九州大学 研究者情報
論文一覧
松岡 悠太(まつおか ゆうた) データ更新日:2019.09.17

助教 /  薬学研究院 創薬科学部門 生体分子情報学講座


原著論文
1. Emoto MC, Sato-Akaba H, Matsuoka Y, Yamada KI, Fujii HG., Non-invasive mapping of glutathione levels in mouse brains by in vivo electron paramagnetic resonance (EPR) imaging: Applied to a kindling mouse model., Neuroscience Letters, 10.1016/j.neulet.2018.10.001., 690, 6-10, 2018.10, [URL], Glutathione (GSH) is an important antioxidant that can protect cells under oxidative stress. Thus, a non-invasive method to measure and map the distribution of GSH in live animals is needed. To image the distribution of GSH levels in specific brain regions, a new method using electron paramagnetic resonance (EPR) imaging with a nitroxide imaging probe was developed. Pixel-based mapping of brain GSH levels was successfully obtained by using the linear relationship between reduction rates for nitroxides in brains, measured by an in vivo EPR imager, and brain GSH levels, measured by an in vitro biochemical assay. The newly developed method was applied to a kindling mouse model induced with pentylenetetrazole (PTZ) to visualize changes in GSH levels in specific brain regions after seizure. The obtained map of brain GSH levels clearly indicated decreased GSH levels around the hippocampal region compared to control mice..
2. Shinto S, Matsuoka Y, Yamato M, Yamada KI, Antioxidant nitroxides protect hepatic cells from oxidative stress-induced cell death, Journal of Clinical Biochemistry and Nutrition, 10.3164/jcbn.17-60, 62, 2, 132-138, 2018.03, [URL], Oxidative stress causes cell death and induces many kinds of disease, including liver disease. Nitroxides are known to react catalytically with free radicals. In this study, the cell protective activities of nitroxides were compared with those of other antioxidants. Nitroxides showed much greater inhibition of hydrogen peroxide-induced cell death than other antioxidants in a hepatic cell line and in primary hepatocytes. The intracellular oxidative stress level at 24 h after hydrogen peroxide stimulation was significantly decreased by nitroxides, but not by other antioxidants. To clarify the mechanism of cell protection by nitroxides, we investigated whether nitroxides inhibited DNA damage and mitogen-activated protein kinase pathway activation. We found that nitroxides reduced caspase3 activation and may have ultimately inhibited cell death. In conclusion, nitroxides are very useful for attenuating cell damage due to oxidative stress. Nitroxides are thus a potential therapeutic agent for oxidative stress-related diseases..
3. Ishida Y, Okamoto Y, Matsuoka Y, Tada A, Janprasit J, Yamato M, Morales NP, Yamada KI, Detection and inhibition of lipid-derived radicals in low-density lipoprotein., Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2017.10.388, 113, 487-493, 2017.10, [URL], Oxidized low density lipoprotein (Ox-LDL) is implicated in a variety of oxidative diseases. To clarify the mechanisms involved and facilitate the investigation of therapeutics, we previously developed a detection method for lipid-derived radicals using the fluorescent probe 2,2,6-trimethyl-6-pentyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)piperidine-1-oxyl (NBD-Pen). In this study, NBD-Pen was used to detect lipid-derived radicals in Ox-LDL from in vitro and in vivo samples using an iron overloaded mouse model. By following the timeline of lipid radical generation using this method, the iron overloaded mice could be successfully treated with the antioxidant trolox, resulting in successful lowering of the plasma lipid peroxidation, aspartate transaminase and alanine transaminase levels. Furthermore, using a combination therapy of the chelating agent deferoxamine and trolox, liver injury and oxidative stress markers were also reduced in iron overloaded mice. The NBD-Pen method is highly sensitive as well as selective and is suitable for targeting minimally modified LDL compared with other existing methods..
4. Emoto MC, Matsuoka Y, Yamada KI, Sato-Akaba H, Fujii HG, Non-invasive imaging of the levels and effects of glutathione on the redox status of mouse brain using electron paramagnetic resonance imaging., Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.02.134., 485, 4, 802-806, 2017.02, [URL], Glutathione (GSH) is the most abundant non-protein thiol that buffers reactive oxygen species in the brain. GSH does not reduce nitroxides directly, but in the presence of ascorbates, addition of GSH increases ascorbate-induced reduction of nitroxides. In this study, we used electron paramagnetic resonance (EPR) imaging and the nitroxide imaging probe, 3-methoxycarbonyl-2,2,5,5-tetramethyl-piperidine-1-oxyl (MCP), to non-invasively obtain spatially resolved redox data from mouse brains depleted of GSH with diethyl maleate compared to control. Based on the pharmacokinetics of the reduction reaction of MCP in the mouse heads, the pixel-based rate constant of its reduction reaction was calculated as an index of the redox status in vivo and mapped as a "redox map". The obtained redox maps from control and GSH-depleted mouse brains showed a clear change in the brain redox status, which was due to the decreased levels of GSH in brains as measured by a biochemical assay. We observed a linear relationship between the reduction rate constant of MCP and the level of GSH for both control and GSH-depleted mouse brains. Using this relationship, the GSH level in the brain can be estimated from the redox map obtained with EPR imaging..
5. Enoki M, Shinto S, Matsuoka Y, Otsuka A, Kaidzu S, Tanito M, Shibata T, Uchida K, Ohira A, Yamato M, Yamada KI, Lipid radicals cause light-induced retinal degeneration, Chemical Communications, 10.1039/c7cc03387g, 53, 79, 10922-10925, 2017.01, [URL], Age-related macular degeneration (AMD) is the leading cause of blindness worldwide. Although the cause of AMD remains unknown, lipid peroxidation (LPO) end-products are critical molecules for its development. Herein, we report the imaging of lipid radicals, which are key factors in the LPO reaction, and therapeutic information using animal models..
6. Matsuoka Y, Ohkubo K, Yamasaki T, Yamato M, Ohtabu H, Shirouzu T, Fukuzumi S, Yamada KI, A profluorescent nitroxide probe for ascorbic acid detection and its application to quantitative analysis of diabetic rat plasma, RSC Advances, 10.1039/C6RA07693A, 60907-60915, 2016.06, [URL].
7. Yamada KI, Mito F, Matsuoka Y, Ide S, Shikimachi K, Fujiki A, Kusakabe D, Ishida Y, Enoki M, Tada A, Ariyoshi M, Yamasaki T, Yamato M, Fluorescence probes to detect lipid-derived radicals, Nature Chemical Biology, 10.1038/nchembio.2105, 12, 608-613, 2016.04, [URL], Lipids and their metabolites are easily oxidized in chain reactions initiated by lipid radicals, forming lipid peroxidation products that include the electrophiles 4-hydroxynonenal and malondialdehyde. These markers can bind cellular macromolecules, causing inflammation, apoptosis and other damage. Methods to detect and neutralize the initiating radicals would provide insights into disease mechanisms and new therapeutic approaches. We describe the first high-sensitivity, specific fluorescence probe for lipid radicals, 2,2,6-trimethyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)-6-pentylpiperidine-1-oxyl (NBD-Pen). NBD-Pen directly detected lipid radicals in living cells by turn-on fluorescence. In a rat model of hepatic carcinoma induced by diethylnitrosamine (DEN), NBD-Pen detected lipid radical generation within 1 h of DEN administration. The lipid radical scavenging moiety of NBD-Pen decreased inflammation, apoptosis and oxidative stress markers at 24 h after DEN, and liver tumor development at 12 weeks. Thus, we have developed a novel fluorescence probe that provides imaging information about lipid radical generation and potential therapeutic benefits in vivo..
8. Matsuoka Y, Yamato M, Yamada KI, Fluorescence probe for the convenient and sensitive detection of ascorbic acid, Journal of Clinical Biochemistry and Nutrition, 10.3164/jcbn.15-105, 58, 16-22, 2016.01, [URL].
9. Emoto MC, Yamato M, Akaba-Sato H, Yamada KI, Matsuoka Y, Fujii HG, Brain imaging in methamphetamine-treated mice using a nitroxide contrast agent for EPR imaging of the redox status and a gadolinium contrast agent for MRI observation of Blood-Brain Barrier function., Free Radical Research, 49(8):1038-47, 49, 8, 1038-1047, 2015.05, [URL].
10. Ito J, Otsuki N, Zhang X, Konno T, Kurahashi T, Takahashi M, Yamato M, Matsuoka Y, Yamada K, Miyata S, Fujii J., Ascorbic acid reverses the prolonged anesthetic action of pentobarbital in Akr1a-knockout mice, Life Sciences, 95(1):1-8, 95, 1, 1-8, 2014.01, [URL], Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, is highly expressed in the liver and is involved in both the detoxification of carbonyl compounds and ascorbic acid biosynthesis. By comparison with wild-type mice, Akr1a-knockout (Akr1a(-/-)) mice and human Akrla-transgenic (Akr1a(tg/+)) mice experience different anesthetic actions from pentobarbital-prolonged in Akr1a-knockout (Akr1a(-/-)) mice and shortened in human Akrla-transgenic (Akr1a(tg/+)) mice..
11. Yamasaki T, Matsuoka Y, Mito F, Yamato M, Yamada KI, Redox potential of nitroxide is an index to evaluate superoxide dismutase mimic activity, Asian Journal of Organic Chemistry, 10.1002/ajoc.201300011, 2, 5, 388-391, 2013.07, [URL], The structure‐reactivity relationship of piperidine nitroxides modified at the C4 position against superoxide was evaluated. The redox potential of nitroxides and N‐oxoammonium cation couples correlates strongly with their reactivity toward superoxide. Thus, the superoxide dismutase activity of a nitroxide can be controlled based on its redox potential..
12. Matsuoka Y, Yamato M, Yamasaki T, Mito F, Yamada KI, Rapid and convenient detection of ascorbic acid using a fluorescent nitroxide switch, Free Radical Biology and Medicine, 53(11):2112-8, 53, 11, 2112-2118, 2012.12, [URL], Ascorbic acid is a small-molecule reductant with multiple functions in vivo. Reducing ascorbic acid intake leads to a lack of hydroxylation of prolines and lysines, causing a looser triple helix and resulting in scurvy. Ascorbic acid also acts as an antioxidant to prevent oxidative stress. Because ascorbic acid is related to disease states, rapid and convenient detection of ascorbic acid should be useful in diagnosis. Nitroxide is reduced to the corresponding hydroxylamine by ascorbic acid and a sensitive and novel approach to its detection employs covalent coupling of nitroxide with a fluorophore, leading to intramolecular quenching of fluorescence emission by electron-exchange interactions. Here, we developed a new fluorophore–nitroxide probe, Naph-DiPy nitroxide, for ascorbic acid. Naph-DiPy nitroxide rapidly reacted with ascorbic acid and showed fluorescence enhancement, but not in response to other reductants or reactive oxygen species. To confirm the practical usefulness of the fluorophore–nitroxide probe, we demonstrated the use of Naph-DiPy nitroxide for the measurement of ascorbic acid in the plasma of osteogenic disorder Shionogi rats when fed an ascorbic acid-deficient diet. The results suggest that this novel fluorophore–nitroxide probe could sensitively and easily detect ascorbic acid and be useful as a tool for the diagnosis of disease states..
13. Yamasaki T, Ito Y, Mito F, Kitagawa K, Matsuoka Y, Yamato M, Yamada KI, Structural Concept of Nitroxide As a Lipid Peroxidation Inhibitor, Journal of Organic Chemistry, 10.1021/jo200361p, 76 (10), 4144-4148, 2011.04, Nitroxides have antioxidative activities toward lipid peroxidation, but the influence of steric factors is not known. We synthesized alkyl-substituted nitroxides at the α-position of the N–O moiety to enhance lipophilicity and the bulk effect. There was good correlation between the IC50 and lipophilicity (log Po/w) of nitroxides with use of the thiobarbituric acid-reactive substances (TBARS) assay. Furthermore, an inhibitory effect on the TBARS assay was dependent upon the number and length of alkyl groups, though nitroxides had almost identical lipophilicity..
14. Yamasaki T, Mito F, Matsuoka Y, Yamato M, Yamada KI, Synthesis and Utilization of α-Substituted Nitroxides, Nitroxides - Theory, Experiment and Applications, 10.5772/39163, 4144-4148, 2012.09, [URL].

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