RESUMO
Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age-related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti-aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR-based anti-aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects.
Assuntos
Envelhecimento/metabolismo , Metformina/farmacologia , Sirolimo/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Estilbenos/farmacologia , Cicatrização/efeitos dos fármacos , Ferimentos não Penetrantes/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Administração Cutânea , Envelhecimento/genética , Animais , Ciclina D1/genética , Ciclina D1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Ativação Enzimática , Feminino , Regulação da Expressão Gênica , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Sprague-Dawley , Resveratrol , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/enzimologia , Pele/lesões , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Cicatrização/fisiologia , Ferimentos não Penetrantes/enzimologia , Ferimentos não Penetrantes/genética , Ferimentos não Penetrantes/patologiaRESUMO
PURPOSE: To investigate the relationship between male osteoporosis and the expression of receptor activator of NF-κB ligand(RANKL) and osteoprotegerin(OPG)-mRNA in male mandible at different ages. METHODS: Between May 2008 and January 2009, bone tissues of the mandible were collected as the experimental material from 46 patients suffering from jaw facial deformity and extraction. The patients with periodontist, systemic disorder and smoking as well as drinking were excluded.They were divided into three groups: young group, whose age was 10-29 years old ;middle age group, whose age was 30-59 years old; aged group, whose age was 60-89 years old. The expression of RANKL mRNA and OPG mRNA was examined by real-time PCR. The data was analyzed using ANOVA followed by least significant difference (LSD) test with SPSS16.0 software package. RESULTS: (1)Compared with the young group, RANKL mRNA level in mandible was 2.1-fold and 5.3-fold higher in the middle age and aged groups, respectively, whereas OPG mRNA level was 3.3-fold and 4.8-fold higher in middle age and aged groups, respectively. RANKL and OPG were positively correlated with age.(2)The ratio of RANKL/OPG in middle age group was lower than that of young group and old group,respectively. CONCLUSIONS: (1)The expression of RANKL and OPG increases with age remarkably.(2)Bone formation of the mandible is activated in middle aged group. The formation is over absorption.(3)Bone formation of the mandible in aged group is at low level. Bone absorption exceeds bone formation.
