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Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-κB signaling pathways: a comparative study on UVB-irradiated human keratinocytes

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Abstract

Icariin (ICA) and icaritin (ICT) exhibit many pharmacological functions including anti-osteoporosis, anti-cardiovascular, and anti-cancer activities; however, there are few comprehensive studies that track the detailed effects on UVB-induced photoaging. The recovery effects of ICA and ICT were investigated in UVB-irradiated human keratinocytes (HaCaTs). The results indicated that ICT and ICA showed strong radical scavenging activity, and the reactive oxygen species (ROS) scavenging activity of ICT was superior. UVB-induced matrix metalloproteinase-1 (MMP-1) expression was blocked by ICA via the inhibition of mitogen-activated protein kinase/activator protein 1 (MAPK/AP-1), which directly reduced extracellular matrix (ECM) degradation. ICT activated nuclear factor erythroid 2 related factor 2 (Nrf2) to improve the anti-oxidative stress capacity and suppress nuclear factor-κB (NF-κB) activation, decreasing vascular endothelial growth factor (VEGF) protein, and inflammatory cytokines induced ECM degrading enzyme secretion. Moreover, ICT was more advantageous to improve transforming growth factor beta 1 (TGF-β1) and procollagen type I expression than ICA, promoting the synthesis of collagen. Therefore, ICA and ICT have potential to treat UVB-induced oxidative stress, inflammation and photoaging, and will be posited as a novel strategy to alleviate photodamage.

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References

  1. S. K. Katiyar, UV-induced immune suppression and photocarcinogenesis: chemoprevention by dietary botanical agents, Cancer Lett., 2007, 255, 1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. A. T. Dinkova-Kostova, Phytochemicals as protectors against ultraviolet radiation: versatility of effects and mechanisms, Planta Med., 2008, 74, 1548–1559.

    Article  CAS  PubMed  Google Scholar 

  3. N. A. Bonekamp, A. Völkl, H. D. Fahimi, M. Schrader, Reactive oxygen species and peroxisomes: struggling for balance, Biofactors, 2009, 35, 346–355.

    Article  CAS  PubMed  Google Scholar 

  4. M. B. Y. Greenwald, M. Frušić-Zlotkin, Y. Soroka, S. Ben-Sasson, H. Bianco-Peled, R. Kohen, A novel role of topical iodine in skin: activation of the Nrf2 pathway, Free Radical Biol. Med., 2017, 104, 238–248.

    Article  CAS  Google Scholar 

  5. N. Wakabayashi, S. L. Slocum, J. J. Skoko, S. Shin, T. W. Kensler, When NRF2 talks, who's listening?, Antioxid. Redox Signaling, 2010, 13, 1649–1663.

    Article  CAS  Google Scholar 

  6. U. Panich, G. Sittithumcharee, N. Rathviboon, S. Jirawatnotai, Ultraviolet radiation-induced skin aging: the role of DNA damage and oxidative stress in epidermal stem cell damage mediated skin aging, Stem Cells Int., 2016, 2016, 1–14.

    Article  CAS  Google Scholar 

  7. A. T. Dinkova-Kostova, A. Y. Abramov, The emerging role of Nrf2 in mitochondrial function, Free Radical Biol. Med., 2015, 88, 179–188.

    Article  CAS  Google Scholar 

  8. Z. W. Sun, S. Y. Park, E. Hwang, M. Y. Zhang, S. A. Seo, P. Lin, T. H. Yi, Thymus vulgaris alleviates UVB irradiation induced skin damage via inhibition of MAPK/AP-1 and activation of Nrf2-ARE antioxidant system, J. Cell. Mol. Med., 2017, 21, 336–348.

    Article  CAS  PubMed  Google Scholar 

  9. Z. W. Sun, S. Y. Park, E. Hwang, B. Park, S. A. Seo, J. G. Cho, M. Y. Zhang, T. H. Yi, Dietary Foeniculum vulgare Mill extract attenuated UVB irradiation-induced skin photoaging by activating of Nrf2 and inhibiting MAPK pathways, Phytomedicine, 2016, 23, 1273–1284.

    Article  CAS  PubMed  Google Scholar 

  10. V. Muthusamy, T. J. Piva, The UV response of the skin: a review of the MAPK, NF-κB and TNF-α signal transduction pathways, Arch. Dermatol. Res., 2010, 302, 5.

    Article  CAS  PubMed  Google Scholar 

  11. F. Guadagni, P. Ferroni, R. Palmirotta, I. Portarena, V. Formica, M. Roselli, TNF/VEGF cross-talk in chronic inflammation-related cancer initiation and progression: an early target in anticancer therapeutic strategy, In vivo, 2007, 21, 147–161.

    CAS  PubMed  Google Scholar 

  12. M. S. Kim, Y. K. Kim, H. C. Eun, K. H. Cho, J. H. Chung, All-trans retinoic acid antagonizes UV-induced VEGF production and angiogenesis via the inhibition of ERK activation in human skin keratinocytes, J. Invest. Dermatol., 2006, 126, 2697–2706.

    Article  CAS  PubMed  Google Scholar 

  13. J. Zhang, W. Ma, Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway, Genet. Mol. Res., 2014, 13, 9324–9335.

    Article  CAS  PubMed  Google Scholar 

  14. M. Wlaschek, I. Tantcheva-Poór, L. Naderi, W. Ma, L. A. Schneider, Z. Razi-Wolf, J. Schüller, K. Scharffetter-Kochanek, Solar UV irradiation and dermal photoaging, J. Photochem. Photobiol., B, 2001, 63, 41–51.

    Article  CAS  Google Scholar 

  15. S. R. Pinnell, Cutaneous photodamage, oxidative stress, and topical antioxidant protection, J. Am. Acad. Dermatol., 2003, 48, 1–22.

    Article  PubMed  Google Scholar 

  16. T. Quan, Z. Qin, W. Xia, Y. Shao, J. J. Voorhees and G. J. Fisher, Matrix-degrading metalloproteinases in photoaging, In. J. Invest. Dermatol. Symp. Proc., Elsevier, 2009.

    Google Scholar 

  17. F. Luchetti, M. Betti, B. Canonico, M. Arcangeletti, P. Ferri, F. Galli, S. Papa, ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells, Free Radical Biol. Med., 2009, 46, 339–351.

    Article  CAS  Google Scholar 

  18. M. Cargnello, P. P. Roux, Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases, Microbiol. Mol. Biol. Rev., 2012, 76, 496.

    Article  PubMed Central  Google Scholar 

  19. M. J. Piao, R. Zhang, N. H. Lee, J. W. Hyun, Phloroglucinol attenuates ultraviolet B radiation-induced matrix metalloproteinase-1 production in human keratinocytes via Inhibitory actions against mitogen-activated protein kinases and activator protein-1, Photochem. Photobiol., 2012, 88, 381–388.

    Article  CAS  PubMed  Google Scholar 

  20. K. C. Kim, S. S. Kang, J. Lee, D. Park, J. W. Hyun, Baicalein attenuates oxidative stress-induced expression of matrix metalloproteinase-1 by regulating the ERK/JNK/AP-1 pathway in human keratinocytes, Biomol. Ther., 2012, 20, 57.

    Article  CAS  Google Scholar 

  21. G. J. Fisher, S. C. Datta, H. S. Talwar, Z. Q. Wang, J. Varani, S. Kang, J. J. Voorhees, Molecular basis of sun-induced premature skin ageing and retinoid antagonism, Nature, 1996, 379 (6563), 335.

    Article  CAS  PubMed  Google Scholar 

  22. F. Verrecchia, A. Mauviel, Control of connective tissue gene expression by TGFβ: role of Smad proteins in fibrosis, Curr. Rheumatol. Rep., 2002, 4, 143–149.

    Article  PubMed  Google Scholar 

  23. X. Q. Lai, Y. X. Ye, C. H. Sun, X. Y. Huang, X. G. Tang, X. F. Zeng, P. H. Yin, Y. Y. Zeng, Icaritin exhibits anti-inflammatory effects in the mouse peritoneal macrophages and peritonitis model, Int. Immunopharmacol., 2013, 16, 41–49.

    Article  CAS  PubMed  Google Scholar 

  24. H. P. Ma, X. N. Ma, B. F. Ge, P. Zhen, J. Zhou, Y. H. Gao, C. J. Xian, K. M. Chen, Icariin attenuates hypoxia-induced oxidative stress and apoptosis in osteoblasts and preserves their osteogenic differentiation potential in vitro, Cell Proliferation, 2014, 47, 527–539.

    Article  CAS  PubMed  Google Scholar 

  25. F. Zhao, Y. Z. Tang, Z. Q. Liu, Protective effect of icariin on DNA against radical-induced oxidative damage, J. Pharm. Pharmacol., 2007, 59, 1729–1732.

    Article  CAS  PubMed  Google Scholar 

  26. W. Zhang, B. C. Xing, L. L. Yang, J. L. Shi, X. M. Zhou, Icaritin attenuates myocardial ischemia and reperfusion injury via anti-inflammatory and anti-oxidative stress effects in rats, Am. J. Chin. Med., 2015, 43, 1083–1097.

    Article  CAS  PubMed  Google Scholar 

  27. S. L. Peng, G. Zhang, B. T. Zhang, B. S. Guo, Y. X. He, A. J. Bakker, X. H. Pan, W. X. Zhen, L. K. Hung, L. Qin, The beneficial effect of icaritin on osteoporotic bone is dependent on the treatment initiation timing in adult ovariectomized rats, Bone, 2013, 55, 230–240.

    Article  CAS  PubMed  Google Scholar 

  28. Z. Q. Wang, X. N. Zhang, H. Wang, L. Qi, Y. Lou, Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway, Neurosci., 2007, 145, 911–922.

    Article  CAS  Google Scholar 

  29. Y. X. Fu, C. Y. Liu, M. J. Guo, Y. Zhao, F. X. Jin, H. S. Yu, Bioconversion utilization of waste-residue from icarrin extraction, J. Food Sci. Technol., 2017, 38, 167–177.

    Google Scholar 

  30. Y. S. Wang, J. G. Cho, E. Hwang, J. E. Yang, W. Gao, M. Z. Fang, S. D. Zheng, T. H. Yi, Enhancement of protective effects of Radix Scutellariae on UVB-induced photodamage in human HaCaT keratinocytes, Appl. Biochem. Biotechnol., 2018, 184, 1073–1093.

    Article  CAS  PubMed  Google Scholar 

  31. E. Hwang, H. T. Ngo, B. Park, S. A. Seo, J. E. Yang, T. H. Yi, Myrcene, an aromatic volatile compound, ameliorates human skin extrinsic aging via regulation of MMPs production, Am. J. Chin. Med., 2017, 1–12.

    Google Scholar 

  32. M. Liu, H. P. Liu, X. M. Lu, C. Li, Z. L. Xiong, F. M. Li, Simultaneous determination of icariin, icariside II and osthole in rat plasma after oral administration of the extract of Gushudan (a Chinese compound formulation) by LC-MS/MS, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci., 2007, 860, 113–120.

    Article  CAS  Google Scholar 

  33. Z. H. Li, D. Alex, S. O. Siu, I. K. Chu, J. Renn, C. Winkler, S. Lou, S. K. W. Tsui, H. Y. Zhao, W. R. Yan, Combined in vivo imaging and omics approaches reveal metabolism of icaritin and its glycosides in zebrafish larvae, Mol. BioSyst., 2011, 7, 2128–2138.

    Article  CAS  PubMed  Google Scholar 

  34. S. Pillai, C. Oresajo, J. Hayward, Ultraviolet radiation and skin aging: roles of reactive oxygen species, inflammation and protease activation, and strategies for prevention of inflammation-induced matrix degradation-a review, Int. J. Cosmet. Sci., 2005, 27, 17–34.

    Article  CAS  PubMed  Google Scholar 

  35. J. Y. Kim, Y. N. Cha, Y. J. Surh, A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders, Mutat. Res., 2010, 690, 12–23.

    Article  CAS  PubMed  Google Scholar 

  36. Y. R. Xu, G. J. Fisher, Ultraviolet (UV) light irradiation induced signal transduction in skin photoaging, J. Dermatol. Sci., Suppl., 2005, 1, S1–S8.

    CAS  Google Scholar 

  37. A. Hirota, Y. Kawachi, M. Yamamoto, T. Koga, K. Hamada, F. Otsuka, Acceleration of UVB-induced photoageing in nrf2 gene-deficient mice, Exp. Dermatol., 2011, 20, 664–668.

    Article  CAS  PubMed  Google Scholar 

  38. A. R. Han, M. H. Nam, K. W. Lee, Plantamajoside inhibits UVB and advanced glycation end products-induced MMP-1 expression by suppressing the MAPK and NF-κB pathways in HaCaT cells, Photochem. Photobiol., 2016, 92, 708–719.

    Article  CAS  PubMed  Google Scholar 

  39. R. Craig, A. Larkin, A. M. Mingo, D. J. Thuerauf, C. Andrews, P. M. McDonough, C. C. Glembotski, p38 MAPK and NF-κB collaborate to induce interleukin-6 gene expression and release evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system, J. Biol. Chem., 2000, 275, 23814–23824.

    Article  CAS  PubMed  Google Scholar 

  40. B. Porée, M. Kypriotou, C. Chadjichristos, G. Beauchef, E. Renard, F. Legendre, M. Melin, S. Gueret, D. J. Hartmann, F. Malléin-Gerin, Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1· Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter, J. Biol. Chem., 2008, 283, 4850–4865.

    Article  PubMed  CAS  Google Scholar 

  41. P. Greenwel, S. Tanaka, D. Penkov, W. Zhang, M. Olive, J. Moll, C. Vinson, M. Di Liberto, F. Ramirez, Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins, Mol. Cell. Biol., 2000, 20, 912–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Y. Jia, J. J. Turek, Inducible nitric oxide synthase links NF-κB to PGE 2 in polyunsaturated fatty acid altered fibroblast in vitro wound healing, Lipids Health Dis., 2005, 4, 14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. P. Wäster, I. Rosdahl, K. Öllinger, Cell fate regulated by nuclear factor-κB-and activator protein-1-dependent signalling in human melanocytes exposed to ultraviolet A and ultraviolet B, Br. J. Dermatol., 2014, 171, 1336–1346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. H. B. Schonthaler, R. Huggenberger, S. K. Wculek, M. Detmar, E. F. Wagner, Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis, Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 21264–21269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. N. Linde, W. Lederle, S. Depner, N. Van Rooijen, C. M. Gutschalk, M. M. Mueller, Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages, J. Pathol., 2012, 227, 17–28.

    Article  CAS  PubMed  Google Scholar 

  46. S. Hirakawa, S. Fujii, K. Kajiya, K. Yano, M. Detmar, Vascular endothelial growth factor promotes sensitivity to ultraviolet B-induced cutaneous photodamage, Blood, 2005, 105, 2392–2399.

    Article  CAS  PubMed  Google Scholar 

  47. J. F. Wu, J. Du, X. Q. Fu, B. Liu, H. H. Cao, T. Li, T. Su, J. H. Xu, A. K. W. Tse, Z. L. Yu, Icaritin, a novel FASN inhibitor, exerts anti-melanoma activities through IGF-1R/STAT3 signaling, Oncotarget, 2016, 7, 51251.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Y. T. Chen, R. L. Zheng, Z. J. Jia, Y. Ju, Flavonoids as superoxide scavengers and antioxidants, Free Radical Biol. Med., 1990, 9, 19–21.

    Article  Google Scholar 

  49. N. Cotelle, J. L. Bernier, J. P. Catteau, J. Pommery, J. C. Wallet, E. M. Gaydou, Antioxidant Properties of Hydroxy-flavones, Free Radical Biol. Med., 2005, 39, 1284.

    Google Scholar 

  50. D. Amić, D. Davidović-Amić, D. Bešlo, N. Trinajstić, Structure-radical scavenging activity relationships of flavonoids, Croat. Chem. Acta, 2003, 76, 55–61.

    Google Scholar 

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Acknowledgments

This work was supported by the TAEYI Life Science Co. Ltd., Republic of Korea. We thank Professor Hong-Shan Yu (College of Biotechnology, Dalian Polytechnic University, Dalian, China) for reagents and technical supports.

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Authors and Affiliations

  1. College of Life Science, Kyung Hee University, 1732, Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 17104, Korea

    Eunson Hwang, Pei Lin, Hien T. T. Ngo, Wei Gao, Yu-Shuai Wang & Tae-Hoo Yi

  2. College of Biotechnology, Dalian Polytechnic University, Ganjingzi-qu, Dalian, China

    Hong-Shan Yu

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  1. Eunson Hwang
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Hwang, E., Lin, P., Ngo, H.T.T. et al. Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-κB signaling pathways: a comparative study on UVB-irradiated human keratinocytes. Photochem Photobiol Sci 17, 1396–1408 (2018). https://doi.org/10.1039/c8pp00174j

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