School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD, UK.
Food Funct. 2018 Nov 14;9(11):5728-5739. doi: 10.1039/c8fo00297e.
Diabetes mellitus characterized by hyperglycemia favors formation of advanced glycation endproducts (AGEs) capable of triggering vascular complications by interfering with imbalanced inflammation and angiogenesis to eventually impede wound-healing. Momordica charantia (MC, bitter melon) has been shown to prevent AGE formation and to promote angiogenesis in diabetic wounds in animal models. However, the mechanism underlying its effects on angiogenesis is unclear. We investigated the effects of methanolic extracts of MC pulp (MCP), flesh (MCF) and charantin (active component of MC) using an in vitro model of angiogenesis. MC extracts or low concentrations of bovine serum albumin-derived AGEs (BSA-AGEs) stimulated proliferation, migration (using wound-healing assay) and tube formation (using Matrigel™-embedded 3D culture) of bovine aortic endothelial cells (BAEC) together with increases in the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, the key angiogenic signaling cytoplasmic protein. Blocking the receptor for AGEs (RAGE) inhibited low BSA-AGE- and MC extract-induced ERK1/2 phosphorylation and tube formation, indicating the crucial role of RAGE in the pro-angiogenic effects of MC extracts. Moreover, inhibitory effects of high BSA-AGE concentration on cell proliferation and migration were reduced by the addition of MC extracts, which reversed the BSA-AGE anti-angiogenic effect on tube formation. Thus, MC extracts exert direct pro-angiogenic signaling mediated via RAGE to overcome the anti-angiogenic effects of high BSA-AGEs, highlighting the biphasic RAGE-dependent mechanisms involved. This study enhances our understanding of the mechanisms underlying the pro-angiogenic effects of MC extracts in improvement of diabetes-impaired wound-healing.
糖尿病的特征是高血糖，有利于形成高级糖基化终产物（AGEs），这些产物通过干扰失衡的炎症和血管生成，最终阻碍伤口愈合，从而引发血管并发症。苦瓜（MC）已被证明可防止AGEs 的形成，并促进糖尿病伤口中的血管生成。然而，其对血管生成影响的机制尚不清楚。我们使用体外血管生成模型研究了苦瓜果肉（MCF）、苦瓜浆（MCP）和苦瓜素（MC 的活性成分）的甲醇提取物的作用。MC 提取物或低浓度牛血清白蛋白衍生的 AGEs（BSA-AGEs）可刺激牛主动脉内皮细胞（BAEC）的增殖、迁移（通过伤口愈合试验）和管状形成（通过 Matrigel™包埋的 3D 培养），同时增加细胞外信号调节激酶（ERK）1/2 的磷酸化，ERK1/2 是关键的血管生成信号细胞质蛋白。阻断 AGEs 的受体（RAGE）可抑制低 BSA-AGE 和 MC 提取物诱导的 ERK1/2 磷酸化和管状形成，表明 RAGE 在 MC 提取物的促血管生成作用中起关键作用。此外，高 BSA-AGE 浓度对细胞增殖和迁移的抑制作用可通过添加 MC 提取物来减少，这可逆转 BSA-AGE 对管状形成的抗血管生成作用。因此，MC 提取物通过 RAGE 发挥直接的促血管生成信号，以克服高 BSA-AGE 的抗血管生成作用，突出了涉及的双相 RAGE 依赖性机制。这项研究增强了我们对 MC 提取物改善糖尿病受损伤口愈合的促血管生成作用机制的理解。
