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Quercetin mitigates valinomycin-induced cellular stress via stress-induced metabolism and cell uptake

Gerard Gonzales (UGent) , Guy Smagghe (UGent) , Hanne Vissenaekens (UGent) , Charlotte Grootaert (UGent) , Andreja Rajkovic (UGent) , Tom Van de Wiele (UGent) , Katleen Raes (UGent) and John Van Camp (UGent)
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Abstract
Scope: Intestinal cells are constantly exposed to luminal toxins. In this study, we investigated the effect of cellular stress caused by valinomycin, which is structurally and functionally similar to the bacterial toxin cereulide, on quercetin metabolism and cellular localization in undifferentiated cells. Methods and results: Coadministration of quercetin and valinomycin (50 mu M quercetin/0.05 mu M valinomycin) reduced intracellular reactive oxygen species content and increased cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) of Caco-2 cells compared to valinomycin-only (0.05 mu M) treatment. Quercertin was effectively metabolized into methyl, glucuronide, and sulfate conjugates, which were mostly secreted into to the culture medium. Three different O-methylated quercetin isomers were detected. Two were exported from the cells and one remained intracellularly. Further, valinomycin caused an increase in the intracellular accumulation of O-methylated quercetin metabolites compared to cells treated only with quercetin. In valinomycin-untreated cells, quercetin and O-methylated quercetin metabolite were localized in the cell membrane, whereas valinomycin treatment resulted in their uptake by the cells. Conclusion: This is the first report on the change in metabolism, localization, and accumulation of O-methylated quercetin metabolites in undifferentiated Caco-2 cells as a response during stress caused by valinomycin. These results indicate a potential cellular stress response mechanism in undifferentiated Caco-2 cells, which adds novel insights into the mechanisms of flavonoid cellular bioactivity.
Keywords
Metabolism, Caco-2, Methylquercetin, Quercetin, Valinomycin, ANTIOXIDANT ACTIVITY RELATIONSHIPS, CACO-2 CELLS, CAULIFLOWER WASTE, MASS-SPECTROMETRY, IN-VITRO, FLAVONOIDS, PERMEABILITY, ABSORPTION, MEMBRANES, MODEL

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Chicago
Gonzales, Gerard, Guy Smagghe, Hanne Vissenaekens, Charlotte Grootaert, Andreja Rajkovic, Tom Van de Wiele, Katleen Raes, and John Van Camp. 2016. “Quercetin Mitigates Valinomycin-induced Cellular Stress via Stress-induced Metabolism and Cell Uptake.” Molecular Nutrition & Food Research 60 (5): 972–980.
APA
Gonzales, G., Smagghe, G., Vissenaekens, H., Grootaert, C., Rajkovic, A., Van de Wiele, T., Raes, K., et al. (2016). Quercetin mitigates valinomycin-induced cellular stress via stress-induced metabolism and cell uptake. MOLECULAR NUTRITION & FOOD RESEARCH, 60(5), 972–980.
Vancouver
1.
Gonzales G, Smagghe G, Vissenaekens H, Grootaert C, Rajkovic A, Van de Wiele T, et al. Quercetin mitigates valinomycin-induced cellular stress via stress-induced metabolism and cell uptake. MOLECULAR NUTRITION & FOOD RESEARCH. 2016;60(5):972–80.
MLA
Gonzales, Gerard, Guy Smagghe, Hanne Vissenaekens, et al. “Quercetin Mitigates Valinomycin-induced Cellular Stress via Stress-induced Metabolism and Cell Uptake.” MOLECULAR NUTRITION & FOOD RESEARCH 60.5 (2016): 972–980. Print.
@article{7214860,
  abstract     = {Scope: Intestinal cells are constantly exposed to luminal toxins. In this study, we investigated the effect of cellular stress caused by valinomycin, which is structurally and functionally similar to the bacterial toxin cereulide, on quercetin metabolism and cellular localization in undifferentiated cells. 
Methods and results: Coadministration of quercetin and valinomycin (50 mu M quercetin/0.05 mu M valinomycin) reduced intracellular reactive oxygen species content and increased cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) of Caco-2 cells compared to valinomycin-only (0.05 mu M) treatment. Quercertin was effectively metabolized into methyl, glucuronide, and sulfate conjugates, which were mostly secreted into to the culture medium. Three different O-methylated quercetin isomers were detected. Two were exported from the cells and one remained intracellularly. Further, valinomycin caused an increase in the intracellular accumulation of O-methylated quercetin metabolites compared to cells treated only with quercetin. In valinomycin-untreated cells, quercetin and O-methylated quercetin metabolite were localized in the cell membrane, whereas valinomycin treatment resulted in their uptake by the cells. 
Conclusion: This is the first report on the change in metabolism, localization, and accumulation of O-methylated quercetin metabolites in undifferentiated Caco-2 cells as a response during stress caused by valinomycin. These results indicate a potential cellular stress response mechanism in undifferentiated Caco-2 cells, which adds novel insights into the mechanisms of flavonoid cellular bioactivity.},
  author       = {Gonzales, Gerard and Smagghe, Guy and Vissenaekens, Hanne and Grootaert, Charlotte and Rajkovic, Andreja and Van de Wiele, Tom and Raes, Katleen and Van Camp, John},
  issn         = {1613-4125},
  journal      = {MOLECULAR NUTRITION \& FOOD RESEARCH},
  keyword      = {Metabolism,Caco-2,Methylquercetin,Quercetin,Valinomycin,ANTIOXIDANT ACTIVITY RELATIONSHIPS,CACO-2 CELLS,CAULIFLOWER WASTE,MASS-SPECTROMETRY,IN-VITRO,FLAVONOIDS,PERMEABILITY,ABSORPTION,MEMBRANES,MODEL},
  language     = {eng},
  number       = {5},
  pages        = {972--980},
  title        = {Quercetin mitigates valinomycin-induced cellular stress via stress-induced metabolism and cell uptake},
  url          = {http://dx.doi.org/10.1002/mnfr.201500999},
  volume       = {60},
  year         = {2016},
}

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