RESUMO
BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.
Assuntos
Camundongos Knockout , Sirtuínas , Cicatrização , Animais , Cicatrização/genética , Sirtuínas/genética , Sirtuínas/metabolismo , Sirtuínas/deficiência , Camundongos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/genética , Inflamação/patologia , Inflamação/metabolismo , MasculinoRESUMO
Diabetic ulcers (DUs) are a common complication of diabetes with high morbidity, poor prognosis, and a high socio-economic burden. The main pathological manifestations of DUs are chronic inflammation, impaired re-epithelialization, and impaired angiogenesis. During the inflammatory phase, neutrophils are one of the main DU cell types and act by releasing neutrophil extracellular traps (NETs), leading to poor healing in DUs. This review summarizes the role of neutrophils in the pathology and treatment of DUs, with a view to potential novel therapies and therapeutic targets.