Oriental Medicine Research Center for Bone and Joint Disease, Kyung Hee University, 149 Sangil-dong, Gangdong-gu, Seoul 134-727, Republic of Korea.
Int Immunopharmacol. 2011 Jan;11(1):46-54. doi: 10.1016/j.intimp.2010.10.003. Epub 2010 Oct 16.
Formononetin, a phytoestrogen from the root of Astragalus membranaceus, is used as a blood enhancer and to improve blood microcirculation in complementary and alternative medicine. The present study investigated the influence of formononetin on the expression of early growth response factor-1 (Egr-1) and growth factors contributing to wound healing. Formononetin significantly increased growth factors such as transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells (HUVECs). Formononetin also increased the expression of Egr-1 transcription factor by 3.2- and 10.5-fold, compared with recombinant VEGF(125) in HUVECs. The formononetin-mediated 12%-43% increase induced endothelial cell proliferation and recovered the migration of wounded HUVECs. In an ex vivo angiogenesis assay, formononetin produced a larger capillary sprouting area than produced using recombinant VEGF(125). Cell proliferation and migration of HUVECs were also greater in the presence of formonectin than VEGF(125). Western blot analysis of scratch-wounded confluent HUVECs showed that formononetin induced the phosphorylation of extracellular signal-regulated kinase (ERK) and slightly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The formononetin-mediated sustained activation of Egr-1 was suppressed by the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PD98059 inhibited the formononetin-induced endothelial proliferation and repair in scratch-wounded HUVECs, SB203580 increased the cell proliferation and wound healing. Formononetin accelerate wound closure rate as early as day 3 after surgery and consistently observed until day 10 after in wound animal model. These data suggest that formononetin promotes endothelial repair and wound healing in a process involving the over-expression of Egr-1 transcription factor through the regulation of the ERK1/2 and p38 MAPK pathways.
芒柄花素是来自黄芪的植物雌激素，用于增强血液和改善血液微循环，在补充和替代医学中使用。本研究探讨了芒柄花素对早期生长反应因子-1 (Egr-1)和促进伤口愈合的生长因子表达的影响。芒柄花素显著增加了转化生长因子-β 1 (TGF-β1)、血管内皮生长因子 (VEGF)、血小板衍生生长因子 (PDGF)和碱性成纤维细胞生长因子 (bFGF)等生长因子在人脐静脉内皮细胞 (HUVECs)中的表达。与重组 VEGF(125)相比，芒柄花素使 Egr-1 转录因子的表达增加了 3.2-10.5 倍。芒柄花素介导的 12%-43%的内皮细胞增殖诱导，并恢复了受伤的 HUVECs的迁移。在体外血管生成试验中，芒柄花素产生的毛细血管发芽面积大于使用重组 VEGF(125)产生的面积。在存在芒柄花素的情况下，HUVECs 的细胞增殖和迁移也大于 VEGF(125)。划痕愈合的 HUVECs 的 Western blot 分析表明，芒柄花素诱导细胞外信号调节激酶 (ERK)磷酸化，轻度抑制丝裂原活化蛋白激酶 (MAPK) p38 的磷酸化。芒柄花素介导的 Egr-1 的持续激活被 ERK 抑制剂 PD98059 和 p38 抑制剂 SB203580 抑制。PD98059 抑制了划痕愈合的 HUVECs 中芒柄花素诱导的内皮增殖和修复，SB203580 增加了细胞增殖和伤口愈合。芒柄花素可在手术后第 3 天加速伤口闭合率，并在伤口动物模型中持续观察到第 10 天。这些数据表明，芒柄花素通过调节 ERK1/2 和 p38 MAPK 通路，促进内皮修复和伤口愈合，其过程涉及 Egr-1 转录因子的过表达。
