2024/05/30 更新

写真a

ホンマ タクジロウ
本間 拓二郎
HOMMA TAKUJIRO
担当
大学院医学研究科 基礎医科学専攻 講師
医学部 医学科
職名
講師
所属
医学研究院
所属キャンパス
阿倍野キャンパス

担当・職階

  • 大学院医学研究科 基礎医科学専攻 

    講師  2022年04月 - 継続中

  • 医学部 医学科 

    講師  2022年04月 - 継続中

取得学位

  • 博士(医学) ( 長崎大学 )

  • 修士(薬学) ( 東京理科大学 )

  • 学士(薬学) ( 東京理科大学 )

研究分野

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 病態医化学

  • ライフサイエンス / 医化学

研究キーワード

  • 酸化ストレス

  • 生化学

  • 分子生物学

研究概要

  • 活性酸素・フリーラジカルによる病気の発症とそれに対する生体防御機構の解析

研究歴

  • 活性酸素・フリーラジカルによる病気の発症とそれに対する生体防御機構の解析

    2014年06月 - 2022年03月 

所属学協会

  • 日本薬理学会

    2022年04月 - 継続中

  • 日本生化学会

    2014年06月 - 継続中

  • 日本酸化ストレス学会

    2014年06月 - 継続中

  • 日本分子生物学会

    2008年07月 - 継続中

受賞歴

  • 山形大学医学会学術賞・銀賞

    本間拓二郎

    2021年03月   山形大学医学会  

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    受賞国:日本国

  • 日本酸化ストレス学会・学術奨励賞

    本間拓二郎

    2021年05月  

  • 第40回Cytoprotection研究会・奨励賞

    本間拓二郎

    2022年03月  

  • 第75回日本酸化ストレス学会学術集会・最優秀ポスター賞

    本間拓二郎

    2022年05月   日本酸化ストレス学会  

  • Cells 2023 Outstanding Reviewer Award

    Takujiro Homma

    2024年04月  

職務経歴(学外)

  • 山形大学大学院医学系研究科   生化学分子生物学講座   助教

    2014年06月 - 2022年03月

学歴

  • 長崎大学   大学院医歯薬学総合研究科   博士課程   卒業・修了

    2009年04月 - 2014年06月

  • 東京理科大学   大学院薬学研究科   修士課程   卒業・修了

    2007年04月 - 2009年03月

  • 東京理科大学   薬学部   薬学科   学士課程   卒業・修了

    2003年04月 - 2007年03月

論文

  • Generation of Rat Monoclonal Antibody for Human Nucleolin. 査読

    Nishino Y, Homma T, Ihara KI, Fujii J, Tachibana T, Yokoyama C

    Monoclonal antibodies in immunodiagnosis and immunotherapy   42 ( 4 )   145 - 149   2023年08月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    DOI: 10.1089/mab.2023.0008

    PubMed

  • Copper chelation by d-penicillamine alleviates melanocyte death induced by rhododendrol without inhibiting tyrosinase. 査読

    Kei Nagatani, Yuko Abe, Takujiro Homma, Junichi Fujii, Tamio Suzuki

    Biochemical and biophysical research communications   663   71 - 77   2023年06月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Oxidative metabolism of rhododendrol (RD), a skin-whitening ingredient, by tyrosinase has caused leukoderma in a certain population of Japanese consumers. Toxic RD metabolites and reactive oxygen species are proposed causes for the melanocyte death. However, the mechanism by which reactive oxygen species are produced during RD metabolism remains elusive. Some phenolic compounds are known to act as suicide substrates for tyrosinase, resulting in release of a copper atom and hydrogen peroxide during its inactivation. We hypothesized that RD may be a suicide substrate for tyrosinase and that the released copper atom may be responsible for the melanocyte death through hydroxyl radical production. In line with this hypothesis, human melanocytes incubated with RD showed an irreversible decrease in tyrosinase activity and underwent cell death. A copper chelator, d-penicillamine, markedly suppressed the RD-dependent cell death without significantly affecting the tyrosinase activity. Peroxide levels in RD-treated cells were not affected by d-penicillamine. Given the unique enzymatic properties of tyrosinase, we conclude that RD acted as a suicide substrate and resulted in release of a copper atom and hydrogen peroxide, which would collectively impair melanocyte viability. These observations further imply that copper chelation may alleviate chemical leukoderma caused by other compounds.

    DOI: 10.1016/j.bbrc.2023.04.062

    PubMed

  • Flow cytometric determination of ferroptosis using a rat monoclonal antibody raised against ferroptotic cells. 査読

    Homma T, Nishino Y, Fujii J, Yokoyama C

    Journal of immunological methods   510   113358 - 113358   2022年11月( ISSN:0022-1759

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    DOI: 10.1016/j.jim.2022.113358

    PubMed

  • Consequences of a peroxiredoxin 4 (Prdx4) deficiency on learning and memory in mice. 査読

    Takujiro Homma, Hiroki Fujiwara, Tsukasa Osaki, Satoshi Fujii, Junichi Fujii

    Biochemical and biophysical research communications   621   32 - 38   2022年07月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Peroxiredoxin 4 (Prdx4) is responsible for the oxidative folding of new proteins that are synthesized in the endoplasmic reticulum (ER). It has recently been suggested that increased ER stress is associated with neurodegenerative diseases, including Alzheimer's disease. Prdx4 is widely distributed throughout the brain, and is also expressed in hippocampal neurons and oligodendrocytes, suggesting that it is associated with learning and memory. We previously established Prdx4-knockout (KO) mice but did not examine the behavioral phenotypes. In the present study, we report on the learning and memory abilities of Prdx4-KO mice based on Morris water maze and the Y-maze tests. The findings indicate that Prdx4-KO mice showed a lower spatial memory ability in both tests. In contrast, the results of the open field test indicated that locomotor activity is significantly increased in Prdx4-KO mice. We then performed mRNA analyses of the brains of Prdx4-KO mice and found an increased expression of genes related to the ER-associated degradation (ERAD) mechanism, which is an important protein quality control system for the maintenance of ER homeostasis. Finally, proteomic analyses of the brains of Prdx4-KO mice showed an aberrant expression in the proteins, which have been suggested to be related to calcium homeostasis and synaptogenesis in neurons. Our collective results suggest that the Prdx4 ablation perturbs oxidative protein folding in the ER, thus leading to aberrant ER homeostasis in neuronal cells, ultimately leading to impaired spatial memory formation.

    DOI: 10.1016/j.bbrc.2022.06.096

    PubMed

  • d-Cysteine supplementation partially protects against ferroptosis induced by xCT dysfunction via increasing the availability of glutathione. 査読

    Takujiro Homma, Tsukasa Osaki, Sho Kobayashi, Hideyo Sato, Junichi Fujii

    Journal of clinical biochemistry and nutrition   71 ( 1 )   48 - 54   2022年07月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国内誌  

    Glutathione (GSH) is synthesized from three amino acids and the overall process is highly dependent on the availability of l-cysteine (l-Cys). GSH serves as an essential cofactor for glutathione peroxidase 4 (Gpx4), which reduces phospholipid hydroperoxides. The inactivation of Gpx4 or an insufficient supply of l-Cys results in the accumulation of lipid hydroperoxides, eventually leading to iron-dependent cell death, ferroptosis. In this study, we investigated the anti-ferroptotic properties of d-cysteine (d-Cys) under conditions of dysfunction in cystine transporter, xCT. l-Cys supplementation completely rescued ferroptosis that had been induced by the erastin-mediated inhibition of xCT in Hepa 1-6 cells. Upon d-Cys supplementation, the erastin-treated cells remained completely viable for periods of up to 24 h but eventually died after 48 h. d-Cys supplementation suppressed the production of lipid peroxides, thereby ferroptosis. The addition of d-Cys sustained intracellular Cys and GSH levels to a certain extent. When Hepa 1-6 cells were treated with a combination of buthionine sulfoximine and erastin, the anti-ferroptotic effect of d-Cys was diminished. These collective results indicate that, although d-Cys is not the direct source of GSH, d-Cys supplementation protects cells from ferroptosis in a manner that is dependent on GSH synthesis via stimulating the uptake of l-Cys.

    DOI: 10.3164/jcbn.21-143

    PubMed

  • The concerted elevation of conjugation reactions is associated with the aggravation of acetaminophen toxicity in Akr1a-knockout mice with an ascorbate insufficiency. 査読

    Soju Kimura, Tsukasa Osaki, Takujiro Homma, Sotai Kimura, Sho Kobayashi, Masaki Nakane, Satoshi Miyata, Hiroshi Itoh, Kaneyuki Kawamae, Junichi Fujii

    Life sciences   120694 - 120694   2022年06月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    AIMS: Acetaminophen (APAP) is a relatively safe analgesic drug, but overdosing can cause acute liver failure. Ingested APAP is detoxified by metabolic conversion through conjugation reactions with glucuronate, sulfate, or glutathione (GSH). The consumption of GSH through conjugation as well as mitochondrial dysfunction is considered to be responsible for the increased susceptibility to APAP-induced hepatotoxicity. Compared to wild-type (WT) mice, Akr1a-knockout (KO) mice are vulnerable to developing hepatotoxicity due to the fact that ascorbate synthesis is attenuated. We used such KO mice to investigate how these conjugation reactions are involved in the hepatotoxicity caused by an overdose of APAP under ascorbate-deficient conditions. MAIN METHODS: APAP (400 mg/kg) was intraperitoneally administered to WT mice and KO mice. In addition to histological and blood biochemical analyses, metabolites in the liver, blood plasma, and urine were measured at several time points by liquid chromatography-mass spectrometry. KEY FINDINGS: Liver damage occurred earlier in the KO mice than in the WT mice. The levels of APAP-Cys, a final metabolite of GSH-conjugated APAP, as well as glucuronidated APAP and sulfated APAP were all higher in the KO mice compared to the WT mice. Treatment of the APAP-administered KO mice with N-acetylcysteine or supplementation of ascorbate suppressed the conjugation reactions at 6 h after APAP had been administrated, which mitigated the degree of liver damage. SIGNIFICANCE: An ascorbate deficiency coordinately stimulates conjugation reactions of APAP, which, combined with the mitochondrial damage caused by APAP metabolites, collectively results in the aggravation of the acute liver failure.

    DOI: 10.1016/j.lfs.2022.120694

    PubMed

  • Methionine Deprivation Reveals the Pivotal Roles of Cell Cycle Progression in Ferroptosis That Is Induced by Cysteine Starvation. 査読

    Takujiro Homma, Sho Kobayashi, Junichi Fujii

    Cells   11 ( 10 )   2022年05月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis, a type of iron-dependent necrotic cell death, is triggered by the accumulation of excessive lipid peroxides in cells. Glutathione (GSH), a tripeptide redox molecule that contains a cysteine (Cys) unit in the center, plays a pivotal role in protection against ferroptosis. When the transsulfuration pathway is activated, the sulfur atom of methionine (Met) is utilized to generate Cys, which can then suppress Cys-starvation-induced ferroptosis. In the current study, we cultured HeLa cells in Met- and/or cystine (an oxidized Cys dimer)- deprived medium and investigated the roles of Met in ferroptosis execution. The results indicate that, in the absence of cystine or Met, ferroptosis or cell cycle arrest, respectively, occurred. Contrary to our expectations, however, the simultaneous deprivation of both Met and cystine failed to induce ferroptosis, although the intracellular levels of Cys and GSH were maintained at low levels. Supplementation with S-adenosylmethionine (SAM), a methyl group donor that is produced during the metabolism of Met, caused the cell cycle progression to resume and lipid peroxidation and the subsequent induction of ferroptosis was also restored under conditions of Met/cystine double deprivation. DNA methylation appeared to be involved in the resumption in the SAM-mediated cell cycle because its downstream metabolite S-adenosylhomocysteine failed to cause either cell cycle progression or ferroptosis to be induced. Taken together, our results suggest that elevated lipid peroxidation products that are produced during cell cycle progression are involved in the execution of ferroptosis under conditions of Cys starvation.

    DOI: 10.3390/cells11101603

    PubMed

  • Superoxide Radicals in the Execution of Cell Death. 査読

    Junichi Fujii, Takujiro Homma, Tsukasa Osaki

    Antioxidants (Basel, Switzerland)   11 ( 3 )   2022年03月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Superoxide is a primary oxygen radical that is produced when an oxygen molecule receives one electron. Superoxide dismutase (SOD) plays a primary role in the cellular defense against an oxidative insult by ROS. However, the resulting hydrogen peroxide is still reactive and, in the presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are the preferred target of hydroxyl radicals. Ferroptosis, a type of necrotic cell death induced by lipid peroxides in the presence of free iron, has attracted considerable interest because of its role in the pathogenesis of many diseases. Radical electrons, namely those released from mitochondrial electron transfer complexes, and those produced by enzymatic reactions, such as lipoxygenases, appear to cause lipid peroxidation. While GPX4 is the most potent anti-ferroptotic enzyme that is known to reduce lipid peroxides to alcohols, other antioxidative enzymes are also indirectly involved in protection against ferroptosis. Moreover, several low molecular weight compounds that include α-tocopherol, ascorbate, and nitric oxide also efficiently neutralize radical electrons, thereby suppressing ferroptosis. The removal of radical electrons in the early stages is of primary importance in protecting against ferroptosis and other diseases that are related to oxidative stress.

    DOI: 10.3390/antiox11030501

    PubMed

  • Nitric oxide protects against ferroptosis by aborting the lipid peroxidation chain reaction. 査読

    Takujiro Homma, Sho Kobayashi, Marcus Conrad, Hiroyuki Konno, Chikako Yokoyama, Junichi Fujii

    Nitric oxide : biology and chemistry   115   34 - 43   2021年10月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis is a type of iron-dependent necrotic cell death, which is typically triggered by the depletion of intracellular glutathione (GSH), which is associated with increased lipid peroxidation. Nitric oxide (NO) is a highly reactive gaseous radical mediator with anti-oxidation properties that terminates lipid peroxidation reactions. In the current study, we report the anti-ferroptotic action of NOC18, an NO donor that spontaneously releases NO, in cells under various ferroptotic conditions in vitro. Our results indicate that, when mouse hepatoma Hepa 1-6 cells are incubated with NOC18, cell death induced by various ferroptotic stimuli such as cysteine (Cys) starvation, the inhibition of glutathione peroxidase 4 (GPX4) and treatment with tertiary-butyl hydroperoxide (TBHP) is significantly reduced. Treatment with NOC18 failed to improve the decrease in the levels of Cys or GSH and the accumulation of ferrous iron upon ferroptotic stimuli. The fluorescent intensity of C11-BODIPY581/591, a probe that is used to detect lipid peroxidation products, was increased somewhat by treatment with NOC18 under conditions of Cys starvation, and the accumulation of lipid peroxidation end-products, as evidenced by the levels of 4-hydroxynonenal, were effectively suppressed. The pre-incubation of TBHP with NOC7, a short-lived NO donor completely eliminated its ability to trigger ferroptosis. These collective results indicate that NO exerts a cytoprotective action against various ferroptotic stimuli by aborting the lipid peroxidation chain reaction.

    DOI: 10.1016/j.niox.2021.07.003

    PubMed

  • Dextran sulphate inhibits an association of prions with plasma membrane at the early phase of infection. 査読

    Takayuki Fuse, Takehiro Nakagaki, Takujiro Homma, Hiroya Tange, Naohiro Yamaguchi, Ryuichiro Atarashi, Daisuke Ishibashi, Noriyuki Nishida

    Neuroscience research   171   34 - 40   2021年10月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    The defining characteristic of prion diseases is conversion of a cellular prion protein (PrPC) to an abnormal prion protein (PrPSc). The exogenous attachment of PrPSc to the surface of a target cell is critical for infection. However, the initial interaction of PrPSc with the cell surface is poorly characterized. In the current study, we specifically focused on the association of PrPSc with cells during the early phase of infection, using an acute infection model. First, we treated mouse neuroblastoma N2a-58 cells with prion strain 22 L-infected brain homogenates and revealed that PrPSc was associated with membrane fractions within three hours, a short exposure time. These results were also observed in PrPC-deficient hippocampus cell lines. We also demonstrate here that PrPSc from 22 L-infected brain homogenates was associated with lipid rafts during the early phase of infection. Furthermore, we revealed that DS500, a glycosaminoglycan mimetic, inhibited both the attachment of PrPSc to membrane fractions and subsequent prion transmission, suggesting that the early association of prions with cell surface is important for prion infection.

    DOI: 10.1016/j.neures.2021.01.004

    PubMed

  • Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides. 査読

    Sho Kobayashi, Takujiro Homma, Nobuaki Okumura, Jia Han, Keita Nagaoka, Hideyo Sato, Hiroyuki Konno, Sohsuke Yamada, Toshifumi Takao, Junichi Fujii

    Free radical biology & medicine   174   12 - 27   2021年10月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    The knockout (KO) of the cystine transporter xCT causes ferroptosis, a type of iron-dependent necrotic cell death, in mouse embryonic fibroblasts, but this does not occur in macrophages. In this study, we explored the gene that supports cell survival under a xCT deficiency using a proteomics approach. Analysis of macrophage-derived peptides that were tagged with iTRAQ by liquid chromatography-mass spectrometry revealed a robust elevation in the levels of carnosine dipeptidase II (CNDP2) in xCT KO macrophages. The elevation in the CNDP2 protein levels was confirmed by immunoblot analyses and this elevation was accompanied by an increase in hydrolytic activity towards cysteinylglycine, the intermediate degradation product of glutathione after the removal of the γ-glutamyl group, in xCT KO macrophages. Supplementation of the cystine-free media of Hepa1-6 cells with glutathione or cysteinylglycine extended their survival, whereas the inclusion of bestatin, an inhibitor of CNDP2, counteracted the effects of these compounds. We established CNDP2 KO mice by means of the CRISPR/Cas9 system and found a decrease in dipeptidase activity in the liver, kidney, and brain. An acetaminophen overdose (350 mg/kg) showed not only aggravated hepatic damage but also renal injury in the CNDP2 KO mice, which was not evident in the wild-type mice that were receiving the same dose. The aggravated renal damage in the CNDP2 KO mice was consistent with the presence of abundant levels of CNDP2 in the kidney, the organ prone to developing ferroptosis. These collective data imply that cytosolic CNDP2, in conjugation with the removal of the γ-glutamyl group, recruits Cys from extracellular GSH and supports redox homeostasis of cells, particularly in epithelial cells of proximal tubules that are continuously exposed to oxidative insult from metabolic wastes that are produced in the body.

    DOI: 10.1016/j.freeradbiomed.2021.07.036

    PubMed

  • Nitric oxide produced by NOS2 copes with the cytotoxic effects of superoxide in macrophages. 査読

    Sho Kobayashi, Takujiro Homma, Junichi Fujii

    Biochemistry and biophysics reports   26   100942 - 100942   2021年07月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Nitric oxide (NO) reacts with superoxide to produce peroxynitrite, a potent oxidant and reportedly exerts cytotoxic action. Herein we validated the hypothesis that interaction of NO with superoxide exerts protection against superoxide toxicity using macrophages from mice with a knockout (KO) of inducible NO synthase (NOS2) and superoxide dismutase 1 (SOD1), either individually or both. While no difference was observed in viability between wild-type (WT) and NOS2KO macrophages, SOD1KO and SOD1-and NOS2-double knockout (DKO) macrophages were clearly vulnerable and cell death was observed within four days. A lipopolysaccharide (LPS) treatment induced the formation of NOS2, which resulted in NO production in WT and these levels were even higher in SOD1KO macrophages. The viability of the DKO macrophages but not SOD1KO macrophages were decreased by the LPS treatment. Supplementation of NOC18, a NO donor, improved the viability of SOD1KO and DKO macrophages both with and without the LPS treatment. The NOS2 inhibitor nitro-l-arginine methyl ester consistently decreased the viability of LPS-treated SOD1KO macrophages but not WT macrophages. Thus, in spite of the consequent production of peroxynitrite in LPS-stimulated macrophages, the coordinated elevation of NO appears to exert anti-oxidative affects by coping with superoxide cytotoxicity upon conditions of inflammatory stimuli.

    DOI: 10.1016/j.bbrep.2021.100942

    PubMed

  • Pleiotropic Actions of Aldehyde Reductase (AKR1A). 査読

    Junichi Fujii, Takujiro Homma, Satoshi Miyata, Motoko Takahashi

    Metabolites   11 ( 6 )   2021年05月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    We provide an overview of the physiological roles of aldehyde reductase (AKR1A) and also discuss the functions of aldose reductase (AKR1B) and other family members when necessary. Many types of aldehyde compounds are cytotoxic and some are even carcinogenic. Such toxic aldehydes are detoxified via the action of AKR in an NADPH-dependent manner and the resulting products may exert anti-diabetic and anti-tumorigenic activity. AKR1A is capable of reducing 3-deoxyglucosone and methylglyoxal, which are reactive intermediates that are involved in glycation, a non-enzymatic glycosylation reaction. Accordingly, AKR1A is thought to suppress the formation of advanced glycation end products (AGEs) and prevent diabetic complications. AKR1A and, in part, AKR1B are responsible for the conversion of d-glucuronate to l-gulonate which constitutes a process for ascorbate (vitamin C) synthesis in competent animals. AKR1A is also involved in the reduction of S-nitrosylated glutathione and coenzyme A and thereby suppresses the protein S-nitrosylation that occurs under conditions in which the production of nitric oxide is stimulated. As the physiological functions of AKR1A are currently not completely understood, the genetic modification of Akr1a could reveal the latent functions of AKR1A and differentiate it from other family members.

    DOI: 10.3390/metabo11060343

    PubMed

  • Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels. 査読

    Naoki Ishii, Takujiro Homma, Yuji Takeda, Naing Ye Aung, Ken-Ichi Yamada, Satoshi Miyata, Hironobu Asao, Mitsunori Yamakawa, Junichi Fujii

    The Journal of nutritional biochemistry   91   108604 - 108604   2021年05月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Aldehyde reductase encoded by the Akr1a gene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility of Akr1a-/- (KO) female mice, litter sizes in the KO mice are typically smaller than those for Akr1a+/+ (WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.

    DOI: 10.1016/j.jnutbio.2021.108604

    PubMed

  • Erythrocytes as a preferential target of oxidative stress in blood. 査読

    Junichi Fujii, Takujiro Homma, Sho Kobayashi, Prashant Warang, Manisha Madkaikar, Malay B Mukherjee

    Free radical research   55 ( 5 )   562 - 580   2021年05月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Red blood cells (RBC) are specifically differentiated to transport oxygen and carbon dioxide in the blood and they lack most organelles, including mitochondria. The autoxidation of hemoglobin constitutes a major source of reactive oxygen species (ROS). Nitric oxide, which is produced by endothelial nitric oxide synthase (NOS3) or via the hemoglobin-mediated conversion of nitrite, interacts with ROS and results in the production of reactive nitrogen oxide species. Herein we present an overview of anemic diseases that are closely related to oxidative damage. Because the compensation of proteins by means of gene expression does not proceed in enucleated cells, antioxidative and redox systems play more important roles in maintaining the homeostasis of RBC against oxidative insult compared to ordinary cells. Defects in hemoglobin and enzymes that are involved in energy production and redox reactions largely trigger oxidative damage to RBC. The results of studies using genetically modified mice suggest that antioxidative enzymes, notably superoxide dismutase 1 and peroxiredoxin 2, play essential roles in coping with oxidative damage in erythroid cells, and their absence limits erythropoiesis, the life-span of RBC and consequently results in the development of anemia. The degeneration of the machinery involved in the proteolytic removal of damaged proteins appears to be associated with hemolytic events. The ubiquitin-proteasome system is the dominant machinery, not only for the proteolytic removal of damaged proteins in erythroid cells but also for the development of erythropoiesis. Hence, despite the fact that it is less abundant in RBC compared to ordinary cells, the aberrant ubiquitin-proteasome system may be associated with the development of anemic diseases via the accumulation of damaged proteins, as typified in sickle cell disease, and impaired erythropoiesis.

    DOI: 10.1080/10715762.2021.1873318

    PubMed

  • Superoxide produced by mitochondrial complex III plays a pivotal role in the execution of ferroptosis induced by cysteine starvation. 査読

    Takujiro Homma, Sho Kobayashi, Hideyo Sato, Junichi Fujii

    Archives of biochemistry and biophysics   700   108775 - 108775   2021年03月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis is a type of iron-dependent, non-apoptotic cell death, which is typically induced by cysteine starvation or by the inhibition of glutathione peroxidase 4 (GPX4) activity with the accompanying elevation in lipid peroxidation product levels. Despite the central role of mitochondria in oxidative metabolism and hence, as main sources of superoxide, the issue of whether mitochondrial superoxide participates in the execution of ferroptosis remains unclear. To gain additional insights into this issue, we employed suppressors of the site IQ electron leak (S1QEL) and suppressors of the site IIIQo electron leak (S3QEL), small molecules that suppress mitochondrial superoxide production from complex I and III, respectively. The findings indicate that S3QEL, but not S1QEL, significantly protected mouse hepatoma Hepa 1-6 cells from lipid peroxidation and the subsequent ferroptosis induced by cysteine (Cys) starvation (cystine deprivation from culture media or xCT inhibition by erastin). The intracellular levels of Cys and GSH remained low irrespective of life or death. Moreover, S3QEL also suppressed ferroptosis in xCT-knockout mouse-derived embryonic fibroblasts, which usually die under conventional cultivating conditions due to the absence of intracellular Cys and GSH. Although it has been reported that erastin induces the hyperpolarization of the mitochondrial membrane potential, no correlation was observed between hyperpolarization and cell death in xCT-knockout cells. Collectively, these results indicate that superoxide production from complex III plays a pivotal role in the ferroptosis that is induced by Cys starvation, suggesting that protecting mitochondria is a promising therapeutic strategy for the treatment of multiple diseases featuring ferroptosis.

    DOI: 10.1016/j.abb.2021.108775

    PubMed

  • Characterization of a rat monoclonal antibody raised against ferroptotic cells. 査読

    Sho Kobayashi, Yumi Harada, Takujiro Homma, Chikako Yokoyama, Junichi Fujii

    Journal of immunological methods   489   112912 - 112912   2021年02月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis is regulated, non-apoptotic cell death in which ferrous iron and lipid peroxidation products play essential roles. While the ferroptotic pathway is now becoming unveiled, it is difficult to determine its involvement in situ because no unique marker for ferroptotic cells is known. In this study, we report on raising a rat monoclonal antibody against mouse-derived Hepa 1-6 cells that had been cultivated in cystine-deprived media. Binding of the resulting antibody, designated as FerAb, increased during advancing ferroptosis which was caused, not only by cystine deprivation but also treatment with erastin or RSL3, while apoptotic cell death induced by a staurosporine treatment had no effect on the binding. The FerAb was found to bind to 4-hydroxy-2-nonenal (HNE)-modified bovine serum albumin, but no specific protein was detected in ferroptotic cells in an immunoblot analysis. These results indicate that non-proteinaceous, HNE-like structural moiety was part of the antigen for FerAb, although the binding profiles of FerAb to ferroptotic cells were different from those of the currently available anti-HNE antibody. Immunocytological detection revealed inhomogenous staining within cells and partial co-localization with peripheral mitochondria and other cellular components. FerAb was found to be applicable for ferroptotic cells in other mouse cells and cultured human cells that were examined. Thus, the properties of the rat monoclonal antibody FerAb established in this study promise to be useful for the characterization of ferroptotic cell death.

    DOI: 10.1016/j.jim.2020.112912

    PubMed

  • Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue. 査読

    Takujiro Homma, Yuji Takeda, Tomoyuki Nakano, Shinya Akatsuka, Daisuke Kinoshita, Toshihiro Kurahashi, Shinichi Saitoh, Ken-Ichi Yamada, Satoshi Miyata, Hironobu Asao, Kaoru Goto, Tetsu Watanabe, Masafumi Watanabe, Shinya Toyokuni, Junichi Fujii

    Free radical biology & medicine   162   255 - 265   2021年01月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Superoxide dismutase 1 (Sod1) plays pivotal roles in antioxidation via accelerating the conversion of superoxide anion radicals into hydrogen peroxide, thus inhibiting the subsequent radical chain reactions. While Sod1 deficient cells inevitably undergo death in culture conditions, Sod1-knockout (KO) mice show relatively mild phenotypes and live approximately two years. We hypothesized that the presence of abundant levels of ascorbic acid (AsA), which is naturally produced in mice, contributes to the elimination of reactive oxygen species (ROS) in Sod1-KO mice. To verify this hypothesis, we employed mice with a genetic ablation of aldehyde reductase (Akr1a), an enzyme that is involved in the biosynthesis of AsA, and established double knockout (DKO) mice that lack both Sod1 and Akr1a. Supplementation of AsA (1.5 mg/ml in drinking water) was required for the DKO mice to breed, and, upon terminating the AsA supplementation, they died within approximately two weeks regardless of age or gender. We explored the etiology of the death from pathophysiological standpoints in principal organs of the mice. Marked changes were observed in the lungs in the form of macroscopic damage after the AsA withdrawal. Histological and immunological analyses of the lungs indicated oxidative damage of tissue and activated immune responses. Thus, preferential oxidative injury that occurred in pulmonary tissues appeared to be primary cause of the death in the mice. These collective results suggest that the pivotal function of AsA in coping with ROS in vivo, is largely in pulmonary tissues that are exposed to a hyperoxygenic microenvironment.

    DOI: 10.1016/j.freeradbiomed.2020.10.023

    PubMed

  • Ferroptosis caused by cysteine insufficiency and oxidative insult. 査読

    Junichi Fujii, Takujiro Homma, Sho Kobayashi

    Free radical research   54 ( 11-12 )   969 - 980   2020年12月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Free iron has long been assumed to be a deteriorating factor in an oxidative insult and was recently found to be directly associated with ferroptosis, a specific type of cell death. The free iron-involved production of lipid peroxides activates the fatal pathway, resulting in nonapoptotic, programed cell death. Lipid peroxides appear to destroy membrane integrity, leading to cell rupture. Glutathione (GSH) is a major redox molecule that functions to protect against ferroptosis by its ability to donate an electron to glutathione peroxidase 4 (GPX4), the sole enzyme that reduces phospholipid hydroperoxides. The availability of free cysteine (Cys) determines the levels of GSH synthesis, and, hence, its deprivation causes ferroptosis. Free iron is provided via ferritinophagy, the chaperone-mediated autophagic degradation of ferritin, but GPX4 also undergoes degradation via chaperone-mediated autophagy. Activated Nrf2 and ATF4 induce the expression of the cystine transporter xCT to cope with ferroptosis. To the contrary, the excessive activation of p53 induces ferroptosis by suppressing the expression of xCT in genetic and nongenetic manners. It therefore appears that xCT functions as the gatekeeper for determining cellular survival by regulating the availability of Cys in the cell. The issue of the extent of involvement of ferroptosis in an in vivo situation largely remains ambiguous. Establishing tools for specifying ferroptotic cells in situ would facilitate our understanding of its roles in pathogenesis.

    DOI: 10.1080/10715762.2019.1666983

    PubMed

  • Emerging connections between oxidative stress, defective proteolysis, and metabolic diseases. 査読

    Takujiro Homma, Junichi Fujii

    Free radical research   54 ( 11-12 )   931 - 946   2020年12月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and autophagy are involved in the clearance of oxidised and/or aggregated proteins, it would be logical to assume that alterations in proteolysis would accompany pathological conditions. Indeed, both systems are themselves susceptible to oxidative modification and therefore could be a prominent target of reactive oxygen species (ROS). Oxidative stress appears to be a common underlying factor in the development of and the pathogenesis of various metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Recent studies, using obesity and hyperglycaemia model mice, reported that both UPS and autophagy systems are inhibited in these mice and that this inhibition is accompanied by lipid accumulation, insulin resistance, and tissue damage. However, the detailed molecular mechanisms that are responsible for regulating intracellular proteolysis in metabolic diseases are not well understood. In the current review, we discuss the correlation between oxidative stress, defective proteolysis, and metabolic diseases. An understanding of how ROS affects intracellular proteolysis may provide new perspectives on the development of and control of diseases.

    DOI: 10.1080/10715762.2020.1734588

    PubMed

  • Testis-specific peroxiredoxin 4 variant is not absolutely required for spermatogenesis and fertility in mice. 査読

    Takujiro Homma, Toshihiro Kurahashi, Naoki Ishii, Nobuyuki Shirasawa, Junichi Fujii

    Scientific reports   10 ( 1 )   17934 - 17934   2020年10月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    PRDX4, a member of peroxiredoxin family, is largely concentrated in the endoplasmic reticulum (ER) and plays a pivotal role in the redox relay during oxidative protein folding as well as in peroxidase reactions. A testis-specific PRDX4 variant transcript (PRDX4t) lacks the conventional exon 1, which encodes the signal peptide that is required for entry into the ER lumen, but instead carries alternative exon 1, which is transcribed from the upstream promoter in a testis-specific manner and results in the PRDX4t protein being localized in the cytosol. However, the potential roles of PRDX4t in male genital action remain unknown. Using a CRISPR/Cas9 system, we first disrupted the testis-specific promoter/exon 1 and generated mice that were specifically deficient in PRDX4t. The resulting PRDX4t knockout (KO) mice underwent normal spermatogenesis and showed no overt abnormalities in the testis. Mating PRDX4t KO male mice with wild-type (WT) female mice produced normal numbers of offspring, indicating that a PRDX4t deficiency alone had no effect on fertility in the male mice. We then generated mice lacking both PRDX4 and PRDX4t by disrupting exon 2, which is communal to these variants. The resulting double knockout (DKO) mice were again fertile, and mature sperm isolated from the epididymis of DKO mice exhibited a normal fertilizing ability in vitro. In the meantime, the protein levels of glutathione peroxidase 4 (GPX4), which plays an essential role in the disulfide bond formation during spermatogenesis, were significantly increased in the testis and caput epididymis of the DKO mice compared with the WT mice. Based on these results, we conclude that the disruption of the function of PRDX4t in the spermatogenic process appears to be compensated by other factors including GPX4.

    DOI: 10.1038/s41598-020-74667-9

    PubMed

  • Ascorbic acid prevents N-nitrosodiethylamine-induced hepatic injury and hepatocarcinogenesis in Akr1a-knockout mice. 査読

    Naoki Ishii, Takujiro Homma, Xin Guo, Ken-Ichi Yamada, Sohsuke Yamada, Junichi Fujii

    Toxicology letters   333   192 - 201   2020年10月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    To gain insights into the benefits of ascorbic acid (AsA) in hepatoprotection, we examined the status of Akr1a-/- (KO) mice, which biosynthesize AsA at about 10% the rate as Akr1a+/+ (WT) mice, in terms of their response to an N-nitrosodiethylamine (NDEA)-induced hepatic injury. The intraperitoneal injection of NDEA (35 mg/kg) started at 4 weeks of age and was performed at weekly intervals thereafter. While the fatality rate was substantial in the KO mice, AsA supplementation (1.5 mg/ml in the drinking water) greatly extended their life-spans. Only two out of 54 KO mice survived to 28 weeks, and both contained approximately an order of magnitude greater number of tumor nodules compared to WT mice or KO mice with AsA supplementation. Histological and biochemical examinations at 20 weeks indicated that AsA potently protected against the hepatotoxic action of NDEA. Interestingly, the AsA levels in the liver were higher in the AsA-supplemented KO mouse groups that had received the NDEA treatment compared to the corresponding control group. While the protein levels of Cyp2e1, an enzyme that plays a major role in the bioactivation of NDEA, had declined to a similar extent among the experimental groups, p-nitrophenol-oxidizing activity was sustained at high levels in the KO mouse livers but AsA supplementation suppressed this activity. These findings confirm that AsA is a potent micronutrient that copes with hepatic injury and cancer development caused by exposure to NDEA in the livers of Akr1a-knockout mice.

    DOI: 10.1016/j.toxlet.2020.08.005

    PubMed

  • Cysteine preservation confers resistance to glutathione-depleted cells against ferroptosis via CDGSH iron sulphur domain-containing proteins (CISDs). 査読

    Takujiro Homma, Sho Kobayashi, Junichi Fujii

    Free radical research   54 ( 6 )   397 - 407   2020年06月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis is a type of iron-dependent, non-apoptotic cell death, which is typically induced by the suppression of phospholipid hydroperoxide-glutathione peroxidase (GPX4) activity and a corresponding elevation in lipid peroxidation products. While the inhibition of the xCT-mediated uptake of cystine commonly causes ferroptosis, the sensitivity of cells to the inhibition of the glutathione (GSH) synthesis by buthionine sulfoximine (BSO) varies considerably. The objective of this study was to clarify the underlying mechanism responsible for these differential responses to the targeted inhibition of either the cysteine (Cys) supply to or GSH synthesis in the cells. While intracellular GSH levels were depleted when mouse hepatoma Hepa 1-6 cells were treated with BSO, intracellular Cys levels rather increased and viability of the cells remained unchanged, suggesting that Cys has a role in this resistance to ferroptosis under conditions of GSH depletion. When the cells were treated with pioglitazone (PGZ), a potent inhibitor of CDGSH iron sulphur domain-containing proteins (CISDs), PGZ alone had no effect on either cell viability or GSH levels but induced ferroptosis under conditions of GSH depletion by the BSO treatment. In the case of the co-treatment with PGZ and BSO, ferrous iron and the levels of lipid peroxides were robustly increased in the cells, but neither endoplasmic reticulum stress nor apoptosis was evident. Collectively, CISDs appeared to exert an anti-ferroptotic function by suppressing free iron toxicity and the subsequent lipid peroxidation with assistance provided by Cys.

    DOI: 10.1080/10715762.2020.1780229

    PubMed

  • Genetic ablation of aldehyde reductase (Akr1a) augments exercise endurance in mice via activation of the PGC-1α-involved pathway. 査読

    Miku Takahashi, Takujiro Homma, Ken-Ichi Yamada, Satoshi Miyata, Osamu Nakajima, Junichi Fujii

    Life sciences   249   117501 - 117501   2020年05月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    AIMS: Aldehyde reductase (AKR1A) is involved in the synthesis of ascorbic acid (AsA) as well as the detoxification of aldehydes. AKR1A-/- (KO) mice produce about 10% of the normal amounts of AsA compared to AKR1A+/+ (WT) mice. We investigated physiologic roles of AKR1A in running using the KO mice. MAIN METHODS: The KO mice were subjected to a treadmill test under either restricted AsA production or a sufficiency by supplementation and compared the results with those of WT mice. Contents of glucose, aspartate aminotransferase, AsA and free fatty acids in blood were measured. Glycogen contents were measured in the liver and skeletal muscle, and hepatic proteins were examined by immunoblot analyses. KEY FINDINGS: Running performance was higher in the KO mice than the WT mice irrespective of the AsA status. After the exercise period, blood glucose levels were decreased in the WT mice but were preserved in the KO mice. Liver glycogen levels were also consistently preserved in the KO mice after exercise. Free fatty acid levels tended to be originally high in blood plasma compared to those of the WT mice and were increased to similar extent in them. A key regulator of energy metabolism, PGC-1α, and the products of downstream target genes that encode for glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphatase, were constitutively at high levels in the KO mice. SIGNIFICANCE: The genetic ablation of AKR1A activates the PGC-1α pathway and spare glucose, which would consequently confer exercise endurance.

    DOI: 10.1016/j.lfs.2020.117501

    PubMed

  • Prion protein interacts with the metabotropic glutamate receptor 1 and regulates the organization of Ca2+ signaling. 査読

    Takehiro Matsubara, Katsuya Satoh, Takujiro Homma, Takehiro Nakagaki, Naohiro Yamaguchi, Ryuichiro Atarashi, Yuka Sudo, Yasuhito Uezono, Daisuke Ishibashi, Noriyuki Nishida

    Biochemical and biophysical research communications   525 ( 2 )   447 - 454   2020年04月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Cellular prion protein (PrP) is a membrane protein that is highly conserved among mammals and mainly expressed on the cell surface of neurons. Despite its reported interactions with various membrane proteins, no functional studies have so far been carried out on it, and its physiological functions remain unclear. Neuronal cell death has been observed in a PrP-knockout mouse model expressing Doppel protein, suggesting that PrP might be involved in Ca2+ signaling. In this study, we evaluated the binding of PrP to metabotropic glutamate receptor 1 (mGluR1) and found that wild-type PrP (PrP-wt) and mGluR1 co-immunoprecipitated in dual-transfected Neuro-2a (N2a) cells. Fluorescence resonance energy transfer analysis revealed an energy transfer between mGluR1-Cerulean and PrP-Venus. In order to determine whether PrP can modulate mGluR1 signaling, we performed Ca2+ imaging analyses following repetitive exposure to an mGluR1 agonist. Agonist stimulation induced synchronized Ca2+ oscillations in cells coexpressing PrP-wt and mGluR1. In contrast, N2a cells expressing PrP-ΔN failed to show ligand-dependent regulation of mGluR1-Ca2+ signaling, indicating that PrP can bind to mGluR1 and modulate its function to prevent irregular Ca2+ signaling and that its N-terminal region functions as a molecular switch during Ca2+ signaling.

    DOI: 10.1016/j.bbrc.2020.02.102

    PubMed

  • Ascorbic acid and CoQ10 ameliorate the reproductive ability of superoxide dismutase 1-deficient female mice†. 査読

    Naoki Ishii, Takujiro Homma, Jaeyong Lee, Hikaru Mitsuhashi, Ken-Ichi Yamada, Naoko Kimura, Yorihiro Yamamoto, And Junichi Fujii

    Biology of reproduction   102 ( 1 )   102 - 115   2020年02月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Superoxide dismutase 1 suppresses oxidative stress within cells by decreasing the levels of superoxide anions. A dysfunction of the ovary and/or an aberrant production of sex hormones are suspected causes for infertility in superoxide dismutase 1-knockout mice. We report on attempts to rescue the infertility in female knockout mice by providing two antioxidants, ascorbic acid and/or coenzyme Q10, as supplements in the drinking water of the knockout mice after weaning and on an investigation of their reproductive ability. On the first parturition, 80% of the untreated knockout mice produced smaller litter sizes compared with wild-type mice (average 2.8 vs 7.3 pups/mouse), and supplementing with these antioxidants failed to improve these litter sizes. However, in the second parturition of the knockout mice, the parturition rate was increased from 18% to 44-75% as the result of the administration of antioxidants. While plasma levels of progesterone at 7.5 days of pregnancy were essentially the same between the wild-type and knockout mice and were not changed by the supplementation of these antioxidants, sizes of corpus luteum cells, which were smaller in the knockout mouse ovaries after the first parturition, were significantly ameliorated in the knockout mouse with the administration of the antioxidants. Moreover, the impaired vasculogenesis in uterus/placenta was also improved by ascorbic acid supplementation. We thus conclude that ascorbic acid and/or coenzyme Q10 are involved in maintaining ovarian and uterus/placenta homeostasis against insults that are augmented during pregnancy and that their use might have positive effects in terms of improving female fertility.

    DOI: 10.1093/biolre/ioz149

    PubMed

  • Heterozygous SOD1 deficiency in mice with an NZW background causes male infertility and an aberrant immune phenotype. 査読

    Takujiro Homma, Yuji Takeda, Satoshi Sakahara, Naoki Ishii, Sho Kobayashi, Hiroyuki Abe, Hironobu Asao, Junichi Fujii

    Free radical research   53 ( 11-12 )   1060 - 1072   2019年12月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    New Zealand white (NZW) mouse is a mutant strain that has a larval defect in the immune system, and a F1 hybrid between NZW and New Zealand Black mouse spontaneously develops systemic lupus erythematosus (SLE). In meantime, the ablation of superoxide dismutase 1 (Sod1) causes autoimmune haemolytic anaemia, a clinical condition of SLE, in mice with a C57BL/6 background. On the basis of our previous studies, we hypothesised that oxidative stress may trigger this aberrant autoimmunity in NZW mice without crossing with another strain. To validate this, we attempted to establish Sod1-/-/NZW mice but this attempt failed to obtain any objective mouse. The congenic Sod1+/-/NZW male mice were completely infertile because of severe oligozoospermia attributed to a defect in spermatogenesis. The levels of the SOD1 protein were about a half in the testes of the Sod1+/-/NZW mice. Sperm from the Sod1+/-/NZW mice were largely defective and showed quite low fertilising ability in in vitro fertilisation assays. Concomitant with an increase in the oxidatively modified proteins, spermatogenic cells underwent more cell death in the testes of the Sod1+/-/NZW mice compared to those of WT/NZW mice. An examination of immunocompetent cells from Sod1+/-/NZW mice indicated an abnormality in T-cell responses. These collective results suggest that the oxidative stress caused by an SOD1 haploinsufficiency exerts deleterious effects on the testis, either directly on spermatogenic cells or via the destabilisation of the autoimmune response in Sod1+/-/NZW mice.

    DOI: 10.1080/10715762.2019.1677901

    PubMed

  • Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro. 査読

    Takujiro Homma, Sho Kobayashi, Hideyo Sato, Junichi Fujii

    Experimental cell research   384 ( 1 )   111592 - 111592   2019年11月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ferroptosis is characterized by an iron-dependent cell death with increased lipid peroxidation and is typically induced by either a decrease in glutathione (GSH) levels due to an insufficient supply of cysteine (Cys) or the inhibition of phospholipid hydroperoxide glutathione peroxidase (Gpx4). While lipid peroxides are the direct trigger for ferroptosis, the issue of how radical species involve in the cytocidal process remains unclear. To gain insights into this issue, we employed edaravone, a free radical scavenger that is clinically approved for the treatment of acute ischemic strokes and amyotrophic lateral sclerosis (ALS), against ferroptotic cell death caused by various situations, notably under cystine deprivation. We initially investigated the effects of edaravone on ferroptosis in mouse hepatoma Hepa 1-6 cells cultivated in cystine-free medium and found that edaravone largely suppressed ferroptosis. Ferroptosis that was induced in the cells by the use of inhibitors for xCT or Gpx4 was also suppressed by edaravone. Moreover, edaravone also suppressed ferroptosis in xCT-knockout mouse-derived embryonic fibroblasts, which usually die in normal cultivating conditions due to the depletion of intracellular Cys and GSH. Although the edaravone treatment had no effects on the intracellular levels of Cys and GSH, both of which remained low in Hepa 1-6 cells under conditions of cystine deprivation, the causative factors for ferroptosis, including ferrous iron and lipid peroxide levels, were significantly suppressed. Collectively, these results indicate that radical species produced at the initial stage of the cytocidal process under Cys-deprived conditions trigger ferroptosis and scavenging these radicals by edaravone represents a promising treatment.

    DOI: 10.1016/j.yexcr.2019.111592

    PubMed

  • Ascorbic acid insufficiency impairs spatial memory formation in juvenile AKR1A-knockout mice. 査読

    Kazuki Kurihara, Takujiro Homma, Sho Kobayashi, Mototada Shichiri, Hiroki Fujiwara, Satoshi Fujii, Ken-Ichi Yamada, Masaki Nakane, Kaneyuki Kawamae, Junichi Fujii

    Journal of clinical biochemistry and nutrition   65 ( 3 )   209 - 216   2019年11月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国内誌  

    AKR1A, an aldo-keto reductase, is involved in the synthesis of ascorbic acid as well as the reduction of a variety of aldehyde compounds. AKR1A-/- mice produce considerably less ascorbic acid (about 10%) compared to AKR1A+/+ mice and require ascorbic acid supplementation in order to breed. To elucidate the roles played by AKR1A in spatial memory, AKR1A-/- male mice were weaned at 4 weeks of age and groups that received ascorbic acid supplementation and no supplementation were subjected to a Morris water maze test. Juvenile AKR1A-/- mice that received no supplementation showed impaired spatial memory formation, even though about 70% of the ascorbic acid remained in the brains of the AKR1A-/- mice at day 7 after weaning. To the contrary, the young adult AKR1A-/- mice at 13-15 weeks of age maintained only 15% of ascorbic acid but showed no significant difference in the spatial memory compared with the AKR1A+/+ mice or ascorbic acid-supplemented AKR1A-/- mice. It is conceivable that juvenile mice require more ascorbic acid for the appropriate level of formation of spatial memory and that maturation of the neural system renders the memory forming process less sensitive to an ascorbic acid insufficiency.

    DOI: 10.3164/jcbn.19-41

    PubMed

  • Induction of ferroptosis by singlet oxygen generated from naphthalene endoperoxide. 査読

    Takujiro Homma, Sho Kobayashi, Junichi Fujii

    Biochemical and biophysical research communications   518 ( 3 )   519 - 525   2019年10月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Singlet oxygen causes a cytotoxic process in tumor cells in photodynamic therapy (PDT) and skin photoaging. The mechanism responsible for this cytotoxicity is, however, not fully understood. 1-Methylnaphthalene-4-propionate endoperoxide (MNPE) is a cell-permeable endoperoxide that generates pure singlet oxygen. We previously reported that cell death induced by MNPE did not show the typical profile of apoptosis, and the cause of this cell death remains elusive. We report herein on an investigation of the mechanism for MNPE-induced cell death from the view point of ferroptosis. The findings indicate that the MNPE treatment decreased the viabilities of mouse hepatoma Hepa 1-6 cells in vitro, and that this decrease was accompanied by increases in the concentrations of both intracellular ferrous iron and the level of lipid peroxidation, but that the caspase-mediated apoptotic pathway was not activated. The intracellular levels of cysteine and glutathione were not affected by the MNPE treatment. Importantly, an assay of lactate dehydrogenase activity revealed that the cell death caused by MNPE was suppressed by ferrostatin-1, a ferroptosis-specific inhibitor. Collectively, these results strongly indicate that ferroptosis is the main cell death pathway induced by singlet oxygen.

    DOI: 10.1016/j.bbrc.2019.08.073

    PubMed

  • An SOD1 deficiency aggravates proteasome inhibitor bortezomib-induced testicular damage in mice. 査読

    Takujiro Homma, Junichi Fujii

    Biochimica et biophysica acta. General subjects   1863 ( 6 )   1108 - 1115   2019年06月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Proteasomes play a key role in maintaining cellular homeostasis by the proteolytic removal of proteins, including ubiquitinated proteins and/or oxidatively-damaged proteins. The proteasome inhibitor bortezomib (BTZ) has been reported to exert testicular toxicity in mice. In the current study, we treated SOD1-knockout (KO) mice with BTZ and investigated the issue of whether oxidative stress is involved in the development of testicular toxicity. The BTZ treatment significantly increased superoxide production and cell death in the testes of SOD1-KO mice compared to wild-type (WT) mice. We also found that high levels of both ubiquitinated proteins and p62 accumulated and underwent aggregation in the seminiferous tubules of BTZ-injected SOD1-KO mice. Furthermore, the proteolytic activities of proteasomes were significantly decreased in the testes of BTZ-injected SOD1-KO mice compared to their WT counterparts. These results suggest that a combination of oxidative stress caused by an SOD1 deficiency and proteasome inhibition by BTZ accelerates the impairment of proteasomes, which results in severe testicular damage in SOD1-KO mice.

    DOI: 10.1016/j.bbagen.2019.04.005

    PubMed

  • A heterozygous deficiency in protein phosphatase Ppm1b results in an altered ovulation number in mice. 査読

    Naoki Ishii, Takujiro Homma, Ren Watanabe, Naoko Kimura, Motoko Ohnishi, Takayasu Kobayashi, Junichi Fujii

    Molecular medicine reports   19 ( 6 )   5353 - 5360   2019年06月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Ppm1b, a metal‑dependent serine/threonine protein phosphatase, catalyzes the dephosphorylation of a variety of phosphorylated proteins. Ppm1b‑/‑ mouse embryos die at the fertilized oocyte stage, whereas Ppm1b+/‑ mice with a C57BL/6 background exhibit no phenotypic abnormalities. Because the C57BL/6 strain produces a limited number of pups, in an attempt to produce Ppm1b‑/‑ mice, congenic Ppm1b+/‑ mice with an ICR background were established, which are more fertile and gave birth to more pups. As a result, however, no Ppm1b‑/‑ offspring were obtained when pairs of Ppm1b+/‑ ICR mice were bred again. Ppm1b+/‑ male and female ICR mice were analyzed from the viewpoint of fecundity. The Ppm1b haploinsufficiency had no effect on testicular weight or the number of sperm in male mice. Despite the fact that the levels of Ppm1b protein in the ovaries of sexually mature Ppm1b+/‑ mice were decreased compared with those of Ppm1b+/+ mice, there appeared to be no significant difference in the histological appearance of the ovaries, litter sizes or plasma progesterone levels at the estrous stage. When superovulation was induced by stimulation using a hormone treatment, the number of ovulated oocytes were the same for Ppm1b+/‑ and Ppm1b+/+ mice at 4 weeks of age when the estrous cycle did not proceed, however, the number of ovulated oocytes was lower in sexually mature Ppm1b+/‑ mice at 11 weeks of age compared with Ppm1b+/+ mice in the first and the second superovulation cycles. These collective results suggest that follicle development is excessive in Ppm1b+/‑ mice, and that this leads to a partial depletion of matured follicles and a corresponding decrease in the number of ovulated oocytes.

    DOI: 10.3892/mmr.2019.10194

    PubMed

  • The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. 査読

    Xin Guo, Hirotsugu Noguchi, Naoki Ishii, Takujiro Homma, Taiji Hamada, Tsubasa Hiraki, Jing Zhang, Kei Matsuo, Seiya Yokoyama, Hiroaki Ishibashi, Tomoko Fukushige, Takuro Kanekura, Junichi Fujii, Hidetaka Uramoto, Akihide Tanimoto, Sohsuke Yamada

    Antioxidants & redox signaling   30 ( 10 )   1271 - 1284   2019年04月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    AIMS: Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC. RESULTS: In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4-/y), and human PRDX4 transgenic (hPRDX4+/+) mice were given a weekly intraperitoneal injection of diethylnitrosamine for 25 weeks. The HCC incidence was higher in PRDX4-/y mice than in WT or hPRDX4+/+ mice. Intrahepatic and circulating oxidative stress and inflammatory cell infiltration in the liver were obviously decreased in hPRDX4+/+ mice, compared with WT mice. Furthermore, in our cohort study, human HCC specimens with low expression of PRDX4 had higher ROS levels and a highly malignant phenotype, which was associated with a reduced overall survival, compared with those with high PRDX4 expression. However, in human HCC cell lines, PRDX4 knockdown led to a rapidly increased intracellular ROS level and suppressed cell proliferation, inducing cell death. Innovation and Conclusion: Our results clearly indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression of HCC, suggesting the potential utility of PRDX4 activators or inhibitors as therapy for different stages and phenotypes of HCC.

    DOI: 10.1089/ars.2017.7426

    PubMed

  • Type I interferon protects neurons from prions in in vivo models. 査読

    Daisuke Ishibashi, Takujiro Homma, Takehiro Nakagaki, Takayuki Fuse, Kazunori Sano, Katsuya Satoh, Tsuyoshi Mori, Ryuichiro Atarashi, Noriyuki Nishida

    Brain : a journal of neurology   142 ( 4 )   1035 - 1050   2019年04月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases.

    DOI: 10.1093/brain/awz016

    PubMed

  • Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice. 査読

    Tomohisa Takagi, Takujiro Homma, Junichi Fujii, Nobuyuki Shirasawa, Hiroyuki Yoriki, Yuma Hotta, Yasuki Higashimura, Katsura Mizushima, Yasuko Hirai, Kazuhiro Katada, Kazuhiko Uchiyama, Yuji Naito, Yoshito Itoh

    Free radical biology & medicine   134   153 - 164   2019年04月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    BACKGROUND AND AIMS: Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4-/y) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model. MATERIALS AND METHODS: Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4-/y male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues. RESULTS: PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4-/y mice were significantly higher compared to those of WT mice. Specifically, PRDX4-/y mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4-/y compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4-/y compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4-/y compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4-/y than WT mice, which was consistent with severe ER stress under PRDX4 deficiency. CONCLUSION: Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4-/y than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation.

    DOI: 10.1016/j.freeradbiomed.2018.12.024

    PubMed

  • Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease. 査読

    Fujii J, Homma T, Kobayashi S, Seo HG

    World journal of biological chemistry   9 ( 1 )   1 - 15   2018年10月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.4331/wjbc.v9.i1.1

    PubMed

  • Mice deficient in aldo-keto reductase 1a (Akr1a) are resistant to thioacetamide-induced liver injury. 査読

    Homma T, Shirato T, Akihara R, Kobayashi S, Lee J, Yamada KI, Miyata S, Takahashi M, Fujii J

    Toxicology letters   294   37 - 43   2018年09月( ISSN:0378-4274

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.toxlet.2018.05.015

    PubMed

  • Unveiling systemic organ disorders associated with impaired lipid catabolism in fasted SOD1-deficient mice. 査読

    Lee J, Homma T, Kobayashi S, Ishii N, Fujii J

    Archives of biochemistry and biophysics   654   163 - 171   2018年09月( ISSN:0003-9861

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.abb.2018.07.020

    PubMed

  • Cystine/glutamate transporter, system x<sub>c</sub><sup>-</sup>, is involved in nitric oxide production in mouse peritoneal macrophages. 査読

    Kobayashi S, Hamashima S, Homma T, Sato M, Kusumi R, Bannai S, Fujii J, Sato H

    Nitric oxide : biology and chemistry   78   32 - 40   2018年08月( ISSN:1089-8603

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.niox.2018.05.005

    PubMed

  • Potential involvement of ubiquitin-proteasome system dysfunction associated with oxidative stress in the pathogenesis of sickle cell disease. 査読

    Warang P, Homma T, Pandya R, Sawant A, Shinde N, Pandey D, Fujii J, Madkaikar M, Mukherjee MB

    British journal of haematology   182 ( 4 )   559 - 566   2018年08月( ISSN:0007-1048

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/bjh.15437

    PubMed

  • Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure. 査読

    Homma T, Kurahashi T, Lee J, Nabeshima A, Yamada S, Fujii J

    Oxidative medicine and cellular longevity   2018   2812904   2018年( ISSN:1942-0900

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1155/2018/2812904

    PubMed

  • The viability of primary hepatocytes is maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production. 査読

    Lee J, Kang ES, Kobayashi S, Homma T, Sato H, Seo HG, Fujii J

    Experimental cell research   361 ( 1 )   178 - 191   2017年12月( ISSN:0014-4827

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.yexcr.2017.10.017

    PubMed

  • Decreased reproductive performance in xCT-knockout male mice. 査読

    Hamashima S, Homma T, Kobayashi S, Ishii N, Kurahashi T, Watanabe R, Kimura N, Sato H, Fujii J

    Free radical research   51 ( 9-10 )   851 - 860   2017年10月( ISSN:1071-5762

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2017.1388504

    PubMed

  • Mice in the early stage of liver steatosis caused by a high fat diet are resistant to thioacetamide-induced hepatotoxicity and oxidative stress. 査読

    Lee J, Homma T, Fujii J

    Toxicology letters   277   92 - 103   2017年08月( ISSN:0378-4274

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.toxlet.2017.06.005

    PubMed

  • Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis. 査読

    Shirato T, Homma T, Lee J, Kurahashi T, Fujii J

    Archives of toxicology   91 ( 3 )   1319 - 1333   2017年03月( ISSN:0340-5761

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00204-016-1785-9

    PubMed

  • Heightened aggressive behavior in mice deficient in aldo-keto reductase 1a (Akr1a). 査読

    Homma T, Akihara R, Okano S, Shichiri M, Yoshida Y, Yamada KI, Miyata S, Nakajima O, Fujii J

    Behavioural brain research   319   219 - 224   2017年02月( ISSN:0166-4328

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbr.2016.11.038

    PubMed

  • A high-fat diet temporarily renders Sod1-deficient mice resistant to an oxidative insult. 査読

    Ito J, Ishii N, Akihara R, Lee J, Kurahashi T, Homma T, Kawasaki R, Fujii J

    The Journal of nutritional biochemistry   40   44 - 52   2017年02月( ISSN:0955-2863

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jnutbio.2016.10.018

    PubMed

  • xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway. 査読

    Kang ES, Lee J, Homma T, Kurahashi T, Kobayashi S, Nabeshima A, Yamada S, Seo HG, Miyata S, Sato H, Fujii J

    Free radical research   51 ( 1 )   80 - 90   2017年01月( ISSN:1071-5762

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2017.1282157

    PubMed

  • Heat stress promotes the down-regulation of IRE1α in cells: An atypical modulation of the UPR pathway. 査読

    Homma T, Fujii J

    Experimental cell research   349 ( 1 )   128 - 138   2016年11月( ISSN:0014-4827

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.yexcr.2016.10.006

    PubMed

  • Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress. 査読

    Akihara R, Homma T, Lee J, Yamada K, Miyata S, Fujii J

    Biochemical and biophysical research communications   478 ( 2 )   765 - 71   2016年09月( ISSN:0006-291X

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2016.08.022

    PubMed

  • Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy. 査読

    Kurahashi T, Lee J, Nabeshima A, Homma T, Kang ES, Saito Y, Yamada S, Nakayama T, Yamada K, Miyata S, Fujii J

    Archives of biochemistry and biophysics   604   36 - 46   2016年08月( ISSN:0003-9861

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.abb.2016.06.004

    PubMed

  • Trichloroethylene exposure aggravates behavioral abnormalities in mice that are deficient in superoxide dismutase. 査読

    Otsuki N, Homma T, Fujiwara H, Kaneko K, Hozumi Y, Shichiri M, Takashima M, Ito J, Konno T, Kurahashi T, Yoshida Y, Goto K, Fujii S, Fujii J

    Regulatory toxicology and pharmacology : RTP   79   83 - 90   2016年08月( ISSN:0273-2300

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.yrtph.2016.05.007

    PubMed

  • The SOD1 transgene expressed in erythroid cells alleviates fatal phenotype in congenic NZB/NZW-F1 mice. 査読

    Otsuki N, Konno T, Kurahashi T, Suzuki S, Lee J, Okada F, Iuchi Y, Homma T, Fujii J

    Free radical research   50 ( 7 )   793 - 800   2016年07月( ISSN:1071-5762

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2016.1178388

    PubMed

  • An SOD1 deficiency enhances lipid droplet accumulation in the fasted mouse liver by aborting lipophagy. 査読

    Kurahashi T, Hamashima S, Shirato T, Lee J, Homma T, Kang ES, Fujii J

    Biochemical and biophysical research communications   467 ( 4 )   866 - 71   2015年11月( ISSN:0006-291X

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2015.10.052

    PubMed

  • SOD1 deficiency decreases proteasomal function, leading to the accumulation of ubiquitinated proteins in erythrocytes. 査読

    Homma T, Kurahashi T, Lee J, Kang ES, Fujii J

    Archives of biochemistry and biophysics   583   65 - 72   2015年10月( ISSN:0003-9861

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.abb.2015.07.023

    PubMed

  • Oxidative stress triggers lipid droplet accumulation in primary cultured hepatocytes by activating fatty acid synthesis. 査読

    Lee J, Homma T, Kurahashi T, Kang ES, Fujii J

    Biochemical and biophysical research communications   464 ( 1 )   229 - 35   2015年08月( ISSN:0006-291X

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2015.06.121

    PubMed

  • SOD1 deficiency induces the systemic hyperoxidation of peroxiredoxin in the mouse. 査読

    Homma T, Okano S, Lee J, Ito J, Otsuki N, Kurahashi T, Kang ES, Nakajima O, Fujii J

    Biochemical and biophysical research communications   463 ( 4 )   1040 - 6   2015年08月( ISSN:0006-291X

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2015.06.055

    PubMed

  • Ubiquitin-specific protease 14 modulates degradation of cellular prion protein. 査読

    Homma T, Ishibashi D, Nakagaki T, Fuse T, Mori T, Satoh K, Atarashi R, Nishida N

    Scientific reports   5   11028   2015年06月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep11028

    PubMed

  • Physiological and pathological views of peroxiredoxin 4. 査読

    Fujii J, Ikeda Y, Kurahashi T, Homma T

    Free radical biology & medicine   83   373 - 9   2015年06月( ISSN:0891-5849

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2015.01.025

    PubMed

  • Oxidative stress as a potential causal factor for autoimmune hemolytic anemia and systemic lupus erythematosus. 査読

    Fujii J, Kurahashi T, Konno T, Homma T, Iuchi Y

    World journal of nephrology   4 ( 2 )   213 - 22   2015年05月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5527/wjn.v4.i2.213

    PubMed

  • Cystathionine is a novel substrate of cystine/glutamate transporter: implications for immune function. 査読

    Kobayashi S, Sato M, Kasakoshi T, Tsutsui T, Sugimoto M, Osaki M, Okada F, Igarashi K, Hiratake J, Homma T, Conrad M, Fujii J, Soga T, Bannai S, Sato H

    The Journal of biological chemistry   290 ( 14 )   8778 - 88   2015年04月( ISSN:0021-9258

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1074/jbc.M114.625053

    PubMed

  • Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs. 査読

    Homma T, Fujii J

    Current drug metabolism   16 ( 7 )   560 - 71   2015年( ISSN:1389-2002

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2174/1389200216666151015114515

    PubMed

  • Strain-Dependent Effect of Macroautophagy on Abnormally Folded Prion Protein Degradation in Infected Neuronal Cells. 査読

    Ishibashi D, Homma T, Nakagaki T, Fuse T, Sano K, Takatsuki H, Atarashi R, Nishida N

    PloS one   10 ( 9 )   e0137958   2015年

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pone.0137958

    PubMed

  • Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals. 査読

    Kurahashi T, Kwon M, Homma T, Saito Y, Lee J, Takahashi M, Yamada K, Miyata S, Fujii J

    Biochemical and biophysical research communications   452 ( 1 )   136 - 41   2014年09月( ISSN:0006-291X

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2014.08.072

    PubMed

  • Persistent prion infection disturbs the function of Oct-1, resulting in the down-regulation of murine interferon regulatory factor-3. 査読

    Homma T, Ishibashi D, Nakagaki T, Fuse T, Sano K, Satoh K, Atarashi R, Nishida N

    Scientific reports   4   6006   2014年08月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep06006

    PubMed

  • Increased expression of p62/SQSTM1 in prion diseases and its association with pathogenic prion protein. 査読

    Homma T, Ishibashi D, Nakagaki T, Satoh K, Sano K, Atarashi R, Nishida N

    Scientific reports   4   4504   2014年03月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep04504

    PubMed

  • Involvement of purinergic signaling in cellular response to gamma radiation. 査読

    Tsukimoto M, Homma T, Ohshima Y, Kojima S

    Radiation research   173 ( 3 )   298 - 309   2010年03月( ISSN:0033-7587

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1667/RR1732.1

    PubMed

  • Low-dose gamma-ray irradiation induces translocation of Nrf2 into nuclear in mouse macrophage RAW264.7 cells. 査読

    Tsukimoto M, Tamaishi N, Homma T, Kojima S

    Journal of radiation research   51 ( 3 )   349 - 53   2010年( ISSN:0449-3060

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1269/jrr.10002

    PubMed

  • 0.5 Gy gamma radiation suppresses production of TNF-alpha through up-regulation of MKP-1 in mouse macrophage RAW264.7 cells. 査読

    Tsukimoto M, Homma T, Mutou Y, Kojima S

    Radiation research   171 ( 2 )   219 - 24   2009年02月( ISSN:0033-7587

     詳細を見る

    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1667/RR1351.1

    PubMed

▼全件表示

書籍等出版物

  • Ferroptosis in Health and Disease (Daolin Tang, ed).

    Junichi Fujii, Sho Kobayashi, Takujiro Homma( 担当: 共著)

    Springer Nature  2019年  ( ISBN:9783030267803

     詳細を見る

    著書種別:学術書  

  • Oxidative stress and dysfunction of the intracellular proteolytic machinery: a pathological hallmark of nonalcoholic fatty liver disease.

    Takujiro Homma, Junichi Fujii( 担当: 共著)

    Elsevier  2019年  ( ISBN:9780128144664

     詳細を見る

    担当ページ:59-70   著書種別:学術書  

  • Glutathione: Biosynthesis, Functions and Biological Implications (Pal Perjesi, ed).

    Junichi Fujii, Sho Kobayashi, Takujiro Homma( 担当: 共著 ,  範囲: Glutathione and related compounds produced by the glutathione-synthesizing pathway.)

    Nova Science Publishers  2019年  ( ISBN:9781536147414

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    著書種別:学術書  

講演・口頭発表等

  • フェロトーシスによる細胞傷害を保護する新規化合物のスクリーニング

    本間拓二郎, 川尻柊斗, 廣谷碧美, 西村百合子, 松永慎司, 有澤光弘, 冨田修平

    第77回日本酸化ストレス学会・第23回日本NO学会合同学術集会  2024年05月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • フェロトーシスによる臓器障害を保護する新規化合物のスクリーニング

    本間拓二郎, 川尻柊斗, 廣谷碧美, 松永慎司, 冨田修平

    第42回Cytoprotection研究会  2024年03月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • 紅参抽出物は細胞内エネルギー代謝を調節することで栄養欠乏時の細胞死から保護する

    本間 拓二郎、松永 慎司、徳留 健太郎、寒川 訓明、寒川 慶一、冨田 修平

    第97回日本薬理学会年会  2023年12月 

     詳細を見る

    会議種別:ポスター発表  

  • フェロトーシスから細胞を保護する新規化合物のスクリーニング

    本間 拓二郎, 川尻 柊斗, 廣谷 碧美, 松永 慎司, 冨田 修平

    第14回スクリーニング学研究会  2023年11月 

     詳細を見る

    会議種別:ポスター発表  

  • 若手による若手のための査読のススメ 招待

    本間拓二郎

    第二回若手放射線影響研究会  2023年01月 

     詳細を見る

    会議種別:口頭発表(招待・特別)  

  • 細胞周期の進行に伴う活性酸素生成はフェロトーシスの実行に重要である

    本間拓二郎, 小林翔, 藤井順逸

    第96回日本薬理学会年会  2022年12月 

  • 細胞周期の進行はシステイン飢餓によるフェロトーシス制御に重要である

    本間拓二郎, 小林翔, 藤井順逸

    第75回日本酸化ストレス学会  2022年05月 

     詳細を見る

    会議種別:ポスター発表  

  • SOD1欠損マウスの生存における抗酸化物質アスコルビン酸の重要性

    本間拓二郎, 尾崎 司, 藤井順逸

    第40回サイトプロテクション研究会  2022年03月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • 遺伝子改変マウスを用いた酸化ストレス研究 招待

    本間拓二郎

    フリーラジカルスクール2021  2022年03月 

     詳細を見る

    会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

  • ペルオキシレドキシン4欠損マウスにおける空間作業記憶障害

    本間拓二郎, 藤原浩樹, 尾崎司, 藤井聡, 藤井順逸

    第29回山形分子生物学セミナー  2021年11月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • ペルオキシレドキシン4欠損マウスにおける空間作業記憶障害

    本間拓二郎, 藤原浩樹, 尾崎司, 藤井聡, 藤井順逸

    第38回山形形態機能研究会  2021年11月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • 一酸化窒素による新規細胞死フェロトーシス抑制機構の解明

    本間 拓二郎, 小林 翔, 藤井 順逸

    第94回日本生化学会大会  2021年11月 

     詳細を見る

    会議種別:ポスター発表  

  • D-システインは細胞内グルタチオン依存的にフェロトーシスを抑制する

    本間 拓二郎, 尾崎 司, 小林 翔, 藤井 順逸

    第16回 D-アミノ酸学会学術講演会  2021年09月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • システイン代謝とレドックス制御 招待

    本間拓二郎

    レドックスR&D 戦略委員会第1回企画シンポジウム「翻訳・アミノ酸代謝調節による生体機能制御」  2021年08月 

     詳細を見る

    会議種別:シンポジウム・ワークショップ パネル(指名)  

  • 一酸化窒素は過酸化脂質ラジカルを消去することでフェロトーシスを抑制する

    本間拓二郎, 小林翔, 藤井順逸

    第74回日本酸化ストレス学会・第21回日本NO学会 合同学術集会  2021年05月 

     詳細を見る

    会議種別:ポスター発表  

  • アスコルビン酸によるスーパーオキシド消去はSOD1欠損マウスの生存に必須である

    本間拓二郎, 武田裕司, 赤塚慎也, 斉藤真一, 浅尾裕信, 豊國伸哉, 藤井順逸

    第74回日本酸化ストレス学会・第21回日本NO学会 合同学術集会  2021年05月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • ミトコンドリア由来スーパーオキシドは肝細胞におけるフェロトーシスの引き金となる

    本間拓二郎, 小林翔, 藤井順逸

    第39回サイトプロテクション研究会  2021年03月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • SOD1およびAkr1a二重欠損マウスの酸化ストレス起因性早期個体死の原因解析

    本間拓二郎, 武田 裕司, 斉藤 真一, 浅尾 裕信, 藤井順逸

    第28回山形分子生物学セミナー  2020年11月 

     詳細を見る

    会議種別:口頭発表(一般)  

  • グルタチオン合成阻害環境下における鉄硫黄クラスター形成反応のフェロトーシス感受性への関与

    本間 拓二郎, 小林 翔, 藤井 順逸

    第73回日本酸化ストレス学会学術集会  2020年10月 

     詳細を見る

    会議種別:ポスター発表  

  • マクロファージNOS2の生成するNOはスーパーオキシドの毒性消去に働く

    本間 拓二郎, 小林 翔, 藤井 順逸

    第73回日本酸化ストレス学会学術集会  2020年10月 

     詳細を見る

    会議種別:ポスター発表  

  • エダラボンをはじめとする各種フリーラジカル消去剤によるフェロトーシス抑制作用

    本間 拓二郎, 小林 翔, 佐藤 英世, 藤井 順逸

    第92回日本生化学会大会  2019年09月  (公社)日本生化学会

     詳細を見る

    会議種別:ポスター発表  

  • フリーラジカル消去剤エダラボンによるフェロトーシス抑制作用

    本間拓二郎, 小林 翔, 佐藤 英世, 藤井 順逸

    第72回日本酸化ストレス学会学術集会  2019年06月 

     詳細を見る

    会議種別:ポスター発表  

▼全件表示

担当教育概要

  • 2022年度 生体と薬物 (3年前期)
    2022年度 薬理学実習 (3年前期)
    2022年度 医学研究科医科学専攻(修士課程) 生体構造機能学
    2022年度 医学研究推進コース3 (3年後期)
    2023年度 生体と薬物 (3年前期)
    2023年度 薬理学実習 (3年前期)
    2023年度 医学研究科医科学専攻(修士課程) 生体構造機能学
    2023年度 医学研究推進コース3 (3年後期)