Academy of Integrative Medicine, Fujian Key Laboratory of Integrative Medicine on Geriatric, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Phytother Res. 2024 Feb;38(2):1013-1027. doi: 10.1002/ptr.8099. Epub 2023 Dec 22.
Type 2 diabetes (T2D) is a metabolic disorder that causes numerous complications including impaired wound healing and poses a significant challenge for the management of diabetic patients. Epigallocatechin-3-gallate (EGCG) is a natural polyphenol that exhibits anti-inflammatory and anti-oxidative benefits in skin wounds, however, the direct effect of EGCG on epidermal keratinocytes, the primary cells required for re-epithelialization in wound healing remains unknown. Our study aims to examine the underlying mechanisms of EGCG's ability to promote re-epithelialization and wound healing in T2D-induced wounds. Murine models of wound healing in T2D were established via feeding high-fat high-fructose diet (HFFD) and the creation of full-thickness wounds. Mice were administered daily with EGCG or vehicle to examine the wound healing response and underlying molecular mechanisms of EGCG's protective effects. Systemic administration of EGCG in T2D mice robustly accelerated the wound healing response following injury. EGCG induced nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and promoted cytokeratin 16 (K16) expression to activate epidermal keratinocytes and robustly promoted re-epithelialization of wounds in diabetic mice. Further, EGCG demonstrated high binding affinity with Kelch-like ECH-associated protein 1 (KEAP1), thereby inhibiting KEAP1-mediated degradation of NRF2. Our findings provide important evidence that EGCG accelerates the wound healing response in diabetic mice by activating epidermal keratinocytes, thereby promoting re-epithelialization of wounds via K16/NRF2/KEAP1 signaling axis. These mechanistic insights into the protective effects of EGCG further suggest its therapeutic potential as a promising drug for treating chronic wounds in T2D.
2 型糖尿病（T2D）是一种代谢紊乱疾病，会导致多种并发症，包括伤口愈合受损，给糖尿病患者的管理带来重大挑战。表没食子儿茶素没食子酸酯（EGCG）是一种天然多酚，具有抗炎和抗氧化作用，可改善皮肤伤口，但 EGCG 对表皮角质形成细胞（伤口愈合中再上皮化所需的主要细胞）的直接作用尚不清楚。我们的研究旨在研究 EGCG 促进 T2D 诱导的伤口再上皮化和愈合的潜在机制。通过给予高脂肪高果糖饮食（HFFD）和全层伤口来建立 T2D 伤口愈合的小鼠模型。每天给予 EGCG 或载体处理来检查伤口愈合反应和 EGCG 保护作用的潜在分子机制。在 T2D 小鼠中系统给予 EGCG 可在损伤后强力加速伤口愈合反应。EGCG 诱导核红细胞相关因子 2（NRF2）的核易位，并促进细胞角蛋白 16（K16）的表达，以激活表皮角质形成细胞，并强力促进糖尿病小鼠伤口的再上皮化。此外，EGCG 与 Kelch 样 ECH 相关蛋白 1（KEAP1）具有高结合亲和力，从而抑制 KEAP1 介导的 NRF2 降解。我们的研究结果提供了重要证据，表明 EGCG 通过激活表皮角质形成细胞来加速糖尿病小鼠的伤口愈合反应，从而通过 K16/NRF2/KEAP1 信号轴促进伤口再上皮化。这些对 EGCG 保护作用的机制见解进一步表明，它具有作为治疗 T2D 慢性伤口的有前途的药物的治疗潜力。
