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Letter to the Editor

Quercetin and heat shock response☆ Dear Editor, In the July 2014 issue of Nutrition Research, Yifan Chen et al [1] showed that acute quercetin treatment improved redox status but did not affect heat shock response in a C57/BL/6J adult mouse model. They selected a single genetic mouse strain; however,genetic determinants may influence mouse response to injury [1,2]. The evidence reported by the authors led to the conclusion that quercetin should not affect the body’s ability to respond to heat-generated stressors [1]. Chen and colleagues used aglycone quercetin, rather than a glycosylated form; and quercetin plasma levels were not addressed in the experimental setting. The novelty reported by Chen et al raised some comments. Despite the most diffused opinion according to which quercetin suppresses heat shock response by inhibiting the heat-induced expression of heat shock proteins (HSPs), both directly and through heat shock factor 1 hyperphosphorylation and DNA binding modulation [3,4], the paper by Chen and colleagues [1] showed that the bioflavonoid affects either HSPs or heat shock factor 1. The effects on HSP may appear as an interesting novelty in the field. Interestingly, in C57/BL/6, Kim and colleagues [5] recently reported the presence of HSPreactive T regulatory (T-reg) cells, whose expansion was inhibited by the dampening effect exerted by quercetin on HSP70, a piece of evidence that raised comments particularly about the possibility of inducing HSP70 expression by the use of pharmacological agents to prevent and treat ischemic kidney injury [6]. Promoting cell response to stress has been related to healthspan and longevity, whereas lowering and inhibiting HSPs in cancer could enhance the effectiveness of chemoprevention against tumors [7]. Flavonoids play a major role in this context. Both quercetin in raw food and the biological context where it acts are fundamental issues for any debate on flavonoid function. Even T-reg response to quercetin could be a fine marker to probe the inflammatory injury due to heat stress, particularly because regulatory T cells need more time than the chemical activity on intracellular enzymatic and signaling systems needs. Furthermore, they modulate immune downregulation; therefore, T cells are proving to be reliable ☆

The author states that he has no conflict of interest.

http://dx.doi.org/10.1016/j.nutres.2015.01.006 0271-5317/© 2015 Elsevier Inc. All rights reserved.

hallmarks of a balanced response to stressors [8]. The authors limited their testing to immune markers such as inflammatory cytokines, but it would be very interesting to also assay T-reg– derived cytokines in plasma samples. This could add an interesting contribution and allow a better understanding of the issue. Although bioflavonoids have been described as molecules able to strengthen cell response to stress [9], the effect of different flavonoids depends on the many factors characterizing the complex behavior of dietary raw sources [10] and gut microflora metabolism [11]. The apparently contradictory evidence about quercetin in cell stress response might be attributed to actions, both pro and anti, which relate the flavonol to either potential benefit [12,13] or potential toxicity [14], depending mostly on the cell “stress-responding” state. Although the pharmacological “ambiguity” of plant flavonoids plays a major role in slowing down the enthusiastic consideration about the beneficial potential of quercetin, nutrition and pharmacology are still not proceeding at the same pace, most likely because of the use of de facto different chemical sources. Additional research and discussion are needed to elucidate the actions of bioflavonoids. Salvatore Chirumbolo Department of Medicine-University of Verona-Italy, LURM Est Policlinico GB Rossi, Piazziale AL Scuro 10, 37134 Verona, Italy Tel.: +39 0 458128456; fax: +39 0 458027403 E-mail address: [email protected]


[1] Chen Y, Islam A, abraham P, Deuster P. Single-dose oral quercetin improves redox status but does not affect heat shock response in mice. Nutr Res 2014;34(7):623–9. [2] De Maio A, Torres MB, Reeves RH. Genetic determinants influencing the response to injury, inflammation and sepsis. Shock 2005;23(1):11–7. [3] Nagai N, Nakai A, Nagata K. Quercetin suppresses heat shock response by down regulation of HSF1. Biochem Biophys Res Commun 1995;208(3):1099–105. [4] Powers MV, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 2007;581(19):3758–69.


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[5] Kim MG, Jung Cho E, Won Lee J, Sook Ko Y, Young Lee H, Jo SK, et al. The heat-shock protein-70-induced renoprotective effect is partially mediated by CD4+ CD25+ Foxp3+ regulatory T cells in ischemia/reperfusion-induced acute kidney injury. Kidney Int 2014;85(1):62–71. [6] O'Neill S, Hughes J. Heat-shock protein–70 and regulatory T cell–mediated protection from ischemic injury. Kidney Int 2014;85(1):5–7. [7] Tytell M, Hooper PL. Heat shock proteins: new keys to the development of cytoprotective therapies. Expert Opin Ther Targets 2001;5(2):267–87. [8] Peterson RA. Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol Pathol 2012;40(2):186–204. [9] Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ. Vitagenes, cellular stress response, and acetylcarnitine: relevance to hormesis. Biofactors 2009;35(2):146–60.

[10] Cheynier V. Polyphenols in foods are more complex than often thought. Am J Clin Nutr 2005;81(1 Suppl.):223S–9S. [11] Moco S, Martin FP, Rezzi S. Metabolomics view on gut microbiome modulation by polyphenol-rich foods. J Proteome Res 2012;11(10):4781–90. [12] Petrussa E, Braidot E, Zancani M, Peresson C, Bertolini A, Patui S, et al. Plant flavonoids—biosynthesis, transport and involvement in stress responses. Int J Mol Sci 2013;14(7): 14950–73. [13] Brodniewicz T, Grynkiewicz G. Plant phenolics as drug leads—what is missing? Acta Pol Pharm 2012;69(6): 1203–17. [14] Chen R, Lin J, Hong J, Han D, Zhang AD, Lan R, et al. Potential toxicity of quercetin: the repression of mitochondrial copy number via decreased POLG expression and excessive TFAM expression in irradiated murine bone marrow. Toxicol Rep 2014;1:450–8.

Quercetin and heat shock response.

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