Xuan Ang, Liu Meng, Zhang Lingli, Lu Guoqing, Liu Hao, Zheng Lishan, Shen Juan, Zou Yong, Zhi Shengyao
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China.
School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Pharmaceuticals (Basel). 2025 Jul 31;18(8):1143. doi: 10.3390/ph18081143.
: The prolonged M1-like pro-inflammatory polarization of macrophages is a key factor in the delayed healing of diabetic ulcers (DU). SIRT3, a primary mitochondrial deacetylase, has been identified as a regulator of inflammation and represents a promising new therapeutic target for DU treatment. Nonetheless, the efficacy of existing SIRT3 agonists remains suboptimal. : Here, we introduce a novel compound, SZC-6, demonstrating promising activity levels. : SZC-6 treatment down-regulated the expression of inflammatory factors in LPS-treated RAW264.7 cells and reduced the proportion of M1 macrophages. Mitosox, IF, and JC-1 staining revealed that SZC-6 preserved cellular mitochondrial homeostasis and reduced the accumulation of reactive oxygen species. In vivo experiments demonstrated that SZC-6 treatment accelerated wound healing in diabetic mice. Furthermore, HE and Masson staining revealed increased neovascularization at the wound site with SZC-6 treatment. Tissue immunofluorescence results indicated that SZC-6 effectively decreased the proportion of M1-like cells and increased the proportion of M2-like cells at the wound site. We also found that SZC-6 significantly reduced MyD88, p-IκBα, and NF-χB p65 protein levels and inhibited the nuclear translocation of P65 in LPS-treated cells. : The study concluded that SZC-6 inhibited the activation of the NF-χB pathway, thereby reducing the inflammatory response and promoting skin healing in diabetic ulcers. SZC-6 shows promise as a small-molecule compound for promoting diabetic wound healing.
巨噬细胞长期的M1样促炎极化是糖尿病溃疡（DU）愈合延迟的关键因素。SIRT3是一种主要的线粒体去乙酰化酶，已被确定为炎症调节因子，是DU治疗中有前景的新治疗靶点。尽管如此，现有SIRT3激动剂的疗效仍不尽人意。在此，我们引入了一种新型化合物SZC-6，其显示出有前景的活性水平。SZC-6处理下调了LPS处理的RAW264.7细胞中炎症因子的表达，并降低了M1巨噬细胞的比例。Mitosox、IF和JC-1染色显示SZC-6维持了细胞线粒体稳态并减少了活性氧的积累。体内实验表明SZC-6处理加速了糖尿病小鼠的伤口愈合。此外，HE和Masson染色显示SZC-6处理后伤口部位的新血管生成增加。组织免疫荧光结果表明SZC-6有效降低了伤口部位M1样细胞的比例并增加了M2样细胞的比例。我们还发现SZC-6显著降低了MyD88、p-IκBα和NF-κB p65蛋白水平，并抑制了LPS处理细胞中P65的核转位。该研究得出结论，SZC-6抑制了NF-κB通路的激活，从而减少炎症反应并促进糖尿病溃疡的皮肤愈合。SZC-6作为一种促进糖尿病伤口愈合的小分子化合物具有前景。
