Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Clin Sci (Lond). 2021 Feb 12;135(4):613-627. doi: 10.1042/CS20201145.
The high disability, mortality and morbidity of diabetic ulcers make it urgent to explore effective strategies for diabetic wound repair. TrxR1 plays a vital role in regulating redox homeostasis in various pathologies. In the present study, the effect of berberine (BBR) on diabetic wounds was investigated in streptozotocin (STZ)-induced diabetic rats and a high glucose (HG)-induced cell model, and the mechanism of BBR on TrxR1 was elucidated. BBR treatment remarkably accelerated wound healing and enhanced extracellular matrix (ECM) synthesis and significantly inhibited HG-induced HaCaT cell damage. Further analysis indicated that BBR activated TrxR1, suppressed its downstream JNK signaling, thereby inhibiting oxidative stress and apoptosis, promoted cell proliferation, down-regulated matrix metalloproteinase (MMP) 9 (MMP9) and up-regulated transforming growth factor-β1 (TGF-β1) and tissue inhibitors of MMP 1 (TIMP1), resulting in accelerated wound healing. Importantly, the enhancement of BBR on wound repair was further abolished by TrxR1 inhibitor. Moreover, in diabetic wounds induced by a combination of STZ injection and high-fat diet, BBR significantly increased wound closure rate and TrxR1 expression, and this was reversed by TrxR1 inhibitor. These data indicated that topical BBR treatment accelerated diabetic wound healing by activating TrxR1. Targeting TrxR1 may be a novel, effective strategy for restoring redox homeostasis and promoting diabetic wound healing.
糖尿病溃疡的高残疾率、死亡率和发病率使得探索有效的糖尿病伤口修复策略变得尤为迫切。TrxR1 在调节各种病理状态下的氧化还原平衡中起着至关重要的作用。在本研究中，研究了小檗碱（BBR）对链脲佐菌素（STZ）诱导的糖尿病大鼠和高葡萄糖（HG）诱导的细胞模型中糖尿病伤口的影响，并阐明了 BBR 对 TrxR1 的作用机制。BBR 处理可显著加速伤口愈合，增强细胞外基质（ECM）合成，并显著抑制 HG 诱导的 HaCaT 细胞损伤。进一步分析表明，BBR 激活了 TrxR1，抑制了其下游 JNK 信号通路，从而抑制了氧化应激和细胞凋亡，促进了细胞增殖，下调了基质金属蛋白酶 9（MMP9），上调了转化生长因子-β1（TGF-β1）和基质金属蛋白酶组织抑制剂 1（TIMP1），从而加速了伤口愈合。重要的是，TrxR1 抑制剂进一步消除了 BBR 对伤口修复的增强作用。此外，在 STZ 注射和高脂肪饮食联合诱导的糖尿病伤口中，BBR 显著增加了伤口闭合率和 TrxR1 表达，而 TrxR1 抑制剂则逆转了这一作用。这些数据表明，局部 BBR 治疗通过激活 TrxR1 加速了糖尿病伤口愈合。靶向 TrxR1 可能是恢复氧化还原平衡和促进糖尿病伤口愈合的一种新的有效策略。
