title: Topical 5-azacytidine accelerates skin wound healing in rats.
abstract: The development of new methods to improve skin wound healing may affect the outcomes of a number of medical conditions. Here, we evaluate the molecular and clinical effects of topical 5-azacytidine on wound healing in rats. 5-Azacytidine decreases the expression of follistatin-1, which negatively regulates activins. Activins, in turn, promote cell growth in different tissues, including the skin. Eight-week-old male Wistar rats were submitted to 8.0-mm punch-wounding in the dorsal region. After 3 days, rats were randomly assigned to receive either a control treatment or the topical application of a solution containing 5-azacytidine (10 mM) once per day. Photo documentation and sample collection were performed on days 5, 9, and 15. Overall, 5-azacytidine promoted a significant acceleration of complete wound healing (99.7% ± 0.7.0 vs. 71.2% ± 2.8 on day 15; n = 10; p < 0.01), accompanied by up to threefold reduction in follistatin expression. Histological examination of the skin revealed efficient reepithelization and cell proliferation, as evaluated by the BrdU incorporation method. 5-Azacytidine treatment also resulted in increased gene expression of transforming growth factor-beta and the keratinocyte markers involucrin and cytokeratin, as well as decreased expression of cytokines such as tumor necrosis factor-alpha and interleukin-10. Lastly, when recombinant follistatin was applied to the skin in parallel with topical 5-azacytidine, most of the beneficial effects of the drug were lost. Thus, 5-azacytidine acts, at least in part through the follistatin/activin pathway, to improve skin wound healing in rodents.
authors.affiliation: Nursing School, University of Campinas, Campinas, Brazil; Laboratory of Cell Signaling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil.
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Gomes
authors.forename: Gabriela F
authors.initials: GF
authors.lastname: de-Souza
authors.forename: Lucas F
authors.initials: LF
authors.lastname: Nascimento
authors.forename: Eva L
authors.initials: EL
authors.lastname: Arantes
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Pedro
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Vitorino
authors.forename: Carla E
authors.initials: CE
authors.lastname: Nunez
authors.forename: Maria H
authors.initials: MH
authors.lastname: Melo Lima
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Eliana P
authors.initials: EP
authors.lastname: Araújo
mesh_terms: D028341:Activins / Q000187:drug effects; D000279:Administration, Cutaneous; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038681:Follistatin / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000293:injuries*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D038681:Follistatin; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D028341:Activins; D016753:Interleukin-10; C032253:involucrin; D007633:Keratins; D001374:Azacitidine