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

使用磷酸烯醇丙酮酸治疗糖尿病皮肤溃疡的新治疗策略

• 批准号: 17590472
• 负责人: IRIE Tetsumi
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590472/
• 关键词: phosphoe nolpyruvic acid (PEP); cell activating agents; diabetic skin ulcer; cell proliferation; growth factors; re-epithelialization; neovasculalization; granulation tissue formation; ホスホエノールピルビン; ホスホエノーピルビン酸

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.

磷酸烯醇丙酮酸（PEP）是一种糖酵解中间体，具有高能量的磷酸键，能够穿透细胞膜。本研究旨在探讨PEP在体外和体内条件下对难治性糖尿病皮肤溃疡愈合过程的影响。结果表明：1)在遗传性糖尿病小鼠的皮肤创面上喷施3%的PEP水溶液，PEP愈合时间较早，具有再上皮化、新生血管化和肉芽组织形成的特点。PEP外敷的效果与市售的碱性成纤维细胞生长因子外敷的效果几乎相等或更有效。2)在PEP的作用下，小鼠巨噬细胞样细胞系RAW264的血管内皮生长因子（VEGF）的生成增加，VEGF是伤口愈合的重要因子。此外，PEP的代谢物丙酮酸促进了生产。3)另一方面，PEP对人真皮成纤维细胞来源的TIG109细胞的增殖没有影响。4) PEP促进了人脐静脉内皮细胞的增殖、迁移和成管，同时增加了VEGF和bFGF的生成。PEP与VEGF中和抗体共孵育可抑制其成管。5) PEP可促进人角质形成细胞系HaCaT的增殖。这些结果表明，细胞活化剂PEP可能通过血管内皮细胞、巨噬细胞和角化细胞的细胞增殖和生长因子的产生促进伤口愈合，这些细胞在愈合中起重要作用。我们认为PEP可能是治疗顽固性糖尿病皮肤溃疡的一个有希望的候选人。