Department of Hand and Foot Orthopedic Surgery, Weifang People's Hospital, Weifang, Shandong, China (mainland).
Weifang Medical University, Weifang, Shandong, China (mainland).
Med Sci Monit. 2019 Oct 23;25:7951-7957. doi: 10.12659/MSM.916950.
BACKGROUND Diabetes causes damage to the soft tissue and bone structure of the foot, referred to as "diabetic foot". Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor, and the role and mechanism of ibrutinib on the diabetic foot have not been elucidated. MATERIAL AND METHODS Male Wister rats were randomly divided into 3 groups: control group, model group, and ibrutinib group. After 14 days, the ulcer wound size of each group was measured, and the ulcer healing rate was calculated. The level of inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha, and IL-6 was detected by enzyme-linked immunosorbent assay (ELISA). Real-time polymerase chain reaction (PCR) was used to analyze the changes of Toll-like receptor 2 (TLR2) and TLR4. The expression of vascular endothelial growth factor (VEGF) and the RAGE (receptor for advanced glycation end product/NF-kappaB (nuclear factor-kappa B) pathway was detected by western blot. RESULTS Blood glucose, blood lipids, serum creatinine, and urea nitrogen (BUN) levels were increased in the model group, together with increased levels of IL-1ß, TNF-alpha, IL-6, as well as TLR2 and TLR4 expression, and there were significant differences compared with the control group (P<0.05). Meanwhile, the model group showed decreased VEGF expression and increased expression of RAGE and NF-kappaB. However, ibrutinib reduced blood sugar, blood lipids, creatinine, and urea nitrogen levels, inhibited the secretion of inflammatory factors, promoted ulcer healing, improved ulcer healing rate, decreased the expression of TLR2, TLR4, RAGE, and NF-kappaB, and increased VEGF expression; there were significant differences in the ibrutinib group compared with the model group (P<0.05). CONCLUSIONS The Btk inhibitor ibrutinib can upregulate VEGF expression, inhibit the expression of TLRs, inhibit the secretion of inflammatory factors, and promote the healing of diabetic foot ulcer possibly by regulating the RAGE/NF-kappaB pathway.
糖尿病会导致足部软组织和骨骼结构受损，称为“糖尿病足”。伊布替尼是一种布鲁顿酪氨酸激酶（Btk）抑制剂，其在糖尿病足中的作用和机制尚不清楚。
雄性 Wistar 大鼠随机分为 3 组：对照组、模型组和伊布替尼组。14 天后，测量各组溃疡伤口大小，计算溃疡愈合率。酶联免疫吸附试验（ELISA）检测白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α和 IL-6 等炎症因子水平。实时聚合酶链反应（PCR）分析 Toll 样受体 2（TLR2）和 TLR4 的变化。采用 Western blot 检测血管内皮生长因子（VEGF）和 RAGE（晚期糖基化终产物受体/核因子-κB（NF-κB）途径）的表达。
模型组血糖、血脂、血肌酐和尿素氮（BUN）水平升高，IL-1β、TNF-α、IL-6 水平升高，TLR2 和 TLR4 表达增加，与对照组比较差异有统计学意义（P<0.05）。同时，模型组 VEGF 表达降低，RAGE 和 NF-κB 表达增加。然而，伊布替尼降低血糖、血脂、肌酐和尿素氮水平，抑制炎症因子分泌，促进溃疡愈合，提高溃疡愈合率，降低 TLR2、TLR4、RAGE 和 NF-κB 表达，增加 VEGF 表达；与模型组比较差异有统计学意义（P<0.05）。
Btk 抑制剂伊布替尼可能通过调节 RAGE/NF-κB 通路上调 VEGF 表达，抑制 TLRs 表达，抑制炎症因子分泌，促进糖尿病足溃疡愈合。
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