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

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 (3,3,and 4,. 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-erythroidderived-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.

Effects of Coffee Intake on Oxidative Stress During Aging-related Alterations in Periodontal Tissue

“…These findings suggest that coffee enhances the antioxidant status of periodontal tissue by upregulating the Nrf2 signaling pathway. This notion is consistent with the previous finding that chlorogenic acid in coffee relieves oxidative stress associated with intestinal inflammation (39).…”

“…High levels of the glutamate cysteine ligase modifier subunit, ferritin, and hypoxanthine phosphoribosyltransferase 1 genes were expressed in the 1.36% coffee group. Glutamate cysteine ligase modifier subunit is a rate-limiting enzyme in the synthesis of glutathione, which is the one of the most abundant intracellular antioxidants (31)(32)(33). Ferritin protects cells against iron-dependent oxidative stress and is involved in the regulation of oxidative stress (34,35).…”

Lactobacillus rhamnosus GG and Oat Beta‐Glucan Regulated Fatty Acid Profiles along the Gut‐Liver‐Brain Axis of Mice Fed with High Fat Diet and Demonstrated Antioxidant and Anti‐Inflammatory Potentials

“…Moreover, short‐term exposure to LPS and other stressors in in vitro studies served to upregulate the Nrf2 pathway as a normal cellular response. [ 42,43 ] Here, our prolonged exposure (three days) downregulated the Nrf2 expression in Caco‐2, modelling the impaired antioxidant capacity that is frequently observed in subjects with prolonged HFD intake. [ 44–48 ] Furthermore, the LPS‐induced suppression of Nrf2 is widely observed in different tissues and cell types in addition to Caco‐2.…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…Stilbenoids (resveratrol and pterostilbene), genistein, epigallocatechin gallate (EGCG), sulforaphane (SFN), curcumin, apigenin and coffee phenolic acids, for example, chlorogenic acid and caffeic acid are effective modulators of enzymatic antioxidants that originate from cellular regulation of redox balance. An example of this includes the capacity to activate the Nrf2 master transcription factor that modulates hundreds of genes involved in antioxidant processes and phase II enzyme detoxification (Kensler et al, ; Liang, Dupuis, Yada, & Kitts, ; Liang & Kitts, ). Interestingly, EGCG, genistein, and curcumin have also been shown to scavenge free radicals directly and inhibit lipid peroxidation (Hodaei, Adibian, Nikpayam, Hedayati, & Sohrab, ; Mao, Gu, Chen, Yu, & He, ; Saraf‐Bank, Ahmadi, Paknahad, Maracy, & Nourian, ).…”