Kanglexin accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling
Kanglexin accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling
复制标题
康乐欣通过 FGFR1/ERK 信号传导促进血管生成，加速糖尿病伤口愈合
DOI：
10.1016/j.biopha.2020.110933
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发表时间：
2020
影响因子：
7.5
通讯作者：
Yang Baofeng
中科院分区：
文献类型：
--
作者：
Zhao Yixiu;Wang Xinhui;Yang Shuang;Song Xia;Sun Na;Chen Chao;Zhang Yannan;Yao Dahong;Huang Jian;Wang Jinhui;Zhang Yan;Yang Baofeng
糖尿病足是非创伤性截肢的主要原因之一。但目前临床上仍缺乏有效治疗糖尿病足的药物。康乐欣是一种具有心血管保护作用的新型蒽醌类化合物。在这里，我们报告KLX通过FGFR 1/ERK信号传导促进血管生成来加速糖尿病伤口愈合。首先，KM小鼠腹腔注射链脲佐菌素建立1型糖尿病模型。在每只小鼠的背部制备直径为5 mm的全层伤口。伤口用KLX处理，每天一次，连续14天。结果显示，KLX显著加速糖尿病伤口的闭合。伤口周围皮肤组织病理学研究表明，KLX促进肉芽组织和新血管的形成，增加胶原沉积，减少炎性细胞浸润。KLX能显著抑制晚期糖基化终产物（AGEs）诱导的人脐静脉内皮细胞（HUVECs）的异常增殖、迁移和小管形成，上调糖尿病创面组织和AGEs处理的HUVECs中磷酸化ERK 1/2的表达。此外，分子对接结果表明KLX具有与FGF受体1（FGFR 1）结合的潜力，后续实验证实FGFR 1抑制剂PD 173074逆转了KLX促进ERK 1/2磷酸化和血管生成的作用，提示KLX通过FGFR 1/ERK信号通路促进血管生成。总之，我们的研究为治疗糖尿病伤口提供了新的有效化合物。更重要的是，KLX有潜力被开发为促进糖尿病伤口愈合的外用药物。
Diabetic foot is one of the main causes of non-traumatic amputation. However, there is still lack of effective drugs to treat diabetic foot in clinical practice. Kanglexin (KLX) is a new anthraquinone compound with cardiovascular protective effects. Here we report that KLX accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling. Firstly, KM mice were injected (ip) with streptozocin to establish type 1 diabetic model. The full thickness wound with the diameter of 5 mm was prepared on the back of each mice. The wounds were treated with KLX once a day for 14 consecutive days. Results showed that KLX significantly accelerated the closure of diabetic wounds. Pathological studies of skin tissues around the wounds showed that KLX promoted the formation of granulation tissue and new blood vessels, increased collagen deposition and reduced inflammatory cell infiltration. Besides, KLX significantly alleviated advanced glycation end products (AGEs) induced abnormal proliferation, migration and tubule formation of human umbilical vein endothelial cells (HUVECs), and up-regulated phospho-ERK1/2 both in the diabetic wound tissue and AGEs treated HUVECs. Moreover, molecular docking results indicated that KLX had the potential to bind with FGF receptor 1 (FGFR1), and subsequent experiments confirmed that FGFR1 inhibitor PD173074 reversed the effect of KLX on promoting the phosphorylation of ERK1/2 and angiogenesis, suggesting that KLX promoted angiogenesis through FGFR1/ERK signaling. In conclusion, our study provides a new effective compound for treating diabetic wounds. More importantly, KLX has the potential to be developed as a topical drug to promote diabetic wound healing.