Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice

Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs) activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values) and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin’s antiphotodamage and antiphotoinflammation activities.

[1]  Chao‐Lin Kuo,et al.  Fisetin‐induced apoptosis of human oral cancer SCC‐4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase‐, and mitochondria‐dependent signaling pathways , 2017, Environmental toxicology.

[2]  G. Petrovski,et al.  Two dietary polyphenols, fisetin and luteolin, reduce inflammation but augment DNA damage-induced toxicity in human RPE cells. , 2017, The Journal of nutritional biochemistry.

[3]  M. Hsu,et al.  Alleviation of Ultraviolet B-Induced Photodamage by Coffea arabica Extract in Human Skin Fibroblasts and Hairless Mouse Skin , 2017, International journal of molecular sciences.

[4]  L. Kemény,et al.  Effects of Locally Applied Glycerol and Xylitol on the Hydration, Barrier Function and Morphological Parameters of the Skin. , 2017, Acta dermato-venereologica.

[5]  Dong Hun Lee,et al.  Perilla frutescens leaves extract ameliorates ultraviolet radiation-induced extracellular matrix damage in human dermal fibroblasts and hairless mice skin. , 2017, Journal of ethnopharmacology.

[6]  M. Youns,et al.  The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways , 2017, PloS one.

[7]  D. Gilot,et al.  Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase , 2016, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[8]  T. Fujita,et al.  Protective and therapeutic effects of fucoxanthin against sunburn caused by UV irradiation. , 2016, Journal of pharmacological sciences.

[9]  Y. Kuo,et al.  Antiinflammatory and Antiphotodamaging Effects of Ergostatrien-3β-ol, Isolated from Antrodia camphorata, on Hairless Mouse Skin , 2016, Molecules.

[10]  Daeui Park,et al.  The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging , 2016, Oncotarget.

[11]  Jae Min Han,et al.  Topical Application of Angelica sinensis Improves Pruritus and Skin Inflammation in Mice with Atopic Dermatitis-Like Symptoms. , 2016, Journal of medicinal food.

[12]  G. Jeong,et al.  Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression. , 2015, International immunopharmacology.

[13]  T. Dainichi,et al.  The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. , 2015, The Journal of allergy and clinical immunology.

[14]  A. Verkman,et al.  Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis , 2015, Nature Communications.

[15]  R. Luiten,et al.  Oxidation events and skin aging , 2015, Ageing Research Reviews.

[16]  Hsiu-Mei Chiang,et al.  Fisetin Ameliorated Photodamage by Suppressing the Mitogen-Activated Protein Kinase/Matrix Metalloproteinase Pathway and Nuclear Factor-κB Pathways. , 2015, Journal of agricultural and food chemistry.

[17]  S. González,et al.  Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals , 2015, Antioxidants.

[18]  Xianglin Shi,et al.  Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin. , 2014, Toxicology and applied pharmacology.

[19]  T. Gansukh,et al.  Increase in cyclooxygenase‐2 (COX‐2) expression in keratinocytes and dermal fibroblasts in photoaged skin , 2014, Journal of cosmetic dermatology.

[20]  N. Gibbs,et al.  Damage to skin extracellular matrix induced by UV exposure. , 2014, Antioxidants & redox signaling.

[21]  V. Adhami,et al.  Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. , 2014, Biochemical pharmacology.

[22]  Seung Eun Lee,et al.  Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice. , 2014, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[23]  P. Maher,et al.  Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice , 2013, Aging cell.

[24]  S. Malik,et al.  Quercetin suppresses inflammation by reducing ERK1/2 phosphorylation and NF kappa B activation in Leptin-induced Human Umbilical Vein Endothelial Cells (HUVECs) , 2013, BMC Research Notes.

[25]  A. Potapovich,et al.  Effects of pre- and post-treatment with plant polyphenols on human keratinocyte responses to solar UV , 2013, Inflammation Research.

[26]  J. Quiles,et al.  Photoprotective potential of strawberry (Fragaria × ananassa) extract against UV-A irradiation damage on human fibroblasts. , 2012, Journal of agricultural and food chemistry.

[27]  S. Katiyar,et al.  Polyphenols: skin photoprotection and inhibition of photocarcinogenesis. , 2011, Mini reviews in medicinal chemistry.

[28]  M. Marques,et al.  Dietary chromones as antioxidant agents--the structural variable. , 2011, Food & function.

[29]  C. Sutherland,et al.  Filaggrin in the frontline: role in skin barrier function and disease , 2009, Journal of Cell Science.

[30]  Y. Kimura,et al.  Effects of ginseng saponins isolated from red ginseng on ultraviolet B-induced skin aging in hairless mice. , 2009, European journal of pharmacology.

[31]  Jae Heun Lee,et al.  HO-1 and JAK-2/STAT-1 signals are involved in preferential inhibition of iNOS over COX-2 gene expression by newly synthesized tetrahydroisoquinoline alkaloid, CKD712, in cells activated with lipopolysacchride. , 2008, Cellular signalling.

[32]  M. Yaar,et al.  Photoageing: mechanism, prevention and therapy , 2007, The British journal of dermatology.

[33]  A. Rawlings,et al.  Moisturizer technology versus clinical performance , 2004, Dermatologic therapy.

[34]  A. Rawlings,et al.  Moisturization and skin barrier function , 2004, Dermatologic therapy.

[35]  V. Villiotou,et al.  Increase of particulate nitric oxide synthase activity and peroxynitrite synthesis in UVB-irradiated keratinocyte membranes. , 1996, The Biochemical journal.

[36]  P. Steinert,et al.  Characterization of a class of cationic proteins that specifically interact with intermediate filaments. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Elmets,et al.  Fisetin Inhibits UVB‐induced Cutaneous Inflammation and Activation of PI3K/AKT/NFκB Signaling Pathways in SKH‐1 Hairless Mice , 2015, Photochemistry and photobiology.

[38]  M. Yaar.  Molecular mechanisms of skin aging. , 1995, Advances in dermatology.