title: The Inhibitory Effects of Anti-Oxidants on Ultraviolet-Induced Up-Regulation of the Wrinkling-Inducing Enzyme Neutral Endopeptidase in Human Fibroblasts.
abstract: We recently reported that the over-expression of skin fibroblast-derived neutral endopeptidase (NEP) plays a pivotal role in impairing the three-dimensional architecture of dermal elastic fibers during the biological mechanism of ultraviolet (UV)-induced skin wrinkling. In that process, a UVB-associated epithelial-mesenchymal cytokine interaction as well as a direct UVA-induced cellular stimulation are associated with the up-regulation of NEP in human fibroblasts. In this study, we characterized the mode of action of ubiquinol10 which may abrogate the up-regulation of NEP by dermal fibroblasts, resulting in a reported in vivo anti-wrinkling action, and compared that with 3 other anti-oxidants, astaxanthin (AX), riboflavin (RF) and flavin mononucleotide (FMN). Post-irradiation treatment with all 4 of those anti-oxidants elicited an interrupting effect on the UVB-associated epithelial-mesenchymal cytokine interaction leading to the up-regulation of NEP in human fibroblasts but with different modes of action. While AX mainly served as an inhibitor of the secretion of wrinkle-inducing cytokines, such as interleukin-1α (IL-1α) and granulocyte macrophage colony stimulatory factor (GM-CSF) in UVB-exposed epidermal keratinocytes, ubiquinol10, RF and FMN predominantly interrupted the IL-1α and GM-CSF-stimulated expression of NEP in dermal fibroblasts. On the other hand, as for the UVA-associated mechanism, similar to the abrogating effects reported for AX and FMN, ubiquinol10 but not RF had the potential to abrogate the increased expression of NEP and matrix-metalloproteinase-1 in UVA-exposed human fibroblasts. Our findings strongly support the in vivo anti-wrinkling effects of ubiquinol10 and AX on human and animal skin and provide convincing proof of the UV-induced wrinkling mechanism that essentially focuses on the over-expression of NEP by dermal fibroblasts as an intrinsic causative factor.
authors.affiliation: Toyo Beauty Co. Ltd., R&D Division, Osaka, Japan.|School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Research Institute for Biological Functions, Chubu University, Aichi, Japan.
authors.forename: Shuko
authors.initials: S
authors.lastname: Terazawa
authors.affiliation: School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Niwano
authors.affiliation: School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.
authors.forename: Yorihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Research Institute for Biological Functions, Chubu University, Aichi, Japan.
authors.forename: Genji
authors.initials: G
authors.lastname: Imokawa
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015260:Neprilysin / Q000235:genetics* / Q000378:metabolism; D015595:Skin Aging / Q000187:drug effects / Q000528:radiation effects; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects* / Q000528:radiation effects*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D014451:Ubiquinone; C026663:ubiquinol-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015260:Neprilysin