Skip to main content

Advertisement

SpringerLink
Log in

Effect of the flavonoids quercetin and taxifolin on UVA-induced damage to human primary skin keratinocytes and fibroblasts

  • Original Papers
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

The ultraviolet (UV) part of solar radiation can permanently affect skin tissue. UVA photons represent the most abundant UV component and stimulate the formation of intracellular reactive oxygen species (ROS), leading to oxidative damage to various biomolecules. Several plant-derived polyphenols are known as effective photoprotective agents. This study evaluated the potential of quercetin (QE) and its structurally related flavonoid taxifolin (TA) to reduce UVA-caused damage to human primary dermal fibroblasts (NHDF) and epidermal keratinocytes (NHEK) obtained from identical donors. Cells pre-treated with QE or TA (1 h) were then exposed to UVA light using a solar simulator. Both flavonoids effectively prevented oxidative damage, such as ROS generation, glutathione depletion, single-strand breaks formation and caspase-3 activation in NHDF. These protective effects were accompanied by stimulation of Nrf2 nuclear translocation, found in non-irradiated and irradiated NHDF and NHEK, and expression of antioxidant proteins, such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and catalase. For most parameters, QE was more potent than TA. On the other hand, TA demonstrated protection within the whole concentration range, while QE lost its protective ability at the highest concentration tested (75 μM), suggesting its pro-oxidative potential. In summary, QE and TA demonstrated UVA-protective properties in NHEK and NHDF obtained from identical donors. However, due to the in vitro phototoxic potential of QE, published elsewhere and discussed herein, further studies are needed to evaluate QE safety in dermatological application for humans as well as to confirm our results on human skin ex vivo and in clinical trials.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  1. Svobodová, A., Walterová, D., & Vostálová, J. (2006). Ultraviolet light-induced alteration to the skin. Biomedical Papers of the Faculty of Medicine of Palacký University, Olomouc Czech Republic, 150(1), 25–38. https://doi.org/10.5507/bp.2006.003

    Article  Google Scholar 

  2. Gęgotek, A., & Skrzydlewska, E. (2015). The role of transcription factor Nrf2 in skin cells metabolism. Archives of Dermatological Research, 307(5), 385–396. https://doi.org/10.1007/s00403-015-1554-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Svobodová, A., & Vostálová, J. (2010). Solar radiation induced skin damage: Review of protective and preventive options. International Journal of Radiation Biology, 86(12), 999–1030. https://doi.org/10.3109/09553002.2010.501842

    Article  CAS  PubMed  Google Scholar 

  4. Saewan, N., & Jimtaisong, A. (2015). Natural products as photoprotection. Journal of Cosmetic Dermatology, 14(1), 47–63. https://doi.org/10.1111/jocd.12123

    Article  PubMed  Google Scholar 

  5. Andres, S., Pevny, S., Ziegenhagen, R., Bakhiya, N., Schäfer, B., Hirsch-Ernst, K. I., & Lampen, A. (2018). Safety aspects of the use of quercetin as a dietary supplement. Molecular Nutrition & Food Research, 62(1), 1. https://doi.org/10.1002/mnfr.201700447

    Article  CAS  Google Scholar 

  6. D’Andrea, G. (2015). Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia, 106, 256–271. https://doi.org/10.1016/j.fitote.2015.09.018

    Article  CAS  PubMed  Google Scholar 

  7. Zhu, X., Li, N., Wang, Y., Ding, L., Chen, H., Yu, Y., & Shi, X. (2017). Protective effects of quercetin on UVB irradiation-induced cytotoxicity through ROS clearance in keratinocyte cells. Oncology Reports, 37(1), 209–218. https://doi.org/10.3892/or.2016.5217

    Article  PubMed  Google Scholar 

  8. Casagrande, R., Georgetti, S. R., Verri, W. A., Jr., Dorta, D. J., dos Santos, A. C., & Fonseca, M. J. (2006). Protective effect of topical formulations containing quercetin against UVB-induced oxidative stress in hairless mice. Journal of Photochemistry and Photobiology B: Biology, 84(1), 21–27. https://doi.org/10.1016/j.jphotobiol.2006.01.006

    Article  CAS  Google Scholar 

  9. Vicentini, F. T., Simi, T. R., Del Ciampo, J. O., Wolga, N. O., Pitol, D. L., Iyomasa, M. M., Bentley, M. V., & Fonseca, M. J. (2008). Quercetin in w/o microemulsion: In vitro and in vivo skin penetration and efficacy against UVB-induced skin damages evaluated in vivo. European Journal of Pharmaceutics and Biopharmaceutics, 69(3), 948–957. https://doi.org/10.1016/j.ejpb.2008.01.012

    Article  CAS  PubMed  Google Scholar 

  10. Choquenet, B., Couteau, C., Paparis, E., & Coiffard, L. J. (2008). Quercetin and rutin as potential sunscreen agents: Determination of efficacy by an in vitro method. Journal of Natural Products, 71(6), 1117–1118. https://doi.org/10.1021/np7007297

    Article  CAS  PubMed  Google Scholar 

  11. Erden Inal, M., & Kahraman, A. (2000). The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. Toxicology, 154(1–3), 21–29. https://doi.org/10.1016/s0300-483x(00)00268-7

    Article  CAS  PubMed  Google Scholar 

  12. Erden Inal, M., Kahraman, A., & Köken, T. (2001). Beneficial effects of quercetin on oxidative stress induced by ultraviolet A. Clinical and Experimental Dermatology, 26(6), 536–539. https://doi.org/10.1046/j.1365-2230.2001.00884.x

    Article  CAS  PubMed  Google Scholar 

  13. Kahraman, A., & Erden Inal, M. (2002). Protective effects of quercetin on ultraviolet A light-induced oxidative stress in the blood of rat. Journal of Applied Toxicology, 22(5), 303–309. https://doi.org/10.1002/jat.863

    Article  CAS  PubMed  Google Scholar 

  14. Maini, S., Fahlman, B. M., & Krol, E. S. (2015). Flavonols protect against UV radiation-induced thymine dimer formation in an artificial skin mimic. Journal of Pharmacy and Pharmaceutical Sciences, 18(4), 600–615. https://doi.org/10.18433/j34w39

    Article  PubMed  Google Scholar 

  15. Kimura, S., Warabi, E., Yanagawa, T., Ma, D., Itoh, K., Ishii, Y., Kawachi, Y., & Ishii, T. (2009). Essential role of Nrf2 in keratinocyte protection from UVA by quercetin. Biochemical and Biophysical Research Communications, 387(1), 109–114. https://doi.org/10.1016/j.bbrc.2009.06.136

    Article  CAS  PubMed  Google Scholar 

  16. Dall’Acqua, S., Miolo, G., Innocenti, G., & Caffieri, S. (2012). The photodegradation of quercetin: Relation to oxidation. Molecules, 17(8), 8898–8907. https://doi.org/10.3390/molecules17088898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Minner, F., Herphelin, F., & Poumay, Y. (2010). Study of epidermal differentiation in human keratinocytes cultured in autocrine conditions. Methods in Molecular Biology, 585, 71–82. https://doi.org/10.1007/978-1-60761-380-0_6

    Article  CAS  PubMed  Google Scholar 

  18. Pivodová, V., Franková, J., Galandáková, A., & Ulrichová, J. (2015). In vitro AuNPs’ cytotoxicity and their effect on wound healing. Nanobiomedicine (Rij), 2, 7. https://doi.org/10.5772/61132

    Article  Google Scholar 

  19. RajnochováSvobodová, A., Zálešák, B., Biedermann, D., Ulrichová, J., & Vostálová, J. (2016). Phototoxic potential of silymarin and its bioactive components. Journal of Photochemistry and Photobiology B: Biology, 156, 61–68. https://doi.org/10.1016/j.jphotobiol.2016.01.011

    Article  CAS  Google Scholar 

  20. RajnochováSvobodová, A., Gabrielová, E., Michaelides, L., Kosina, P., Ryšavá, A., Ulrichová, J., Zálešák, B., & Vostálová, J. (2018). UVA-photoprotective potential of silymarin and silybin. Archives of Dermatological Research, 310(5), 413–424. https://doi.org/10.1007/s00403-018-1828-6

    Article  CAS  Google Scholar 

  21. Ryšavá, A., Čížková, K., Franková, J., Roubalová, L., Ulrichová, J., Vostálová, J., Vrba, J., Zálešák, B., & RajnochováSvobodová, A. (2020). Effect of UVA radiation on the Nrf2 signalling pathway in human skin cells. Journal of Photochemistry and Photobiology B: Biology, 209, 111948. https://doi.org/10.1016/j.jphotobiol.2020.111948

    Article  CAS  Google Scholar 

  22. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 25(4), 402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  23. Rajnochová Svobodová, A., Ryšavá, A., Psotová, M., Kosina, P., Zálešák, B., Ulrichová, J., & Vostálová, J. (2017). The phototoxic potential of the flavonoids, taxifolin and quercetin. Photochemistry and Photobiology, 93(5), 1240–1247. https://doi.org/10.1111/php.12755

    Article  CAS  PubMed  Google Scholar 

  24. Hatahet, T., Morille, M., Hommoss, A., Devoisselle, J. M., Müller, R. H., & Bégu, S. (2016). Quercetin topical application, from conventional dosage forms to nanodosage forms. European Journal of Pharmaceutics and Biopharmaceutics, 108, 41–53. https://doi.org/10.1016/j.ejpb.2016.08.011

    Article  CAS  PubMed  Google Scholar 

  25. Svobodová, A., Walterová, D., & Psotová, J. (2006). Influence of silymarin and its flavonolignans on H(2)O(2)-induced oxidative stress in human keratinocytes and mouse fibroblasts. Burns, 32(8), 973–979. https://doi.org/10.1016/j.burns.2006.04.004

    Article  PubMed  Google Scholar 

  26. Živković, L., Bajić, V., Topalović, D., Bruić, M., & Spremo-Potparević, B. (2019). Antigenotoxic effects of biochaga and dihydroquercetin (taxifolin) on H2O2-induced DNA damage in human whole blood cells. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2019/5039372

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chaiprasongsuk, A., Onkoksoong, T., Pluemsamran, T., Limsaengurai, S., & Panich, U. (2016). Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses. Redox Biology, 8, 79–90. https://doi.org/10.1016/j.redox.2015.12.006

    Article  CAS  PubMed  Google Scholar 

  28. Ryšavá, A., Vostálová, J., & RajnochováSvobodová, A. (2021). Effect of ultraviolet radiation on the Nrf2 signalling pathway in skin cells. International Journal of Radiation Biology. https://doi.org/10.1080/09553002.2021.1962566

    Article  PubMed  Google Scholar 

  29. Zhao, Y., Zhang, C. F., Rossiter, H., Eckhart, L., König, U., Karner, S., Mildner, M., Bochkov, V. N., Tschachler, E., & Gruber, F. (2013). Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes. Journal of Investigative Dermatology, 133(6), 1629–1637. https://doi.org/10.1038/jid.2013.26

    Article  CAS  PubMed  Google Scholar 

  30. Applegate, L. A., Noël, A., Vile, G., Frenk, E., & Tyrrell, R. M. (1995). Two genes contribute to different extents to the heme oxygenase enzyme activity measured in cultured human skin fibroblasts and keratinocytes: Implications for protection against oxidant stress. Photochemistry and Photobiology, 61(3), 285–291. https://doi.org/10.1111/j.1751-1097.1995.tb03973.x

    Article  CAS  PubMed  Google Scholar 

  31. Niggli, H. J., & Applegate, L. A. (1997). Glutathione response after UVA irradiation in mitotic and postmitotic human skin fibroblasts and keratinocytes. Photochemistry and Photobiology, 65(4), 680–684. https://doi.org/10.1111/j.1751-1097.1997.tb01911.x

    Article  CAS  PubMed  Google Scholar 

  32. Kuang, H., Tang, Z., Zhang, C., Wang, Z., Li, W., Yang, C., Wang, Q., Yang, B., & Kong, A. N. (2017). Taxifolin activates the Nrf2 anti-oxidative stress pathway in mouse skin epidermal JB6 P+ cells through epigenetic modifications. International Journal of Molecular Sciences, 18(7), 1546. https://doi.org/10.3390/ijms18071546

    Article  CAS  PubMed Central  Google Scholar 

  33. Xie, X., Feng, J., Kang, Z., Zhang, S., Zhang, L., Zhang, Y., Li, X., & Tang, Y. (2017). Taxifolin protects RPE cells against oxidative stress-induced apoptosis. Molecular Vision, 23, 520–528.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Liang, L., Gao, C., Luo, M., Wang, W., Zhao, C., Zu, Y., Efferth, T., & Fu, Y. (2013). Dihydroquercetin (DHQ) induced HO-1 and NQO1 expression against oxidative stress through the Nrf2-dependent antioxidant pathway. Journal of Agricultural and Food Chemistry, 61(11), 2755–2761. https://doi.org/10.1021/jf304768p

    Article  CAS  PubMed  Google Scholar 

  35. Islam, J., Shree, A., Vafa, A., Afzal, S. M., & Sultana, S. (2021). Taxifolin ameliorates benzo[a]pyrene-induced lung injury possibly via stimulating the Nrf2 signalling pathway. International Immunopharmacology, 96, 107566. https://doi.org/10.1016/j.intimp.2021.107566

    Article  CAS  PubMed  Google Scholar 

  36. Wang, W., Ma, B. L., Xu, C. G., & Zhou, X. J. (2020). Dihydroquercetin protects against renal fibrosis by activating the Nrf2 pathway. Phytomedicine, 69, 153185. https://doi.org/10.1016/j.phymed.2020.153185

    Article  CAS  PubMed  Google Scholar 

  37. Chan, K., & Kan, Y. W. (1999). Nrf2 is essential for protection against acute pulmonary injury in mice. Proceedings of the National Academy of Sciences of the United States of America, 96(22), 12731–12736. https://doi.org/10.1073/pnas.96.22.12731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shindo, Y., & Hashimoto, T. (1997). Time course of changes in antioxidant enzymes in human skin fibroblasts after UVA irradiation. Journal of Dermatological Science, 14(3), 225–232. https://doi.org/10.1016/s0923-1811(96)00578-6

    Article  CAS  PubMed  Google Scholar 

  39. RajnochováSvobodová, A., Galandáková, A., Šianská, J., Doležal, D., Ulrichová, J., & Vostálová, J. (2011). Acute exposure to solar simulated ultraviolet radiation affects oxidative stress-related biomarkers in skin, liver and blood of hairless mice. Biological and Pharmaceutical Bulletin, 34(4), 471–479. https://doi.org/10.1248/bpb.34.471

    Article  Google Scholar 

  40. Rice-Evans, C. A., & Miller, N. J. (1996). Antioxidant activities of flavonoids as bioactive components of food. Biochemical Society Transactions, 24(3), 790–795. https://doi.org/10.1042/bst0240790

    Article  CAS  PubMed  Google Scholar 

  41. Gažák, R., Svobodová, A., Psotová, J., Sedmera, P., Přikrylová, V., Walterová, D., & Křen, V. (2004). Oxidised derivatives of silybin and their antiradical and antioxidant activity. Bioorganic & Medicinal Chemistry, 12(21), 5677–5687. https://doi.org/10.1016/j.bmc.2004.07.064

    Article  CAS  Google Scholar 

  42. Osorio, E., Pérez, E. G., Areche, C., Ruiz, L. M., Cassels, B. K., Flórez, E., & Tiznado, W. (2013). Why is quercetin a better antioxidant than taxifolin? Theoretical study of mechanisms involving activated forms. Journal of Molecular Modeling, 19(5), 2165–2172. https://doi.org/10.1007/s00894-012-1732-5

    Article  CAS  PubMed  Google Scholar 

  43. Metodiewa, D., Jaiswal, A. K., Cenas, N., Dickancaité, E., & Segura-Aguilar, J. (1999). Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free Radical Biology and Medicine, 26(1–2), 107–116. https://doi.org/10.1016/s0891-5849(98)00167-1

    Article  CAS  PubMed  Google Scholar 

  44. Boots, A. W., Kubben, N., Haenen, G. R., & Bast, A. (2003). Oxidized quercetin reacts with thiols rather than with ascorbate: Implication for quercetin supplementation. Biochemical and Biophysical Research Communications, 308(3), 560–565. https://doi.org/10.1016/s0006-291x(03)01438-4

    Article  CAS  PubMed  Google Scholar 

  45. Li, C., Zhang, W. J., Choi, J., & Frei, B. (2016). Quercetin affects glutathione levels and redox ratio in human aortic endothelial cells not through oxidation but formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase. Redox Biology, 9, 220–228. https://doi.org/10.1016/j.redox.2016.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Boots, A. W., Li, H., Schins, R. P., Duffin, R., Heemskerk, J. W., Bast, A., & Haenen, G. R. (2007). The quercetin paradox. Toxicology and Applied Pharmacology, 222(1), 89–96. https://doi.org/10.1016/j.taap.2007.04.004

    Article  CAS  PubMed  Google Scholar 

  47. Vásquez-Espinal, A., Yañez, O., Osorio, E., Areche, C., García-Beltrán, O., Ruiz, L. M., Cassels, B. K., & Tiznado, W. (2019). Theoretical study of the antioxidant activity of quercetin oxidation products. Frontiers in Chemistry, 27, 818. https://doi.org/10.3389/fchem.2019.00818

    Article  CAS  Google Scholar 

  48. Kosina, P., Paloncýová, M., Rajnochová Svobodová, A., Zálešák, B., Biedermann, D., Ulrichová, J., & Vostálová, J. (2018). Dermal delivery of selected polyphenols from Silybum marianum. Theoretical and experimental study. Molecules, 24(1), 61. https://doi.org/10.3390/molecules24010061

    Article  CAS  PubMed Central  Google Scholar 

  49. Filipe, P., Silva, J. N., Haigle, J., Freitas, J. P., Fernandes, A., Santus, R., & Morlière, P. (2005). Contrasting action of flavonoids on phototoxic effects induced in human skin fibroblasts by UVA alone or UVA plus cyamemazine, a phototoxic neuroleptic. Photochemical & Photobiological Sciences, 4(5), 420–428. https://doi.org/10.1039/b416811a

    Article  CAS  Google Scholar 

  50. Tian, R., Yang, Z., Lu, N., & Peng, Y. Y. (2019). Quercetin, but not rutin, attenuated hydrogen peroxide-induced cell damage via heme oxygenase-1 induction in endothelial cells. Archives of Biochemistry and Biophysics, 676, 108157. https://doi.org/10.1016/j.abb.2019.108157

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to express our thanks Iveta Hatalová (University Hospital Olomouc) for the support with skin tissue donor recruitment and Dr. Jana Franková (Department of Medical Chemistry and Biochemistry) for the extraction of human primary epidermal keratinocytes.

Funding

This study was financially supported by the grants IGA_LF_2021_011 and the Institutional Support of Palacký University, Olomouc—RVO 61989592.

Author information

Authors and Affiliations

  1. Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515, Olomouc, Czech Republic

    Alena Rajnochová Svobodová, Alena Ryšavá, Lenka Roubalová, Jitka Ulrichová, Jiří Vrba & Jitka Vostálová

  2. Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77900, Olomouc, Czech Republic

    Kateřina Čížková

  3. Department of Plastic and Aesthetic Surgery, University Hospital Olomouc, I. P. Pavlova 6, 77900, Olomouc, Czech Republic

    Bohumil Zálešák

Authors
  1. Alena Rajnochová Svobodová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alena Ryšavá
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kateřina Čížková
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lenka Roubalová
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jitka Ulrichová
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiří Vrba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bohumil Zálešák
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jitka Vostálová
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ARS and JVo designed the experiments, performed some experiments (ROS generation, GSH level, DNA damage) and wrote the first draft of the manuscript. AR was responsible for preparation of samples for immunocytochemical, Western blot and RT-PCR analysis. She also performed and evaluated Western blots. KC was responsible for the evaluation of immunocytochemical sections. LR and JVr were responsible for RT-PCR analysis. BZ was responsible for recruitment of skin tissue donors and sample collection. JU was responsible for critical proofreading of data and the text of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jitka Vostálová.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The Ethics Committee of University Hospital Olomouc and the Faculty of Medicine and Dentistry, Palacký University, Olomouc approved the use of superfluous skin from human volunteers (ref. number 41/09). All volunteers signed their written informed consent.

Consent of publication

All authors agree with the publication of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajnochová Svobodová, A., Ryšavá, A., Čížková, K. et al. Effect of the flavonoids quercetin and taxifolin on UVA-induced damage to human primary skin keratinocytes and fibroblasts. Photochem Photobiol Sci 21, 59–75 (2022). https://doi.org/10.1007/s43630-021-00140-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43630-021-00140-9

Keywords

Search

Navigation