Abstract
Chlorogenic acid (CGA) exists as multiple isomers (e.g., 3-CQA, 4-CQA, 5-CQA, 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA) in foods such as coffee beverages, fruits and vegetables. This study aimed to investigate relative activities of these six different CGA isomers to modify redox biology in inflamed Caco-2 cells that involved Nrf2 signaling. Caco-2 cells were pre-treated with individual CGA isomers to assess the relative effectiveness to mitigate oxidative stress. Isomer-specific capacity of different CGA isomers for direct free radical scavenging activity and potential endogenous control of oxidative stress were determined using chemical assays and cell-based experiments, respectively. Molecular dynamics simulations of the CGA and Keap1-Nrf2 complex were performed to predict CGA structure-specific interactions. Results demonstrated that dicaffeoylquinic acid (diCQA including 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA) isomers had greater (p < 0.05) affinity to ameliorate oxidative stress through direct free radical scavenging activity. This observation corresponded to greater (p < 0.05) capacity to activate Nrf2 signaling compared to caffeoylquinic acid (CQA including 3-CQA, 4-CQA, and 5-CQA) isomers in inflamed differentiated Caco-2 cells. Simulations revealed that differences between the ability of CQA and diCQA to interact with the Keap1-Nrf2 complex may be due to differences in relative orientation within this complex. The observed CGA isomer-specific affinity for CQA to activate Nrf2 signaling was confirmed by nuclear translocation of Nrf2 induced by CGA and greater (p < 0.05) upregulation of genes related to Nrf2 expression.
Highlights
IntroductionThe ester formed between one molecule of caffeic acid and one molecular of quinic acid is called caffeoylquinic acid (CQA)
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Chlorogenic acids (CGAs) are phenolic acids with vicinal hydroxyl groups present on aromatic residues that are derived from esterification of cinnamic acids and quinic acid [1, 2]
Different letters indicate significant (p < 0.05) differences observed between treatment groups analyzed by one-way ANOVA followed by Bonferroni post hoc analysis at p < 0.05 using GraphPad Prism
Summary
The ester formed between one molecule of caffeic acid and one molecular of quinic acid is called caffeoylquinic acid (CQA). The ester formed between two molecules of caffeic acid, and one molecular quinic acid is called dicaffeoylquinic acid (diCQA); 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA are isomers within the diCQA subgroup that are commonly present in many plant foods [3]. As a direct-acting antioxidant, CGAs interact with both reactive oxygen species (ROS) and reactive nitrogen species (RNS) by donating hydrogen atoms to reactive molecules to transform them to less active radicals [6,7,8]. The CGAs may act to prevent excessive generation of free radicals within the cell, important because without coupling with endogenous ROS control, subsequent biological damage of important cellular constituents will result [10]. A complete understanding of this complex multifunctional affinity to control redox balance in intestinal cells is still in question
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