title: Azelaic acid reduced senescence-like phenotype in photo-irradiated human dermal fibroblasts: possible implication of PPARγ.
abstract: Azelaic acid (AzA) has been used for the treatment for inflammatory skin diseases, such as acne and rosacea. Interestingly, an improvement in skin texture has been observed after long-time treatment with AzA. We previously unrevealed that anti-inflammatory activity of AzA involves a specific activation of PPARγ, a nuclear receptor that plays a relevant role in inflammation and even in ageing processes. As rosacea has been considered as a photo-aggravated disease, we investigated the ability of AzA to counteract stress-induced premature cell senescence (SIPS). We employed a SIPS model based on single exposure of human dermal fibroblasts (HDFs) to UVA and 8-methoxypsoralen (PUVA), previously reported to activate a senescence-like phenotype, including long-term growth arrest, flattened morphology and increased synthesis of matrix metalloproteinases (MMPs) and senescence-associated β-galactosidase (SA-β-gal). We found that PUVA-treated HDFs grown in the presence of AzA maintained their morphology and reduced MMP-1 release and SA-β-galactosidase-positive cells. Moreover, AzA induced a reduction in ROS generation, an up-modulation of antioxidant enzymes and a decrease in cell membrane lipid damages in PUVA-treated HDFs. Further evidences of AzA anti-senescence effect were repression of p53 and p21, increase in type I pro-collagen and abrogation of the enhanced expression of growth factors, such as HGF and SCF. Interestingly, PUVA-SIPS showed a decreased activation of PPARγ and AzA counteracted this effect, suggesting that AzA effect involves PPARγ modulation. All together these data showed that AzA interferes with PUVA-induced senescence-like phenotype and its ability to activate PPAR-γ provides relevant insights into the anti-senescence mechanism.
authors.affiliation: Cutaneous Physiopatology Laboratory, San Gallicano Dermatology Institute, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Briganti
authors.forename: Enrica
authors.initials: E
authors.lastname: Flori
authors.forename: Arianna
authors.initials: A
authors.lastname: Mastrofrancesco
authors.forename: Daniela
authors.initials: D
authors.lastname: Kovacs
authors.forename: Emanuela
authors.initials: E
authors.lastname: Camera
authors.forename: Matteo
authors.initials: M
authors.lastname: Ludovici
authors.forename: Giorgia
authors.initials: G
authors.lastname: Cardinali
authors.forename: Mauro
authors.initials: M
authors.lastname: Picardo
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects; D024042:Collagen Type I / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003879:Dermatologic Agents / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008730:Methoxsalen / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D011701:PUVA Therapy; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology; D011347:Procollagen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D024042:Collagen Type I; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003879:Dermatologic Agents; D003998:Dicarboxylic Acids; D047495:PPAR gamma; D010743:Phospholipids; D017319:Photosensitizing Agents; D011347:Procollagen; D017382:Reactive Oxygen Species; D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; D001616:beta-Galactosidase; D020781:Matrix Metalloproteinase 1; C010038:azelaic acid; D008730:Methoxsalen