Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
Int J Mol Sci. 2020 Mar 13;21(6):1966. doi: 10.3390/ijms21061966.
Diabetes mellitus is a growing global health issue nearly across the world. Diabetic patients who are prone to develop diabetes-related complications often exhibit progressive neuropathy (painless and sensory loss). It is usual for small wounds to progress to ulceration, which especially worsens with peripheral arterial disease and in the presence of anaerobic bacteria, culminating into gangrene. In our study, vaccarin (VAC), the main active monomer extracted from Chinese herb , is proven to have a role in promoting diabetic chronic wound healing through a cytoprotective role under high glucose conditions.
We constructed a pressure ulcer on both VAC-treated and control mice based on a type 1 diabetes (T1DM) model. The wound healing index was evaluated by an experimental wound assessment tool (EWAT). We also determined the effect of VAC on the proliferation and cell migration of human microvascular endothelial cells (HMEC-1) by a cell counting kit (CCK-8), a scratch and transwell assay.
The results demonstrated that VAC could promote the proliferation and migration of high glucose-stimulated HMEC-1 cells, which depend on the activation of FOXP2/AGGF1. Activation of the angiogenic factor with G patch and FHA domains 1 (AGGF1) caused enhanced phosphorylation of serine/threonine kinase (Akt) and extracellular regulated protein kinases (Erk1/2). By silencing the expression of forkhead box p2 (FOXP2) protein by siRNA, both mRNA and protein expression of AGGF1 were downregulated, leading to a decreased proliferation and migration of HMEC-1 cells. In addition, a diabetic chronic wound model in vivo unveiled that VAC had a positive effect on chronic wound healing, which involved the activation of the above-mentioned pathways.
In summary, our study found that VAC promoted chronic wound healing in T1DM mice by activating the FOXP2/AGGF1 pathway, indicating that VAC may be a promising candidate for the treatment of the chronic wounds of diabetic patients.
糖尿病是一个在全球范围内日益严重的健康问题。容易发生糖尿病相关并发症的糖尿病患者通常表现出进行性神经病变（无痛和感觉丧失）。小伤口进展为溃疡很常见，尤其是在合并外周动脉疾病和存在厌氧菌的情况下，最终导致坏疽。在我们的研究中，从中药中提取的主要活性单体之一淫羊藿苷（VAC）已被证明在高糖条件下通过细胞保护作用在促进糖尿病慢性伤口愈合方面发挥作用。
我们基于 1 型糖尿病（T1DM）模型在 VAC 处理和对照小鼠上构建了压疮。通过实验性伤口评估工具（EWAT）评估伤口愈合指数。我们还通过细胞计数试剂盒（CCK-8）、划痕和 Transwell 测定确定 VAC 对高糖刺激的人微血管内皮细胞（HMEC-1）增殖和细胞迁移的影响。
结果表明，VAC 可以促进高糖刺激的 HMEC-1 细胞的增殖和迁移，这依赖于叉头框 P2（FOXP2）/AGGF1 的激活。含 G 补丁和 FHA 结构域 1（AGGF1）的血管生成因子的激活导致丝氨酸/苏氨酸激酶（Akt）和细胞外调节蛋白激酶（Erk1/2）的磷酸化增强。通过 siRNA 沉默叉头框 P2（FOXP2）蛋白的表达，AGGF1 的 mRNA 和蛋白表达均下调，导致 HMEC-1 细胞的增殖和迁移减少。此外，体内糖尿病慢性伤口模型表明，VAC 对慢性伤口愈合有积极作用，涉及上述途径的激活。
总之，我们的研究发现，VAC 通过激活 FOXP2/AGGF1 通路促进 T1DM 小鼠的慢性伤口愈合，表明 VAC 可能是治疗糖尿病患者慢性伤口的有前途的候选药物。
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