Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Galangin Activates the ERK/AKT-Driven Nrf2 Signaling Pathway to Increase the Level of Reduced Glutathione in Human Keratinocytes

  • Hewage, Susara Ruwan Kumara Madduma (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Piao, Mei Jing (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Kang, Kyoung Ah (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Ryu, Yea Seong (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Fernando, Pattage Madushan Dilhara Jayatissa (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Oh, Min Chang (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Park, Jeong Eon (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Shilnikova, Kristina (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Moon, Yu Jin (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Shin, Dae O (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University) ;
  • Hyun, Jin Won (School of Medicine and Institute for Nuclear Science and Technology, Jeju National University)
  • Received : 2016.05.22
  • Accepted : 2016.08.02
  • Published : 2017.07.01
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Abstract

Previously, we demonstrated that galangin (3,5,7-trihydroxyflavone) protects human keratinocytes against ultraviolet B (UVB)-induced oxidative damage. In this study, we investigated the effect of galangin on induction of antioxidant enzymes involved in synthesis of reduced glutathione (GSH), and investigated the associated upstream signaling cascades. By activating nuclear factor-erythroid 2-related factor (Nrf2), galangin treatment significantly increased expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS). This activation of Nrf2 depended on extracellular signal-regulated kinases (ERKs) and protein kinase B (AKT) signaling. Inhibition of GSH in galangin-treated cells attenuated the protective effect of galangin against the deleterious effects of UVB. Our results reveal that galangin protects human keratinocytes by activating ERK/AKT-Nrf2, leading to elevated expression of GSH-synthesizing enzymes.

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References

  1. Afolayan, A. J. and Meyer, J. J. (1997) The antimicrobial activity of 3,5,7-trihydroxyflavoneisolated from the shoots of Helichrysum aureonitens. J. Ethnopharmacol. 57, 177-181. https://doi.org/10.1016/S0378-8741(97)00065-2
  2. Bolfa, P., Vidrighinescu, R., Petruta, A., Dezmirean, D., Stan, L., Vlase, L., Damiane, G., Catoi, C., Filip, A. and Clichici, S. (2013) Photoprotective effects of Romanian propolis on skin of mice exposed to UVB irradiation. Food Chem. Toxicol. 62, 329-342. https://doi.org/10.1016/j.fct.2013.08.078
  3. Chen, J. S., Huang, P. H., Wang, C. H., Lin, F. Y., Tsai, H. Y., Wu, T. C., Lin, S. J. and Chen, J. W. (2011) Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract. Atherosclerosis 214, 301-309. https://doi.org/10.1016/j.atherosclerosis.2010.11.010
  4. Ciolino, H. P. and Yeh, G. C. (1999) The flavonoid galangin is an inhibitor of CYP1A1activity and an agonist/antagonist of the aryl hydrocarbon receptor. Br. J. Cancer 79, 1340-1346. https://doi.org/10.1038/sj.bjc.6690216
  5. Copple, I. M., Goldring, C. E., Kitteringham, N. R. and Park, B. K. (2008) The Nrf2-Keap1 defense pathway: role in protection against drug-induced toxicity. Toxicology 246, 24-33. https://doi.org/10.1016/j.tox.2007.10.029
  6. Cushnie, T. P. and Lamb, A. J. (2006) Assessment of the antibacterial activity of galangin against 4-quinolone resistant strains of Staphylococcus aureus. Phytomedicine 13, 187-191. https://doi.org/10.1016/j.phymed.2004.07.003
  7. Drew, R. and Miners, J, O. (1984) The effects of buthionine sulphoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem. Pharmacol. 33, 2989-2994. https://doi.org/10.1016/0006-2952(84)90598-7
  8. Filomeni, G., Rotilio, G. and Ciriolo, M. R. (2002) Cell signalling and the glutathione redox system. Biochem. Pharmacol. 64, 1057-1064. https://doi.org/10.1016/S0006-2952(02)01176-0
  9. Ha, B. G., Park, M. A., Lee C. M. and Kim, Y. C. (2015) Antioxidant activity and anti-wrinkle effects of Aceriphyllum rossii leaf ethanol extract. Toxicol. Res. 31, 363-369. https://doi.org/10.5487/TR.2015.31.4.363
  10. Halliwell, B. (2007) Biochemistry of oxidative stress. Biochem. Soc. Trans. 35, 1147-1150. https://doi.org/10.1042/BST0351147
  11. Harvey, C. J., Thimmulappa, R. K., Singh, A., Blake, D. J., Ling, G., Wakabayashi, N., Fujii, J., Myers, A. and Biswal, S. (2009) Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic. Biol. Med. 46, 443-453. https://doi.org/10.1016/j.freeradbiomed.2008.10.040
  12. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D. and Yamamoto, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76-86. https://doi.org/10.1101/gad.13.1.76
  13. Jaiswal, A. K. (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic. Biol. Med. 36, 1199-1207. https://doi.org/10.1016/j.freeradbiomed.2004.02.074
  14. Kudugunti, S. K., Vad, N. M., Ekogbo, E. and Moridani, M. Y. (2011) Efficacy of caffeic acid phenethyl ester (CAPE) in skin B16-F0 melanoma tumor bearing C57BL/6 mice. Invest. New Drugs 29, 52-62. https://doi.org/10.1007/s10637-009-9334-5
  15. Madduma Hewage, S. R., Piao, M. J., Kim, K. C., Cha, J. W., Han, X., Choi, Y. H., Chae, S. and Hyun, J. W. (2015) Galangin (3,5,7-trihydroxyflavone) shields human keratinocytes from ultraviolet Binduced oxidative stress. Biomol. Ther. (Seoul) 23, 165-173. https://doi.org/10.4062/biomolther.2014.130
  16. Marrot, L. and Meunier, J. R. (2008) Skin DNA photodamage and its biological consequences. J. Am. Acad. Dermatol. 58, S139-S148. https://doi.org/10.1016/j.jaad.2007.12.007
  17. Martin, D., Rojo, A. I., Salinas, M., Diaz, R., Gallardo, G., Alam, J., Ruiz de Galarreta, C. M. and Cuadrado, A. (2004) Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J. Biol. Chem. 279, 8919-8929. https://doi.org/10.1074/jbc.M309660200
  18. Nioi, P., McMahon, M., Itoh, K., Yamamoto, M. and Hayes, J. D. (2003) Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem. J. 374, 337-348. https://doi.org/10.1042/bj20030754
  19. Papaiahgari, S., Zhang, Q., Kleeberger, S. R., Cho, H. Y. and Reddy, S. P. (2006) Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid. Redox Signal. 8, 43-52. https://doi.org/10.1089/ars.2006.8.43
  20. Park, G. and Oh, M. S. (2015) Acceleration of heat shock-induced collagen breakdown in human dermal fibroblasts with knockdown of NF-E2-related factor 2. BMB Rep. 48, 467-472. https://doi.org/10.5483/BMBRep.2015.48.8.215
  21. Surh, Y. J., Kundu, J. K. and Na, H. K. (2008) Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 74, 1526-1539. https://doi.org/10.1055/s-0028-1088302
  22. Valacchi, G., Sticozzi, C., Pecorelli, A., Cervellati, F., Cervellati, C. and Maioli, E. (2012) Cutaneous responses to environmental stressors. Ann. N. Y. Acad. Sci. 1271, 75-81. https://doi.org/10.1111/j.1749-6632.2012.06724.x
  23. Waster, P. K. and Ollinger, K. M. (2009) Redox-dependent translocation of p53 to mitochondria or nucleus in human melanocytes after UVA-and UVB-induced apoptosis. J. Invest. Dermatol. 129, 1769-1781. https://doi.org/10.1038/jid.2008.421
  24. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. and Turner, N. D. (2004) Glutathione metabolism and its implications for health. J. Nutr. 134, 489-492. https://doi.org/10.1093/jn/134.3.489
  25. Zhang, H. and Forman, H. J. (2012) Glutathione synthesis and its role in redox signaling. Semin. Cell Dev. Biol. 23, 722-728. https://doi.org/10.1016/j.semcdb.2012.03.017

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