| Project/Area Number |
16590889
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kumamoto University |
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Principal Investigator |
NISHIKAWA Takeshi Kumamoto University, Faculty of Medical and Pharmaceutical sciences, Research Associate, 大学院・医学薬学研究部, 助手 (70336212)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAMURA Nobuhiro Kumamoto University, University Hospital, Lecturer, 医学部附属病院, 講師 (40274716)
SAKAKIDA Michiharu Kumamoto University, Faculty of Medical and Pharmaceutical sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (50170577)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Diabetes Mellitus / Diabetic complications / Mitochondria / Oxidative stress / AMPK / PGC-1α / MnSOD / Mitochondria biogenesis / 活性酸素 |
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| Research Abstract |
The production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) has been proposed as a key event in the development of diabetic complications. The association between the pathogenesis of diabetes mellitus and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetic complications, this study aimed to investigated the effect of metformin and AICAR on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells (HUVECs). Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated adenosine 5'-monophosphate -activated protein kinase (AMPK) activity and increased the expression of PPAR□co-activator-1□(PGC-1□) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPK□1 (DN-AMPK) diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1□ completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factors (NRF)-1 and mitochondrial DNA transcription factor A (mtTFA), and stimulated the mitochondrial proliferation. DN-AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1□ pathway. Our findings suggested that a blockade of hyperglycemia-induced mtROS production though AMPK activation, PGC-1□ induction, or MnSOD induction could therefore be useful in the design of new pharmacological approaches to prevent diabetes complications.
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