| Project/Area Number |
17591899
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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 |
Emergency medicine
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| Research Institution | KANAZAWA MEDICAL UNIVERSITY |
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Principal Investigator |
SHIMADA Hiroki Kanazawa Medical University, Molecular and Cell Structural Science, Assistant Professor, 医学部, 講師 (60278108)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAI Kei-Ichi Kanazawa Medical University, Molecular and Cell Structural Science, Professor, 医学部, 教授 (60027092)
SIMAMURA Eriko Kanazawa Medical University, Molecular and Cell Structural Science, Professor, 医学部, 講師 (00267741)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | paraquat / mitochondria / cytotoxicity / NADH-quinone oxidoreductasem / voltage-dependent anion channel / superoxide / hydrogen peroxide / NADH / voltage-dependent anion channel / NADH-quinone oxidoreductase_m / permeability transition pore |
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| Research Abstract |
Paraquat is an herbicide that forms reactive oxygen metabolites, which are toxic to humans. With respect to the cytotoxicmechanisms, we identified a NADH-quinone oxidoreductasem activity located on the mitochondria and propose the participationof a voltage-dependent anion channel, VDAC.
When isolated rat mitochondria were incubated with NADH and paraquat, H_2O_2 was produced by NADH-quinoneoxidoreductasem activity of the outer membrane and the mitochondria were damaged. These changes were suppressed bybenzoquinone, 4,4'-diisothiocyanatostilbene-2,29-disulfic acid and anti-VDAC1 antibody. NADH-quinone oxidoreductasemactivity was located by zymography at the 500kDa band on native-polyacrylamide electrophoresis, and it contained VDAC protein in a Western blot. VDAC1-overexpressed HeLa cells treated with paraquat produced more intracellular H_2O_2 thancontrols and were more sensitive to paraquat. In contrast, mitochondria in VDAC1 knockdown cells did not produce H_2O_2 andhad a higher survival rate after exposure to paraquat. The results indicate that mitochondrial VDAC protein was associated with reactive oxygen species that mediated paraquat toxicity.
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