A novel therapeutic strategy for treatment of diabetic skin ulcer using phosphoenolpyruvic acid

点击翻译按钮获取中文摘要

Phosphoenolpyruvic acid (PEP), a glycolytic intermediate, has a high energy phosphate bond, and is capable of penetrating through the cel1 membrane. The aim of this research is to examine the effect of PEP on the healing process of intractable diabetic skin ulcer under in-vitro and in-vivo conditions. We obtained the following results:1) When PEP n 3% aqueous solution was sprayed onto the skin wounds of genetically diabetic mice, PEP showed earlier healing with re-epithelialization, neovasculalization and granulation tissue formation. The efficacy of PEP sprayed topically was almost equal to or more effective than that of the commercially available topical preparation of basic fibroblast growth factor.2) The production of vascular endothelial growth factor (VEGF), an important factor for wound healing, from mouse macrophage-like cell line RAW264 was increased in the presence of PEP. In addition, a metabolite of PEP, pyruvic acid facilitated the production.3) On the other hand, PEP did not affect the cell proliferation in TIG109 cells, derived from human dermal fibroblast.4) PEP facilitated the proliferation, migration and tube formation of human umbilical vein endothelial cells, and simultaneously increased the production of VEGF and bFGF. The tube formation by PEP was inhibited by co-incubation with VEGF neutralized antibody.5) PEP increased the proliferation of human keratinocyte cell line HaCaT.These results indicate that a cell activating agent PEP potentially promotes wound healing through the cell proliferation and the production of growth factors in vascular endothelial cells, macrophages and keratinocytes, the cells of which play an important role n the healing. We suggest that PEP can be a promising candidate for the treatment of intractable diabetic skin ulcer.