species (ROS), as well as the expression
of reduced (GSH) and oxidized (GSSG) glutathione. This translated to a 40% reduction
in the GSH/GSSG ratio. We found that responses in these parameters were associated
with increased Nrf2 activation ( p < 0.05). ROS generation and increased IL-8 secretion
were found in challenged cells, indicating an association between induced oxidation
and inflammatory status. Oxidative stress was ameliorated by CGA isomers, which scavenged
intracellular ROS, increased GSH, and activated Nrf2 signaling. diCQA isomers were
relatively more effective at reducing IL-8 ( p < 0.05). The observed increase in Nrf2
signaling led to upregulated expression of some Nrf2 target genes ( GPX2, KEAP1, and
NFE2L2) in Caco-2 cells and activated the Nrf2-Keap1-ARE-signaling pathway. These
findings indicate that CGA isomers present in coffee have bioactivity toward alleviating
oxidative stress associated with intestinal inflammation.
[1
]Food, Nutrition, and Health Program, Faculty of Land and Food Systems, The University
of British Columbia, 2205 East Mall, Vancouver, British Columbia V6T 1Z4, Canada