Abstract：
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-1β, 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.
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-1β, 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.
摘要：
背景：糖尿病性溃疡（DU）的特征是慢性炎症和延迟的再上皮形成，发病率高，经济负担重。难治性伤口的主要治疗策略包括手术，非侵入性伤口治疗，和毒品，而最佳方案仍存在争议。Sirtuin-6（SIRT6）是组蛋白脱乙酰酶，是在伤口愈合中发挥抗炎和促增殖作用的关键表观遗传因子。然而,SIRT6在DU中的确切功能尚不清楚。
方法：我们通过将SIRT6flox/flox纯合小鼠与UBC-creERT2+转基因小鼠杂交，产生了他莫昔芬诱导的SIRT6基因敲除小鼠。系统性SIRT6无效小鼠，在正常或糖尿病条件下，用于评估SIRT6在DU治疗中的效果。通过Western印迹和RT-qPCR检测SIRT6和炎性细胞因子的基因和蛋白表达。组织病理学检查证实了改变的再上皮化（PCNA），炎症（NF-κBp50和F4/80），和在DU恢复期间的血管生成(CD31)标记物。
结果：SIRT6基因敲除抑制了DU的愈合能力，呈现减弱的再上皮化（PCNA），加剧的炎症反应（NF-κBp50，F4/80，IL-1β，Tnf-α,Il-6、Il-10和Il-4)，与对照小鼠相比，血管增生（CD31）。
结论：SIRT6可以通过改善表皮增殖来促进受损的伤口愈合，炎症,和血管生成。我们的研究强调了SIRT6激动剂用于DU治疗的治疗潜力。
方法：我们通过将SIRT6flox/flox纯合小鼠与UBC-creERT2+转基因小鼠杂交，产生了他莫昔芬诱导的SIRT6基因敲除小鼠。系统性SIRT6无效小鼠，在正常或糖尿病条件下，用于评估SIRT6在DU治疗中的效果。通过Western印迹和RT-qPCR检测SIRT6和炎性细胞因子的基因和蛋白表达。组织病理学检查证实了改变的再上皮化（PCNA），炎症（NF-κBp50和F4/80），和在DU恢复期间的血管生成(CD31)标记物。
结果：SIRT6基因敲除抑制了DU的愈合能力，呈现减弱的再上皮化（PCNA），加剧的炎症反应（NF-κBp50，F4/80，IL-1β，Tnf-α,Il-6、Il-10和Il-4)，与对照小鼠相比，血管增生（CD31）。
结论：SIRT6可以通过改善表皮增殖来促进受损的伤口愈合，炎症,和血管生成。我们的研究强调了SIRT6激动剂用于DU治疗的治疗潜力。
