| Project/Area Number |
16K08391
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
Lee Seon Hwa 東北大学, 薬学研究科, 助教 (60519776)
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| Co-Investigator(Kenkyū-buntansha) |
大江 知行 東北大学, 薬学研究科, 教授 (10203712)
佐藤 涼 東北大学, 薬学研究科, 助教 (20757166)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Oxidative stress, / Lipid peroxidation, / Pyridoxamine, / Mass spectrometry, / Protein modification / Chemical modification, / Mass spectrometry / Oxidative stress / Lipid peroxidation / Pyridoxamine / 酸化ストレス / 内因性ピリドキサミン / 化学修飾 |
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| Outline of Final Research Achievements |
Pyridoxamine (PM) is a drug candidate for various chronic diseases because it can inhibit advanced glycation end product formation. PM might therefore prevent protein damage from lipid hydroperoxide-derived aldehydes 4-oxo-2(E)-nonenal (ONE) and 4-hydroxy-2(E)-nonenal (HNE). Upon reaction with PM, ONE and HNE yielded an identical product containing a pyrrole ring, which structure was characterized by LC-MS and NMR. When human serum albumin (HSA) was reacted with a linoleic acid hydroperoxide, ONE modified more residues than did HNE. Upon treatment with PM, the formation of ONE-modified HSA peptides, but not of HNE-modified peptides, was reduced. Concomitantly, PM-ONE adducts increased in a dose-dependent manner. The inhibition effect of PM was confirmed in the cell system subjected to oxidative stress. Therefore, PM can inhibit lipid hydroperoxide-derived damage to proteins by trapping ONE preferentially, and the resulting PM-ONE adducts can be used as a dosimeter for ONE production.
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| Academic Significance and Societal Importance of the Research Achievements |
今回、過酸化脂質由来の求電子性アルデヒド化合物とPMの反応機構、反応生成物、および修飾阻害効果を精査した。これらの知見からPMは、糖尿病のみならず、酸化・脂質化の関与する様々な慢性疾患（高脂血症、老化など）さらには生活習慣（喫煙、飲酒など）によるタンパク質ダメージの抑制効果も期待される。同様にPMは、化学発癌や薬物毒性などの原因となる求電子性代謝物の捕捉を通して、タンパク質・DNA修飾を抑制する効果も期待される。
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