Details of the Researcher

PHOTO

Takashi Toyama
Section
Graduate School of Pharmaceutical Sciences
Job title
Associate Professor
Degree

Research History 8

  • 2025/04 - Present
    東北大学大学院　薬学研究科　准教授

  • 2021/10 - Present
    University of Tsukuba

  • 2022/04 - 2025/03
    東北大学大学院　薬学研究科　講師

  • 2015/04 - 2022/03
    Tohoku University

  • 2013/08 - 2015/03
    National Institutes of Natural Sciences

  • 2012/04 - 2015/03
    Tokyo University of Science　Graduate School of Pharmaceutical Sciences

  • 2011/08 - 2012/03
    University of Tsukuba　Graduate School of Comprehensive Human Sciences

  • 2010/04 - 2011/07
    University of Tsukuba　Graduate School of Comprehensive Human Sciences

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Education 3

  • University of Tsukuba

    2008/04 - 2011/07

  • University of Tsukuba

    2006/04 - 2008/03

  • Tokyo University of Pharmacy and Life Sciences　School of Life Science　School of Life Science

    2002/04 - 2006/03

Committee Memberships 1

  • ASIATOX　The Asian Society of Toxicology（ASIATOX）, Councilor

    2026 - Present

Research Areas 4

  • Life sciences / Hygiene and public health (laboratory) /

  • Environmental science/Agricultural science / Environmental effects of chemicals /

  • Nanotechnology/Materials / Chemical biology /

  • Life sciences / Pharmaceuticals - health and biochemistry /

Papers 74

  1. Electrophilic monocarbonyl curcumin derivatives reveal differential vulnerabilities in the selenium metabolic network Peer-reviewed

    Wang Yinuo, Takashi Toyama, Hiroyuki Yamakoshi, Hiroki Taguchi, Hayato Takashima, Ryo Watanabe, Yuichiro Mita, Junya Ito, Eikan Mishima, Yasutoshi Akiyama, Hiroyuki Shibata, Noriko Noguchi, Toshinari Takamura, Marcus Conrad, Yoshihisa Tomikoka, Yoshiharu Iwabuchi, Yoshiro Saito

    Free Radical Biology and Medicine　253　487-499　2026/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.freeradbiomed.2026.06.004 　

    ISSN： 0891-5849

  2. The selenoprotein P/ApoER2 axis facilitates selenium accumulation in selenoprotein P-accepting cells and confers prolonged resistance to ferroptosis Peer-reviewed

    Atsuya Ichikawa, Takashi Toyama, Hiroki Taguchi, Satoru Shiina, Hayato Takashima, Kazuaki Takahashi, Yasumitsu Ogra, Ayako Mizuno, Kotoko Arisawa, Yoshiro Saito

    Redox Biology　103664-103664　2025/05

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2025.103664 　

    ISSN： 2213-2317

  3. PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization Peer-reviewed

    Junya Ito, Toshitaka Nakamura, Takashi Toyama, Deng Chen, Carsten Berndt, Gereon Poschmann, André Santos Dias Mourão, Sebastian Doll, Mirai Suzuki, Weijia Zhang, Jiashuo Zheng, Dietrich Trümbach, Naoya Yamada, Koya Ono, Masana Yazaki, Yasutaka Kawai, Mieko Arisawa, Yusuke Ohsaki, Hitoshi Shirakawa, Adam Wahida, Bettina Proneth, Yoshiro Saito, Kiyotaka Nakagawa, Eikan Mishima, Marcus Conrad

    Molecular Cell　2024/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.molcel.2024.10.028 　

    ISSN： 1097-2765

  4. A convenient method to assess chemical modification of protein thiols by electrophilic metals Peer-reviewed

    Takashi Toyama, Yasuhiro Shinkai, Toshiyuki Kaji, Yoshito Kumagai

    JOURNAL OF TOXICOLOGICAL SCIENCES　38　(3)　477-484　2013/06

    DOI： 10.2131/jts.38.477 　

    ISSN： 0388-1350

    eISSN： 1880-3989

  5. Isothiocyanates Reduce Mercury Accumulation via an Nrf2-Dependent Mechanism during Exposure of Mice to Methylmercury Peer-reviewed

    Takashi Toyama, Yasuhiro Shinkai, Akira Yasutake, Koji Uchida, Masayuki Yamamoto, Yoshito Kumagai

    ENVIRONMENTAL HEALTH PERSPECTIVES　119　(8)　1117-1122　2011/08

    DOI： 10.1289/ehp.1003123 　

    ISSN： 0091-6765

  6. Promotion of Lead-induced Cytotoxicity in Differentiating Neural Cells and Protective Effects of Selenium Peer-reviewed

    Satoru Shiina, Hayato Takashima, Hiroki Taguchi, Takayuki Kaneko, Kota Noritsugu, Takashi Toyama, Yoshiro Saito

    Biological Trace Element Research　2026/08/10

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s12011-026-05285-1 　

    eISSN： 1559-0720

  7. Nrf2 activation by the monocarbonyl curcumin derivative GO-Y015 confers cellular protection against arsenite toxicity by reducing intracellular arsenic levels Peer-reviewed

    Md. Tanvir Islam, Hiroki Taguchi, Hiroyuki Yamakoshi, Wang Yinuo, Hiroyuki Shibata, Yoshiharu Iwabuchi, Takashi Toyama, Yoshiro Saito

    Scientific Reports　2026/04/18

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-026-49334-0 　

    eISSN： 2045-2322

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    Abstract Curcumin, a bioactive phenolic compound derived from turmeric, attenuates heavy metal toxicity, including inorganic arsenite (As(III)), via activation of the Nrf2–Keap1 signaling pathway; however, its low solubility and stability limit its bioactivity. To address these limitations, we synthesized curcumin derivatives and investigated the cytoprotective effects of a monocarbonyl analog, GO-Y015. GO-Y015 exhibited cytotoxicity comparable to curcumin at concentrations below 8 µM but significantly reduced As(III)-induced cytotoxicity. Pretreatment with GO-Y015 markedly improved cell viability under cytotoxic As(III) exposure, whereas curcumin showed minimal protective effects. Mechanistically, GO-Y015 induced robust Nrf2 activation in a concentration- and time-dependent manner, resulting in increased expression of downstream targets, including HO-1, GCLC, and MRP2. Pharmacological inhibition of Nrf2 (ML385), GSH synthesis (BSO), or MRP transporters (MK571) abolished the cytoprotective effects, indicating dependence on the Nrf2–GSH–MRP axis. Furthermore, ICP-MS analysis demonstrated that GO-Y015 significantly reduced intracellular arsenic accumulation after 2 h exposure. These findings indicate that GO-Y015 enhances arsenic detoxification and reduces cytotoxicity by promoting GSH-dependent conjugation and MRP-mediated efflux.

  8. A Novel ICP-MS Strategy Identifies Arsenite as an Inhibitor of Selenocysteine-tRNASec Charging Peer-reviewed

    Hayato Takashima, Reiko Makino, Hiroki Taguchi, Yoshika Takenaka, Yasutoshi Akiyama, Yoshihisa Tomikoka, Daigo Sumi, Takashi Toyama, Yoshiro Saito

    The Journal of Toxicological Sciences　2026/04

  9. Arsenite sensitizes to ferroptosis by disrupting selenium metabolism and reducing GPx4 expression Peer-reviewed

    Hayato Takashima, Reiko Makino, Hiroki Taguchi, Junya Ito, Eikan Mishima, Yoshika Takenaka, Yasutoshi Akiyama, Daigo Sumi, Marcus Conrad, Yoshihisa Tomikoka, Takashi Toyama, Yoshiro Saito

    Toxicology　154409-154409　2026/01

    Publisher: Elsevier BV

    DOI： 10.1016/j.tox.2026.154409 　

    ISSN： 0300-483X

  10. Cysteine redoxome landscape in the liver of male mice fed a high-fat high-sucrose diet Peer-reviewed

    Cynthia M. Galicia-Medina, Hein Ko Oo, Takumi Nishiuchi, Ryota Tanida, Tuerdiguli Abuduyimiti, Hisanori Goto, Yujiro Nakano, Yumie Takeshita, Kiyo-aki Ishii, Takashi Toyama, Yoshiro Saito, Hiroaki Takayama, Toshinari Takamura

    Journal of Biological Chemistry　110730-110730　2025/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.jbc.2025.110730 　

    ISSN： 0021-9258

  11. NRF2-dependent suppression of selenoprotein P expression promotes intracellular selenium metabolic remodeling and upregulation of antioxidant selenoproteins in hepatocellular carcinoma Peer-reviewed

    Kotoko Arisawa, Moeka Natori, Tetta Hiranuma, Misaki Shimizu, Yuto Yamazaki, Yasuhiro Miki, Takashi Toyama, Yoshiro Saito

    Redox Biology　103821-103821　2025/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2025.103821 　

    ISSN： 2213-2317

  12. Gender differences in plasma element concentrations and associations between selenoprotein P and iron metabolism in a community-based cohort study Peer-reviewed

    Yoshiro Saito, Misaki Shimizu, Mitsuharu Sato, An Masuda, Kotoko Arisawa, Keiko Taguchi, Takashi Toyama, Ikuko N. Motoike, Kengo Kinoshita, Seizo Koshiba, Masayuki Yamamoto, Toshinari Takamura

    Scientific Reports　15　(1)　2025/07/13

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-025-10581-2 　

    eISSN： 2045-2322

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    Abstract Essential trace elements, such as iron (Fe) and selenium (Se), play physiological roles in our body, whereas environmental toxic metals, such as arsenic (As), cadmium (Cd), and mercury (Hg), are known to be associated with various disease risks. However, the relationship between elements, biochemical parameters, and lifestyle habits based on multi-elemental analysis in healthy individuals has not been fully verified. Multi-elemental analysis is useful for evaluating the change in the concentration of these elements and metals. In the present study using totally 100 µL plasma samples from the Tohoku Medical Megabank (TMM) community-based cohort study (total of 506 specimens), we conducted a multi-elemental analysis to evaluate 14 elements in generally healthy subjects. We further determined Se-transporter selenoprotein P levels using the originally developed ELISA method, since increases and decreases in selenoprotein P levels are associated with various disease risks. Multiple correlation analyses between the obtained measured values and several factors suggest that elements such as Fe, Se, and Hg, as well as selenoprotein P levels, are associated with gender differences. We also found that factors such as Fe, Se, As, Hg, hematocrit value, hemoglobin (Hb) content, and HbA1c are correlated with selenoprotein P levels. Furthermore, correlations between Fe levels and Hb content and between As/Hg and fish consumption were found. These findings demonstrate the suitability of multi-elemental analyses with limited plasma sample amounts, clearly show gender-differentiated elements, and establish a significant relationship between selenoprotein P and Fe metabolism.

  13. Lactoferrin attenuates renal fibrosis and uremic sarcopenia in a mouse model of adenine-induced chronic kidney disease Peer-reviewed

    Yukina Iwamoto, Seiko Yamakoshi, Akiyo Sekimoto, Koji Hosomi, Takashi Toyama, Yoshiro Saito, Jun Kunisawa, Nobuyuki Takahashi, Eikan Mishima, Emiko Sato

    The Journal of Nutritional Biochemistry　110039-110039　2025/07

    Publisher: Elsevier BV

    DOI： 10.1016/j.jnutbio.2025.110039 　

    ISSN： 0955-2863

  14. Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria. International-journal Peer-reviewed

    Yusuke Hirata, Yuto Yamada, Soma Taguchi, Ryota Kojima, Haruka Masumoto, Shinnosuke Kimura, Takuya Niijima, Takashi Toyama, Ryoji Kise, Emiko Sato, Yasunori Uchida, Junya Ito, Kiyotaka Nakagawa, Tomohiko Taguchi, Asuka Inoue, Yoshiro Saito, Takuya Noguchi, Atsushi Matsuzawa

    Cell death & disease　15　(12)　884-884　2024/12/06

    DOI： 10.1038/s41419-024-07237-w 　

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    Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.

  15. Assessing the role of selenium in Minamata disease through reanalysis of historical samples Peer-reviewed

    Mineshi Sakamoto, Masumi Marumoto, Koichi Haraguchi, Takashi Toyama, Yoshiro Saito, Steven J. Balogh, Chiharu Tohyama, Masaaki Nakamura

    Environment International　109242-109242　2024/12

    Publisher: Elsevier BV

    DOI： 10.1016/j.envint.2024.109242 　

    ISSN： 0160-4120

  16. Remodeling of Selenium Metabolism through Adduct Formation of Selenoprotein P with Epigallocatechin Gallate Peer-reviewed

    Takashi Toyama, Katsuki Sato, Yoshiro Saito

    Metallomics Research　4　(3)　1-6　2024/11

    DOI： 10.11299/metallomicsresearch.MR202403 　

  17. Inhibition of Selenium Supply Function of Selenoprotein P through Adduct Formation by Sulforaphane. International-journal Peer-reviewed

    Xinying Ye, Takashi Toyama, Wang Yinuo, Runa Kudo, Siu Stephanie, Kotoko Arisawa, Yoshiro Saito

    The Journal of nutritional biochemistry　109781-109781　2024/10/15

    DOI： 10.1016/j.jnutbio.2024.109781 　

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    Selenium is a potent nucleophile essential for selenoenzymes, such as glutathione peroxidase (also known as GSH-Px; GPX; GPx) and selenoprotein P (also known as SelP; SEPP1; SELENOP; SeP). SeP is predominantly secreted from the liver and functions as a selenium carrier in plasma. We previously found that sulforaphane, an electrophilic phytochemical, reduces SeP production in cultured hepatocytes and mouse liver, however, the effect of electrophilic modification of SeP by SFN on selenium transport and metabolism remains unclear. In the present study, we demonstrate that sulforaphane covalently modifies selenocysteine/cysteine residues of SeP using an acidic biotin PAEC5 maleimide labeling assay, which allows for focused-labeling of selenocysteine residues. Although the SFN-SeP adduct can be taken up by HepG2 cells and degraded by the lysosome, it was less effective in inducing GPx expression. Our findings indicate that SFN disrupts the selenium supply pathway through the formation of the SeP-SFN adduct.

  18. Selenoprotein P expression in glioblastoma as a regulator of ferroptosis sensitivity: preservation of GPX4 via the cycling-selenium storage Peer-reviewed

    Xi Zheng, Takashi Toyama, Stephanie Siu, Takayuki Kaneko, Hikari Sugiura, Shota Yamashita, Yoshiteru Shimoda, Masayuki Kanamori, Kotoko Arisawa, Hidenori Endo, Yoshiro Saito

    Scientific Reports　14　(1)　2024/01/05

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-024-51259-5 　

    eISSN： 2045-2322

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    Abstract Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded by the SELENOP gene) is a unique selenium-containing protein that exhibits high expression levels in astroglia. SeP is thought to be associated with ferroptosis sensitivity through the induction of glutathione peroxidase 4 (GPX4) via selenium supplementation. In this study, to elucidate the role of SeP in GBM, we analyzed its expression in GBM patients and found that SeP expression levels were significantly higher when compared to healthy subjects. Knock down of SeP in cultured GBM cells resulted in a decrease in GPX1 and GPX4 protein levels. Under the same conditions, cell death caused by RSL3, a ferroptosis inducer, was enhanced, however this enhancement was canceled by supplementation of selenite. These results indicate that SeP expression contributes to preserving GPX and selenium levels in an autocrine/paracrine manner, i.e., SeP regulates a dynamic cycling-selenium storage system in GBM. We also confirmed the role of SeP expression in ferroptosis sensitivity using patient-derived primary GBM cells. These findings indicate that expression of SeP in GBM can be a significant therapeutic target to overcome anticancer drug resistance.

  19. Impact of selenium content in fetal bovine serum on ferroptosis susceptibility and selenoprotein expression in cultured cells.

    Hayato Takashima, Takashi Toyama, Eikan Mishima, Kei Ishida, Yinuo Wang, Atsuya Ichikawa, Junya Ito, Syunsuke Yogiashi, Stephanie Siu, Mayumi Sugawara, Satoru Shiina, Kotoko Arisawa, Marcus Conrad, Yoshiro Saito

    The Journal of toxicological sciences　49　(12)　555-563　2024

    DOI： 10.2131/jts.49.555 　

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    Ferroptosis, a mode of cell death involving iron-dependent lipid peroxidation, has attracted widespread attention in the development of anticancer drugs and toxicological studies as a potential mechanism of chemical-induced cytotoxicity. This process is regulated by several antioxidant enzymes, of which the selenium-containing glutathione peroxidase 4 (GPx4) is the prime regulator. However, accurately and reproducibly evaluating ferroptosis in cultured cells is challenging since numerous experimental factors in in vitro setting can influence the results. In the present study, we found that the expression levels of selenoproteins, such as GPx4 and GPx1, fluctuate across several cell lines depending on the selenium content of different origin of fetal bovine serum (FBS). Cells cultured in FBS containing higher selenium concentrations exhibited elevated GPx4 expression, and were resistant to ferroptosis induced by erastin and RSL3. These findings suggest that the variability of selenium content in different FBS batches can significantly influence the susceptibility of cells to ferroptosis, highlighting the importance of standardizing these factors to enhance the reproducibility of ferroptosis-related experiments.

  20. Supersulfides in Environmental Toxicology and Hygiene

    Kazuhiro Nishiyama, Takashi Toyama

    YAKUGAKU ZASSHI　144　(1)　39-40　2024/01/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/yakushi.23-00162-f 　

    ISSN： 0031-6903

    eISSN： 1347-5231

  21. Ccdc152 is not necessary for male fertility, but contributes to maintaining sperm morphology

    Ryua HARIMA, Takahiro SASAKI, Takayuki KANEKO, Fuka ASO, Hayato TAKASHIMA, Takashi TOYAMA, Kenshiro HARA, Kentaro TANEMURA, Yoshiro SAITO

    Journal of Reproduction and Development　2024

    Publisher: Japanese Society of Animal Reproduction

    DOI： 10.1262/jrd.2024-058 　

    ISSN： 0916-8818

    eISSN： 1348-4400

  22. The Role of Supersulfide in Methylmercury Detoxification Invited Peer-reviewed

    Takashi Toyama, Runa Kudo, Yoshiro Saito

    YAKUGAKU ZASSHI　144　(1)　41-45　2024/01/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/yakushi.23-00162-1 　

    ISSN： 0031-6903

    eISSN： 1347-5231

  23. Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2 Peer-reviewed

    Xinying Ye, Takashi Toyama, Keiko Taguchi, Kotoko Arisawa, Takayuki Kaneko, Ryouhei Tsutsumi, Masayuki Yamamoto, Yoshiro Saito

    Communications Biology　6　(1)　2023/10/19

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-023-05449-y 　

    eISSN： 2399-3642

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    Abstract Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.

  24. Potential Association between Methylmercury Neurotoxicity and Inflammation Peer-reviewed

    Yo Shinoda, Masahiro Akiyama, Takashi Toyama

    Biological and Pharmaceutical Bulletin　46　(9)　1162-1168　2023/09/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpb.b23-00075 　

    ISSN： 0918-6158

    eISSN： 1347-5215

  25. An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase Peer-reviewed

    Ayako Mizuno, Takashi Toyama, Atsuya Ichikawa, Naoko Sakai, Yuya Yoshioka, Yukina Nishito, Renya Toga, Hiroshi Amesaka, Takayuki Kaneko, Kotoko Arisawa, Ryouhei Tsutsumi, Yuichiro Mita, Shun-ichi Tanaka, Noriko Noguchi, Yoshiro Saito

    Journal of Biological Chemistry　299　(8)　105009-105009　2023/07

    Publisher: Elsevier BV

    DOI： 10.1016/j.jbc.2023.105009 　

    ISSN： 0021-9258

  26. Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth. International-journal Peer-reviewed

    Takashi Toyama, Sidi Xu, Yoshitomi Kanemitsu, Takashi Hasegawa, Takuya Noguchi, Jin-Yong Lee, Atsushi Matsuzawa, Akira Naganuma, Gi-Wook Hwang

    Archives of toxicology　2023/05/17

    DOI： 10.1007/s00204-023-03520-5 　

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    We previously found that methylmercury induces expression of oncostatin M (OSM), which is released extracellularly and binds to tumor necrosis factor receptor 3 (TNFR3), possibly enhancing its own toxicity. However, the mechanism by which methylmercury causes OSM to bind to TNFR3 rather than to its known receptors, OSM receptor and LIFR, is unknown. In this study, we aimed to elucidate the effect of methylmercury modification of cysteine residues in OSM on binding to TNFR3. Immunostaining of TNFR3-V5-expressing cells suggested that methylmercury promoted binding of OSM to TNFR3 on the cell membrane. In an in vitro binding assay, OSM directly bound to the extracellular domain of TNFR3, and this binding was promoted by methylmercury. Additionally, the formation of a disulfide bond in the OSM molecule was essential for the binding of both proteins, and LC/MS analysis revealed that methylmercury directly modified the 105th cysteine residue (Cys105) in OSM. Next, mutant OSM, in which Cys105 was replaced by serine or methionine, increased the binding to TNFR3, and a similar effect was observed in immunoprecipitation using cultured cells. Furthermore, cell proliferation was inhibited by treatment with Cys105 mutant OSMs compared with wildtype OSM, and this effect was cancelled by TNFR3 knockdown. In conclusion, we revealed a novel mechanism of methylmercury toxicity, in which methylmercury directly modifies Cys105 in OSM, thereby inhibiting cell proliferation via promoting binding to TNFR3. This indicates a chemical disruption in the interaction between the ligand and the receptor is a part of methylmercury toxicity.

  27. Metal-binding properties of selenoprotein P—its relation to structure and function Peer-reviewed

    Takashi Toyama, Takayuki Kaneko, Kotoko Arisawa, Yoshiro Saito

    Metallomics Research　2　(3)　18-27　2022/12

    DOI： 10.11299/metallomicsresearch.MR202209 　

  28. Role of selenoprotein P expression in the function of pancreatic β cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation International-journal Peer-reviewed

    Nanako Kitabayashi, Shohei Nakao, Yuichiro Mita, Kotoko Arisawa, Takayuki Hoshi, Takashi Toyama, Kiyo-aki Ishii, Toshinari Takamura, Noriko Noguchi, Yoshiro Saito

    Free Radical Biology and Medicine　183　89-103　2022/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.freeradbiomed.2022.03.009 　

    ISSN： 0891-5849

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    Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic β cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic β cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic β cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK.

  29. A non-nucleotide agonist that binds covalently to cysteine residues of STING Peer-reviewed

    Kentaro Matsumoto, Shenwei Ni, Hiroyuki Arai, Takashi Toyama, Yoshiro Saito, Takehiro Suzuki, Naoshi Dohmae, Kojiro Mukai, Tomohiko Taguchi

    Cell Structure and Function　48　(1)　59-70　2022

    Publisher: Japan Society for Cell Biology

    DOI： 10.1247/csf.22085 　

    ISSN： 0386-7196

    eISSN： 1347-3700

  30. Effects of the Interplay between Selenocystine and Methylmercury on Their Cytotoxicity and Glucose-Driven Insulin Secretion from Mouse Insulinoma Cells Peer-reviewed

    Daichi Chida, Takashi Toyama, Takanori Chiba, Takayuki Kaneko, Kotoko Arisawa, Yoshiro Saito

    BPB Reports　5　(4)　74-79　2022

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpbreports.5.4_74 　

    eISSN： 2434-432X

  31. Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia International-journal Peer-reviewed

    Takashi Toyama, Takayuki Hoshi, Takuya Noguchi, Yoshiro Saito, Atsushi Matsuzawa, Akira Naganuma, Gi-Wook Hwang

    Scientific Reports　11　(1)　9832-9832　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-021-89210-7 　

    eISSN： 2045-2322

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    <title>Abstract</title>We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.

  32. Identification of a novel endogenous long non-coding RNA that inhibits selenoprotein P translation International-journal Peer-reviewed

    Yuichiro Mita, Risa Uchida, Sayuri Yasuhara, Kohei Kishi, Takayuki Hoshi, Yoshitaka Matsuo, Tadashi Yokooji, Yoshino Shirakawa, Takashi Toyama, Yasuomi Urano, Toshifumi Inada, Noriko Noguchi, Yoshiro Saito

    Nucleic Acids Research　49　(12)　6893-6907　2021/06/18

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkab498 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    <title>Abstract</title> Selenoprotein P (SELENOP) is a major plasma selenoprotein that contains 10 Sec residues, which is encoded by the UGA stop codon. The mRNA for SELENOP has the unique property of containing two Sec insertion sequence (SECIS) elements, which is located in the 3′ untranslated region (3′UTR). Here, we coincidentally identified a novel gene, CCDC152, by sequence analysis. This gene was located in the antisense region of the SELENOP gene, including the 3′UTR region in the genome. We demonstrated that this novel gene functioned as a long non-coding RNA (lncRNA) that decreased SELENOP protein levels via translational rather than transcriptional, regulation. We found that the CCDC152 RNA interacted specifically and directly with the SELENOP mRNA and inhibited its binding to the SECIS-binding protein 2, resulting in the decrease of ribosome binding. We termed this novel gene product lncRNA inhibitor of SELENOP translation (L-IST). Finally, we found that epigallocatechin gallate upregulated L-IST in vitro and in vivo, to suppress SELENOP protein levels. Here, we provide a new regulatory mechanism of SELENOP translation by an endogenous long antisense ncRNA.

  33. Comprehensive analyses of the cysteine thiol oxidation of PKM2 reveal the effects of multiple oxidation on cellular oxidative stress response International-journal Peer-reviewed

    Hayato Irokawa, Satoshi Numasaki, Shin Kato, Kenta Iwai, Atsushi Inose-Maruyama, Takumi Ohdate, Gi-Wook Hwang, Takashi Toyama, Toshihiko Watanabe, Shusuke Kuge

    Biochemical Journal　478　(7)　1453-1470　2021/04/16

    Publisher: Portland Press Ltd.

    DOI： 10.1042/bcj20200897 　

    ISSN： 0264-6021

    eISSN： 1470-8728

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    Redox regulation of proteins via cysteine residue oxidation is involved in the control of various cellular signal pathways. Pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, is critical for the metabolic shift from glycolysis to the pentose phosphate pathway under oxidative stress in cancer cell growth. The PKM2 tetramer is required for optimal pyruvate kinase (PK) activity, whereas the inhibition of inter-subunit interaction of PKM2 induced by Cys358 oxidation has reduced PK activity. In the present study, we identified three oxidation-sensitive cysteine residues (Cys358, Cys423 and Cys424) responsible for four oxidation forms via the thiol oxidant diamide and/or hydrogen peroxide (H2O2). Possibly due to obstruction of the dimer-dimer interface, H2O2-induced sulfenylation (-SOH) and diamide-induced modification at Cys424 inhibited tetramer formation and PK activity. Cys423 is responsible for intermolecular disulfide bonds with heterologous proteins via diamide. Additionally, intramolecular polysulphide linkage (–Sn–, n ≧ 3) between Cys358 and an unidentified PKM2 Cys could be induced by diamide. We observed that cells expressing the oxidation-resistant PKM2 (PKM2C358,424A) produced more intracellular reactive oxygen species (ROS) and exhibited greater sensitivity to ROS-generating reagents and ROS-inducible anti-cancer drugs compared with cells expressing wild-type PKM2. These results highlight the possibility that PKM2 inhibition via Cys358 and Cys424 oxidation contributes to eliminating excess ROS and oxidative stress.

  34. Increased expression of TCF3, transcription factor 3, is a defense response against methylmercury toxicity in mouse neuronal C17.2 cells

    Takashi Toyama, Yanjiao Wang, Min-Seok Kim, Tsutomu Takahashi, Akira Naganuma, Gi-Wook Hwang

    Toxicological Research　2021/01/22

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s43188-021-00087-0 　

    ISSN： 1976-8257

    eISSN： 2234-2753

  35. Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms Peer-reviewed

    Takuya Noguchi, Yuto Sekiguchi, Yuki Kudoh, Rio Naganuma, Tomohiro Kagi, Akiko Nishidate, Kazuhiro Maeda, Chizuru Ishii, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa

    Cell Death & Disease　12　(1)　2021/01

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41419-020-03335-7 　

    eISSN： 2041-4889

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    <title>Abstract</title>Anticancer drug gefitinib causes inflammation-based side effects, such as interstitial pneumonitis. However, its mechanisms remain unknown. Here, we provide evidence that gefitinib elicits pro-inflammatory responses by promoting mature-interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release. Mitochondrial reactive oxygen species (mtROS) driven by gefitinib stimulated the formation of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, leading to mature-IL-1β release. Notably, gefitinib also stimulated HMGB1 release, which is, however, not mediated by the NLRP3 inflammasome. On the other hand, gefitinib-driven mtROS promoted the accumulation of γH2AX, a hallmark of DNA damage, leading to the activation of poly (ADP-ribose) polymerase-1 (PARP-1) and subsequent active release of HMGB1. Together our results reveal the potential ability of gefitinib to initiate sterile inflammation via two distinct mechanisms, and identified IL-1β and HMGB1 as key determinants of gefitinib-induced inflammation that may provide insights into gefitinib-induced interstitial pneumonitis.

  36. Elaidic Acid Potentiates Extracellular ATP-Induced Apoptosis via the P2X7-ROS-ASK1-p38 Axis in Microglial Cell Lines Peer-reviewed

    Yusuke Hirata, Yuki Nada, Yuto Yamada, Takashi Toyama, Kohji Fukunaga, Gi-Wook Hwang, Takuya Noguchi, Atsushi Matsuzawa

    Biological and Pharmaceutical Bulletin　43　(10)　1562-1569　2020/10/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpb.b20-00409 　

    ISSN： 0918-6158

    eISSN： 1347-5215

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    trans-Fatty acids (TFAs) are unsaturated fatty acids with at least one carbon-carbon double bond in trans configuration. TFA consumption has been epidemiologically associated with neurodegenerative diseases (NDs) including Alzheimer's disease. However, the underlying mechanisms of TFA-related NDs remain unknown. Here, we show a novel microglial signaling pathway that induces inflammation and cell death, which is dramatically enhanced by elaidic acid (EA), the most abundant TFA derived from food. We found that extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from injured cells, induced activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway, which is one of the major stress-responsive mitogen-activated protein (MAP) kinase signaling pathways, and subsequent caspase-3 cleavage and DNA ladder formation (hallmarks of apoptosis) in mouse microglial cell lines including BV2 and MG6 cells. Furthermore, we found that in these microglial cell lines, EA, but not its cis isomer oleic acid, facilitated extracellular ATP-induced ASK1/p38 activation and apoptosis, which was suppressed by pharmacological inhibition of either p38, reactive oxygen species (ROS) generation, P2X purinoceptor 7 (P2X7), or Ca2+/calmodulin-dependent kinase II (CaMKII). These results demonstrate that in microglial cells, extracellular ATP induces activation of the ASK1-p38 MAP kinase pathway and ultimately apoptosis downstream of P2X7 receptor and ROS generation, and that EA promotes ATP-induced apoptosis through CaMKII-dependent hyperactivation of the ASK1-p38 pathway, in the same manner as in macrophages. Our study may provide an insight into the pathogenesis of NDs associated with TFAs.

  37. Hydrogen Peroxide Causes Cell Death via Increased Transcription of HOXB13 in Human Lung Epithelial A549 Cells International-journal Peer-reviewed

    Naoki Endo, Takashi Toyama, Akira Naganuma, Yoshiro Saito, Gi-Wook Hwang

    Toxics　8　(4)　78-78　2020/09/28

    Publisher: MDPI AG

    DOI： 10.3390/toxics8040078 　

    eISSN： 2305-6304

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    Although homeobox protein B13 (HOXB13) is an oncogenic transcription factor, its role in stress response has rarely been examined. We previously reported that knockdown of HOXB13 reduces the cytotoxicity caused by various oxidative stress inducers. Here, we studied the role of HOXB13 in cytotoxicity caused by hydrogen peroxide in human lung epithelial A549 cells. The knockdown of HOXB13 reduced hydrogen peroxide-induced cytotoxicity; however, this phenomenon was largely absent in the presence of antioxidants (Trolox or N-acetyl cysteine (NAC)). This suggests that HOXB13 may be involved in the cytotoxicity caused by hydrogen peroxide via the production of reactive oxygen species (ROS). Hydrogen peroxide also increased both the mRNA and protein levels of HOXB13. However, these increases were rarely observed in the presence of a transcriptional inhibitor, which suggests that hydrogen peroxide increases protein levels via increased transcription of HOXB13. Furthermore, cell death occurred in A549 cells that highly expressed HOXB13. However, this cell death was mostly inhibited by treatment with antioxidants. Taken together, our findings indicate that HOXB13 may be a novel factor involved in the induction of oxidative stress, which causes cell death via intracellular ROS production.

  38. Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury Peer-reviewed

    Masayuki Sato, Takashi Toyama, Min-Seok Kim, Jin-Yong Lee, Takayuki Hoshi, Nobuhiko Miura, Akira Naganuma, Gi-Wook Hwang

    Life Sciences　118031-118031　2020/06

    Publisher: Elsevier BV

    DOI： 10.1016/j.lfs.2020.118031 　

    ISSN： 0024-3205

  39. The Antibiotic Cefotaxime Works as Both an Activator of Nrf2 and an Inducer of HSP70 in Mammalian Cells Peer-reviewed

    Mayuka Yamada, Midori Suzuki, Takuya Noguchi, Takumi Yokosawa, Yuto Sekiguchi, Natsumi Mutoh, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa

    BPB Reports　3　(1)　16-21　2020/01

  40. The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells. International-journal Peer-reviewed

    Takashi Toyama, Sidi Xu, Ryo Nakano, Takashi Hasegawa, Naoki Endo, Tsutomu Takahashi, Jin-Yong Lee, Akira Naganuma, Gi-Wook Hwang

    Cells　9　(1)　45　2020

    DOI： 10.3390/cells9010045 　

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    Homeobox protein B13 (HOXB13), a transcription factor, is related to methylmercury toxicity; however, the downstream factors involved in enhancing methylmercury toxicity remain unknown. We performed microarray analysis to search for downstream factors whose expression is induced by methylmercury via HOXB13 in human embryonic kidney cells (HEK293), which are useful model cells for analyzing molecular mechanisms. Methylmercury induced the expression of oncostatin M (OSM), a cytokine of the interleukin-6 family, and this was markedly suppressed by HOXB13 knockdown. OSM knockdown also conferred resistance to methylmercury in HEK293 cells, and no added methylmercury resistance was observed when both HOXB13 and OSM were knocked down. Binding of HOXB13 to the OSM gene promoter was increased by methylmercury, indicating the involvement of HOXB13 in the enhancement of its toxicity. Because addition of recombinant OSM to the medium enhanced methylmercury toxicity in OSM-knockdown cells, extracellularly released OSM was believed to enhance methylmercury toxicity via membrane receptors. We discovered tumor necrosis factor receptor (TNF) receptor 3 (TNFR3) to be a potential candidate involved in the enhancement of methylmercury toxicity by OSM. This toxicity mechanism was also confirmed in mouse neuronal stem cells. We report, for the first time, that HOXB13 is involved in enhancement of methylmercury toxicity via OSM-expression induction and that the synthesized OSM causes cell death by binding to TNFR3 extracellularly.

  41. Methylmercury induces the expression of chemokine CCL4 via SRF activation in C17.2 mouse neural stem cells Peer-reviewed

    Min Seok Kim, Tsutomu Takahashi, Jin Yong Lee, Takashi Toyama, Takayuki Hoshi, Shusuke Kuge, Yasuyuki Fujiwara, Akira Naganuma, Gi Wook Hwang

    Scientific Reports　9　(1)　4631　2019/12/01

    DOI： 10.1038/s41598-019-41127-y 　

    eISSN： 2045-2322

  42. Induction of chemokine CCL3 by NF-κB reduces methylmercury toxicity in C17.2 mouse neural stem cells Peer-reviewed

    Tsutomu Takahashi, Min Seok Kim, Miyuki Iwai-Shimada, Takayuki Hoshi, Masatake Fujimura, Takashi Toyama, Yasuyuki Fujiwara, Akira Naganuma, Gi Wook Hwang

    Environmental Toxicology and Pharmacology　71　103216　2019/10

    DOI： 10.1016/j.etap.2019.103216 　

    ISSN： 1382-6689

    eISSN： 1872-7077

  43. Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload. International-journal Peer-reviewed

    Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Takashi Toyama, Kazuhiro Nishiyama, Yasuhiro Shinkai, Takuro Numaga-Tomita, Daiju Yamazaki, Yasunari Kanda, Takaaki Akaike, Yoshito Kumagai, Motohiro Nishida

    Science signaling　12　(587)　2019/06/25

    DOI： 10.1126/scisignal.aaw1920 　

    ISSN： 1945-0877

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    Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Exposure to MeHg at 10 ppm did not induce weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with cilnidipine, an inhibitor of the interaction between Drp1 and filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of cysteine residues in proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys624, a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic polysulfide (Cys624-S(n)H). MeHg exposure induced the depolysulfidation of Cys624-S(n)H in Drp1, which led to filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.

  44. Methylmercury causes neuronal cell death via M1-microglial activation in organotypic slices prepared from mouse cerebral cortex Peer-reviewed

    Takayuki Hoshi, Takashi Toyama, Akira Naganuma, Gi-Wook Hwang

    Fundamental Toxicological Sciences　6　(5)　167-170　2019

    Publisher: Japanese Society of Toxicology

    DOI： 10.2131/fts.6.167 　

    eISSN： 2189-115X

  45. Evaluation of M1-microglial activation by neurotoxic metals using optimized organotypic cerebral slice cultures Peer-reviewed

    Takayuki Hoshi, Takashi Toyama, Youichi Shinozaki, Schuichi Koizumi, Jin Yong Lee, Akira Naganuma, Gi-Wook Hwang

    Journal of Toxicological Sciences　44　(7)　471-479　2019

    DOI： 10.2131/jts.44.471 　

    ISSN： 1880-3989

    eISSN： 0388-1350

  46. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence Peer-reviewed

    Nishimura, Akiyuki, Shimauchi, Tsukasa, Tanaka, Tomohiro, Shimoda, Kakeru, Toyama, Takashi, Kitajima, Naoyuki, Ishikawa, Tatsuya, Shindo, Naoya, Numaga-Tomita, Takuro, Yasuda, Satoshi, Sato, Yoji, Kuwahara, Koichiro, Kumagai, Yoshito, Akaike, Takaaki, Ide, Tomomi, Ojida, Akio, Mori, Yasuo, Nishida, Motohiro

    Science signaling　11　(556)　2018/11

    DOI： 10.1126/scisignal.aat5185 　

    ISSN： 1937-9145

    eISSN： 1937-9145

  47. Activation of ornithine decarboxylase protects against methylmercury toxicity by increasing putrescine Peer-reviewed

    Masayuki Sato, Takashi Toyama, Jin Yong Lee, Nobuhiko Miura, Akira Naganuma, Gi Wook Hwang

    Toxicology and Applied Pharmacology　356　120-126　2018/10/01

    DOI： 10.1016/j.taap.2018.08.002 　

    ISSN： 0041-008X

    eISSN： 1096-0333

  48. Chemokine CCL4 induced in mouse brain has a protective role against methylmercury toxicity Peer-reviewed

    Tsutomu Takahashi, Min Seok Kim, Miyuki Iwai-Shimada, Masatake Fujimura, Takashi Toyama, Akira Naganuma, Gi Wook Hwang

    Toxics　6　(3)　36　2018/07/07

    DOI： 10.3390/toxics6030036 　

    eISSN： 2305-6304

  49. Methylmercury Induces Cytotoxicity through Inhibition of PTEN Activity by a Decrease in Its Solubility Peer-reviewed

    Takumi Kobayashi, Takashi Toyama, Jin-Yong Lee, Nobuhiko Miura, Shusuke Kuge, Akira Naganuma, Gi-Wook Hwang

    BPB report　1　1-5　2018

  50. Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells Peer-reviewed

    Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Elko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fuji, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike

    CHEMICAL RESEARCH IN TOXICOLOGY　30　(9)　1673-1684　2017/09

    DOI： 10.1021/acs.chemrestox.7b00120 　

    ISSN： 0893-228X

    eISSN： 1520-5010

  51. TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice Peer-reviewed

    Sayaka Oda, Takuro Numaga-Tomita, Naoyuki Kitajima, Takashi Toyama, Eri Harada, Tsukasa Shimauchi, Akiyuki Nishimura, Tatsuya Ishikawa, Yoshito Kumagai, Lutz Birnbaumer, Motohiro Nishida

    SCIENTIFIC REPORTS　7　(1)　7511　2017/08

    DOI： 10.1038/s41598-017-07903-4 　

    ISSN： 2045-2322

  52. Small interfering RNA-mediated knockdown of the transcription factor TCF3 enhances sensitivity to methylmercury in mouse neural stem cells. Peer-reviewed

    Takahashi T, Wang Y, Toyama T, Kim M.S, Kuge S, Hwang G.W, Naganuma A

    Fundam. Toxicol. Sci.　4　(2)　41-43　2017/03

    Publisher: The Japanese Society of Toxicology

    DOI： 10.2131/fts.4.41 　

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    <p>We have reported that four transcription factors (PAX4, PAX6, TCF3, and HMGA1) were markedly activated in the cerebellum of mice treated with methylmercury. In this study, to clarify the relationship between these transcription factors and methylmercury toxicity, siRNA targeting each of the four transcription factors were introduced individually into C17.2 mouse neural stem cells, and the sensitivity of the cells to methylmercury was investigated. Among the four transcription factors, knockdown of the gene for TCF3 increased the methylmercury sensitivity of C17.2 cells. Therefore, we suggest that TCF3 may have a protective effect against methylmercury toxicity.</p>

  53. Methylmercury induces the expression of TNF-alpha selectively in the brain of mice Peer-reviewed

    Miyuki Iwai-Shimada, Tsutomu Takahashi, Min-Seok Kim, Masatake Fujimura, Hitoyasu Ito, Takashi Toyama, Akira Naganuma, Gi-Wook Hwang

    SCIENTIFIC REPORTS　6　38294　2016/12

    DOI： 10.1038/srep38294 　

    ISSN： 2045-2322

  54. Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells Peer-reviewed

    Takamitsu Unoki, Yumi Abiko, Takashi Toyama, Takashi Uehara, Koji Tsuboi, Motohiro Nishida, Toshiyuki Kaji, Yoshito Kumagai

    SCIENTIFIC REPORTS　6　28944　2016/06

    DOI： 10.1038/srep28944 　

    ISSN： 2045-2322

  55. Methylmercury induces release of a cytotoxic factor from HEK293 cells into medium Peer-reviewed

    T Toyama, S Murakami, S Kuge, GW Hwang, A Naganuma

    Fundamental Toxicological Sciences　2　(5)　223-226　2015/12

    DOI： 10.2131/fts.2.223 　

  56. Metabolomic analysis of low molecular weight substances released into medium from HEK293 cells treated with methylmercury Peer-reviewed

    Toyama Takashi, Hwang Gi-Wook, Naganuma Akira

    Fundamental Toxicological Sciences　2　(5)　227-228　2015/12

    Publisher: The Japanese Society of Toxicology

    DOI： 10.2131/fts.2.227 　

    ISSN： 2189-115X

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    This study attempted to identify substances that are driven out of HEK293 cells by methylmercury. Metabolomic analysis revealed that the levels of 3-phenylpropionic acid, citrulline, lactic acid, ornithine, proline and beta-alanine in the cell culture medium were increased by the treatment of cells with methylmercury. Address to the mechanism underlying the release of these substances will provide useful information to elucidate the toxicity mechanism of methylmercury.

  57. Citrulline enhances methylmercury toxicity in HEK293 and C17.2 cells Peer-reviewed

    Toyama Takashi, Hwang Gi-Wook, Naganuma Akira

    Fundamental Toxicological Sciences　2　(6)　229-231　2015/12

    Publisher: The Japanese Society of Toxicology

    DOI： 10.2131/fts.2.229 　

    ISSN： 2189-115X

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    We identified 3-phenylpropionic acid, citrulline, lactic acid, ornithine, proline, and beta-alanine as low-molecular weight substances that are released from cells treated with methylmercury. In this study, we studied their effect on cellular sensitivity to methylmercury. Treating HEK293 and C17.2 cells with each of the six substances minimally affected the proliferation of both cell lines. Among these six substances, however, only citrulline slightly but significantly increased the sensitivity of C17.2 and HEK293 cells to low levels of methylmercury. Citrulline is thought to be a methylmercury toxicity-enhancing factor whose extracellular release is enhanced by methylmercury.

  58. S-Mercuration of ubiquitin carboxyl-terminal hydrolase L1 through Cys152 by methylmercury causes inhibition of its catalytic activity and reduction of monoubiquitin levels in SH-SY5Y cells Peer-reviewed

    Takashi Toyama, Yumi Abiko, Yuko Katayama, Toshiyuki Kaji, Yoshito Kumagai

    JOURNAL OF TOXICOLOGICAL SCIENCES　40　(6)　887-893　2015/12

    DOI： 10.2131/jts.40.887 　

    ISSN： 0388-1350

    eISSN： 1880-3989

  59. Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury Peer-reviewed

    Kento Makino, Kosaku Okuda, Eisuke Sugino, Tadashi Nishiya, Takashi Toyama, Takao Iwawaki, Masatake Fujimura, Yoshito Kumagai, Takashi Uehara

    NEUROTOXICITY RESEARCH　27　(2)　99-105　2015/02

    DOI： 10.1007/s12640-014-9494-8 　

    ISSN： 1029-8428

    eISSN： 1476-3524

  60. Establishment of a Novel Therapeutic Strategy for Heart Failure Based on the Mechanism Underlying Maintenance of Redox Homeostasis by Reactive Sulfur Species

    Motohiro Nishida, Takashi Toyama, Yoshito Kumagai, Takuro Numaga-Tomita

    YAKUGAKU ZASSHI　134　(12)　1239-1243　2014/12/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/yakushi.14-00209-1 　

    ISSN： 0031-6903

    eISSN： 1347-5231

  61. Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function Peer-reviewed

    Viorica Raluca Contu, Yaichiro Kotake, Takashi Toyama, Katsuhiro Okuda, Masatsugu Miyara, Shuichiro Sakamoto, Shigeyoshi Samizo, Seigo Sanoh, Yoshito Kumagai, Shigeru Ohta

    JOURNAL OF NEUROCHEMISTRY　130　(6)　826-838　2014/09

    DOI： 10.1111/jnc.12762 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  62. Role of 8-nitro-cGMP and its redox regulation in cardiovascular electrophilic signaling Peer-reviewed

    Motohiro Nishida, Takashi Toyama, Takaaki Akaike

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY　73　10-17　2014/08

    DOI： 10.1016/j.yjmcc.2014.02.003 　

    ISSN： 0022-2828

    eISSN： 1095-8584

  63. Glutathione-mediated reversibility of covalent modification of ubiquitin carboxyl-terminal hydrolase L1 by 1,2-naphthoquinone through Cys152, but not Lys4 Peer-reviewed

    Takashi Toyama, Yasuhiro Shinkai, Aid Yazawa, Hidenao Kakehashi, Toshiyuki Kaji, Yoshito Kumagai

    CHEMICO-BIOLOGICAL INTERACTIONS　214　41-48　2014/05

    DOI： 10.1016/j.cbi.2014.02.008 　

    ISSN： 0009-2797

    eISSN： 1872-7786

  64. Identification and Quantification of in Vivo Metabolites of 9,10-Phenanthrenequinone in Human Urine Associated with Producing Reactive Oxygen Species Peer-reviewed

    Miki Asahi, Mio Kawai, Takashi Toyama, Yoshito Kumagai, Thanyarat Chuesaard, Ning Tang, Takayuki Kameda, Kazuichi Hayakawa, Akira Toriba

    CHEMICAL RESEARCH IN TOXICOLOGY　27　(1)　76-85　2014/01

    DOI： 10.1021/tx400338t 　

    ISSN： 0893-228X

    eISSN： 1520-5010

  65. The Role of the Keap1/Nrf2 Pathway in the Cellular Response to Methylmercury Peer-reviewed

    Yoshito Kumagai, Hironori Kanda, Yasuhiro Shinkai, Takashi Toyama

    OXIDATIVE MEDICINE AND CELLULAR LONGEVITY　2013　848279　2013

    DOI： 10.1155/2013/848279 　

    ISSN： 1942-0900

  66. S-Mercuration of rat sorbitol dehydrogenase by methylmercury causes its aggregation and the release of the zinc ion from the active site Peer-reviewed

    Hironori Kanda, Takashi Toyama, Azusa Shinohara-Kanda, Akihiro Iwamatsu, Yasuhiro Shinkai, Toshiyuki Kaji, Makoto Kikushima, Yoshito Kumagai

    ARCHIVES OF TOXICOLOGY　86　(11)　1693-1702　2012/11

    DOI： 10.1007/s00204-012-0893-4 　

    ISSN： 0340-5761

  67. DNA microarray analysis of human neuroblastoma SH-SY5Y cells exposed to methylmercury Peer-reviewed

    Takashi Toyama, Eiko Yoshida, Yasuhiro Shinkai, Yoshito Kumagai

    JOURNAL OF TOXICOLOGICAL SCIENCES　36　(6)　843-845　2011/12

    DOI： 10.2131/jts.36.843 　

    ISSN： 0388-1350

    eISSN： 1880-3989

  68. Detoxification of Methylmercury by Hydrogen Sulfide-Producing Enzyme in Mammalian Cells Peer-reviewed

    Eiko Yoshida, Takashi Toyama, Yasuhiro Shinkai, Tomohiro Sawa, Takaaki Akaike, Yoshito Kumagai

    CHEMICAL RESEARCH IN TOXICOLOGY　24　(10)　1633-1635　2011/10

    DOI： 10.1021/tx200394g 　

    ISSN： 0893-228X

  69. Carbon monoxide derived from heme oxygenase-2 mediates reduction of methylmercury toxicity in SH-SY5Y cells Peer-reviewed

    Takashi Toyama, Yasuhiro Shinkai, Daigo Sumi, Yoshito Kumagai

    TOXICOLOGY AND APPLIED PHARMACOLOGY　249　(1)　86-90　2010/11

    DOI： 10.1016/j.taap.2010.08.021 　

    ISSN： 0041-008X

    eISSN： 1096-0333

  70. Role of aquaporin 9 in cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes Peer-reviewed

    Yasuhiro Shinkai, Daigo Sumi, Takashi Toyama, Toshiyuki Kaji, Yoshito Kumagai

    TOXICOLOGY AND APPLIED PHARMACOLOGY　237　(2)　232-236　2009/06

    DOI： 10.1016/j.taap.2009.03.014 　

    ISSN： 0041-008X

  71. Reduction of arginase I activity and manganese levels in the liver during exposure of rats to methylmercury: a possible mechanism Peer-reviewed

    Hironori Kanda, Daigo Sumi, Akiko Endo, Takashi Toyama, Cheng-Liang Chen, Makoto Kikushima, Yoshito Kumagai

    ARCHIVES OF TOXICOLOGY　82　(11)　803-808　2008/11

    DOI： 10.1007/s00204-008-0307-9 　

    ISSN： 0340-5761

  72. Downregulation of arginase II and renal apoptosis by inorganic mercury: overexpression of arginase II reduces its apoptosis Peer-reviewed

    Hironori Kanda, Makoto Kikushima, Shino Homma-Takeda, Daigo Sumi, Akiko Endo, Takashi Toyama, Nobuhiko Miura, Akira Naganuma, Yoshito Kumagai

    ARCHIVES OF TOXICOLOGY　82　(2)　67-73　2008/02

    DOI： 10.1007/s00204-007-0244-z 　

    ISSN： 0340-5761

    eISSN： 1432-0738

  73. Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity Peer-reviewed

    Takashi Toyama, Daigo Sumi, Yasuhiro Shinkai, Akira Yasutake, Keiko Taguchi, Kit I. Tong, Masayuki Yamamoto, Yoshito Kumagai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　363　(3)　645-650　2007/11

    DOI： 10.1016/j.bbrc.2007.09.017 　

    ISSN： 0006-291X

  74. Activation of the Nrf2 pathway, but decreased gamma-glutamylcysteine synthetase heavy subunit chain levels and caspase-3-dependent apoptosis during exposure of primary mouse hepatocytes to diphenylarsinic acid Peer-reviewed

    Daigo Sumi, Aiko Manji, Yasuhiro Shinkai, Takashi Toyama, Yoshito Kumagai

    TOXICOLOGY AND APPLIED PHARMACOLOGY　223　(3)　218-224　2007/09

    DOI： 10.1016/j.taap.2007.06.001 　

    ISSN： 0041-008X

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Industrial Property Rights 6

  1. 抗ウイルス剤

    外山 喬士, 有澤 美枝子, 斎藤 芳郎, 矢▼崎▲ 雅菜, 千田 大智, 赤池 孝章, 松永 哲郎

    Property Type: Patent

  2. antibody mimetics

    Property Type: Patent

  3. 抗ウイルス薬

    外山 喬士、有澤 美枝子、斎藤 芳郎、矢▼崎▲ 雅菜 、千田 大智、赤池 孝章、松永 哲郎

    Property Type: Patent

    Holder: 外山 喬士、有澤 美枝子、斎藤 芳郎、矢▼崎▲ 雅菜 、千田 大智、赤池 孝章、松永 哲郎

  4. COVID-19治療剤

    東 光佳, 吹上 知穂, 今田 岐, 岸本 矢誉衣, 平澤 典保, 斎藤 芳郎, 外山 喬士

    Property Type: Patent

  5. セレノプロテインPを標的としたグリオブラストーマ治療薬

    斎藤芳郎, 外山喬士, 杉浦ひかり

    Property Type: Patent

  6. グリオブラストーマの治療薬のスクリーニング方法、治療薬、予後判定方法

    斎藤芳郎, 外山喬士, 杉浦ひかり

    Property Type: Patent

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Research Projects 27

  1. レドックスバイオミメティクスの創出 ー哺乳類-植物の異生物間の抗酸化機構の活用ー

    伊藤隼哉, 外山喬士, 辻井 雅, 三島英換

    Offer Organization: 東北大学

    System: 新領域創成のための挑戦研究デュオ (FRiD)

    Category: 新領域創成のための挑戦研究デュオ (FRiD)

    2025/05 - 2030/03

  2. 脳セレン輸送機構の理解と応用による有害金属動態と毒性の制御

    外山喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究（B）

    Institution: 東北大学

    2026/04 - 2029/03

  3. システインの超セレン化を介したアドホックな抗酸化活性能の獲得

    外山喬士, 山越博幸

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究 (萌芽)

    2026/04 - 2028/03

  4. 食品添加セレンの有用性・安全性と新規評価法に関する研究

    外山喬士, 岩井美幸

    Offer Organization: 消費者庁

    System: 食品衛生基準科学研究費

    Category: ⾷品の規格基準の策定に資する研究（２６ＺＡ０７０１）

    Institution: 東北大学

    2026/04 - 2028/03

  5. Elucidation of the molecular pathology of chronic diseases and establishment of new treatment methods based on trace element research

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2024/04 - 2028/03

  6. メチル水銀結合標的分子の新規解析法開発による診断マーカーの探索

    外山 喬士

    Offer Organization: 環境省

    System: 令和6年度重金属による健康影響に関する総合的研究

    Category: 環境省「令和６年度 水俣病に関する総合的研究」委託事業

    Institution: 環境省

    2024/07 - 2027/03

  7. Elucidation of the direct metabolic control mechanisms of producing cells by secreted proteins

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2024/06/28 - 2026/03/31

  8. メチル水銀無機化と重金属解毒隔離を担うセレノプロテインPの新機能

    外山 喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

  9. 環境と生命をつなぐコバレントセンス

    田口恵子, 外山喬士, 上原孝, 伊藤昭博, 武田一貴, 磯辺洋輔, 闐闐 孝介

    Offer Organization: TIA 連携プログラム探索推進事業「かけはし」

    System: 2025年度 TIA 連携プログラム探索推進事業「かけはし｣

    2025/06 - 2026/03

  10. 微量元素プロファイルに基づく宇宙空間における健康維持/ 疾患リスク管理システムの開発

    斎藤芳郎, 外山 喬士, 有澤琴子, 岩井美幸

    Offer Organization: JAXA

    System: JAXA「きぼう」利⽤定型プロトコルによる医学系研究

    2024/04 - 2025/03

  11. 新奇セレン含有化合物ライブラリーを⽤いた多機能性を有する感染症治療薬の創出

    山本 雅之, 斎藤 芳郎, 外山 喬士, 有澤 美枝子, 田口 恵子, 小林 博幸

    Offer Organization: AMED

    System: ゲノム・オミックス･タンパク質構造情報を活⽤したアカデミア発の創薬⽀援 (Fast track project)

    2024/04 - 2025/03

  12. リンホトキシンβ受容体を介したメチル水銀による脳神経障害機構の解明

    黄 基旭, 山縣 涼太, 外山 喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北医科薬科大学

    2022/04 - 2025/03

  13. Ebselen誘導体をベースとした経口抗ウイルス薬の開発

    外山喬士, 斎藤芳郎, 有澤美枝子, 赤池孝章

    Offer Organization: AMED

    System: 橋渡し研究戦略的推進プログラム

    Category: シーズA

    2022/04 - 2024/03

  14. Regulatory mechanism of selenoprotein P expression and its deterioration mechanism of glucose metabolism

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2020/04 - 2024/03

  15. 糖尿病増悪因子セレノプロテインPのエピガロカテキンガレートによる中和作用 Competitive

    外山 喬士

    Offer Organization: 本庄八郎記念お茶財団

    System: 研究助成金

    Institution: 本庄八郎記念お茶財団

    2022/08 - 2023/07

  16. 含セレン化合物のミックスモード作用を介したウイルス増殖抑制剤の開発

    外山喬士, 松永哲郎, 有澤美枝子

    Offer Organization: AMED

    System: 新興・再興感染症に対する革新的医薬品等開発推進研究事業

    Category: 新興・再興感染症に対する革新的医薬品等開発推進研究事業

    Institution: 東北大学

    2022/07 - 2023/03

  17. Lysosomal redox control via hepatic-brain crosstalk and its disruption by methylmercury

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2021/07 - 2023/03

  18. 重金属・微量元素の多様な変動と疾患を理解する分子病態学「疾患メタロミクス」の創成

    斎藤芳郎, 外山喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究（萌芽）

    Institution: 挑戦的研究（萌芽）

    2021/04 - 2023/03

  19. Disruption of redox status via an essential-metal and harmful-metal interaction

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Tohoku University

    2020/04 - 2022/03

  20. Investigation of the defense mechanisms by the transcription factor TCF3 against methylmercury toxicity

    Hwang Gi-Wook

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    2019/04 - 2022/03

    More details Close

    We previously identified TCF3 as a transcription factor that is activated in the brains of methylmercury-treated mice. In this study, we have shown that TCF3 inhibited the induction of apoptosis via mitochondrial damage as a novel protective factor against methylmercury-induced neurotoxicity. We also found that suppression of TCF3 degradation by proteasome is involved in TCF3 activation by methylmercury and that activated TCF3 is recruited to the promoter region of the SRXN1 gene, which encodes sulfiredoxin 1, thereby suppressing methylmercury-induced apoptosis. Furthermore, both TCF3 and SRXN1 were shown to be selectively increased in neurons in the brains of methylmercury-treated mice.

  21. Methylmercury induced neuronal damage via M1-microglial activation

    Toyama Takashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Tohoku University

    2019/04 - 2021/03

    More details Close

    In this study, we newly established a mouse cerebral cortex slice culture that can evaluates inflammatory microglial activation. We also found that methylmercury induces inflammatory cytokine (tumor necrosis factor-alpha; TNF-α) in microglia in the mouse brain with the new methodology and in vivo experiments. Interestingly TNF-α is released out from microglia by methylmercury and induced neuronal cell death via TNFR1 on neurons. We further confirmed that methylmercury induced TNF-α induction is dependent on mitochondrial ROS production and activation of its downstream ASK1/p38 signaling. Hence the present study indicates inflammatory crosstalk between microglia and neurons are crucial for methylmercury-induced neuronal toxicity, and this could be an outstanding finding in the toxicology of methylmercury.

  22. Molecular mechanism for toxic effect of methylmercury

    NAGANUMA AKIRA

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: Tohoku University

    2015/05 - 2020/03

    More details Close

    We have found for the first time that methylmercury induces brain-specific expression of TNFα. Further, although research on TNFα has been actively carried out worldwide, induction of TNFα expression via tmRT1 is not known. The results obtained by this study not only clearly explain the mechanism of methylmercury toxicity, but also lead to the creation of a new research field called: induction of TNFα expression via tmRT1.

  23. Cytostatic factor that released from methylmercury exposed cells

    Takashi Toyama

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2017/04 - 2019/03

    More details Close

    In this study, 4-hydroperoxynonenal was identified as a candidate of cytostatic factor that released from neuronal stem cells by methylmercury. When the cells were treated with both 4-hydroxynonenal and methylmercury, effect of cell growth inhibition by methylmercury was significantly increased by co-treatment of 4-hydroxynonenal. Therefore, this factor can be a cytostatic factor that released from the cell exposed to methylmercury. In addition, it was suggested that the production of this factor is enhanced through two pathways. One is increased reactive oxygen species production associated with mitochondrial over-activation by methylmercury and the other is inhibition of glutathione peroxidase by covalent modification of Cys or seleno Cys that responsible for its activity.

  24. Mechanism underlying the reduction of methylmercury toxicity by putrescine

    Hwang Gi-Wook

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2016/04 - 2019/03

    More details Close

    We have previously found that the level of putrescine, a polyamine, was increased in the brains of mice administered methylmercury (MeHg), and addition of putrescine to culture medium reduced MeHg toxicity in C17.2 mouse neural stem cells. In this study, we investigated the role of ornithine decarboxylase (ODC), an enzyme involved in putrescine synthesis, in response to MeHg toxicity, and found that MeHg increased ODC activity in mouse cerebrum and cerebellum, but this increase was hardly observed in the kidney and liver, where MeHg accumulated at a high concentration. MeHg also increased the putrescine level and ODC enzyme activity in C17.2 cells, and these increases were due to the stabilization of the ODC enzyme by MeHg. We also found that putrescine suppressed apoptosis through mitochondrial dysfunction caused by MeHg. This is the first study to provide evidence that increased ODC activity may be a protective response against MeHg-induced neurotoxicity.

  25. Mechanism underlying the reduction of methylmercury toxicity by Ragulator complex which is an autophagy regulator

    HWANG Gi-Wook, TAKAHASHI TSUTOMU, TOYAMA TAKASHI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2013/04 - 2016/03

    More details Close

    In this study, we found that methylmercury induced the autophagy through the function-loss of Ragulator complex which suppresses autophagy induction, but not known mechanisms. In addition, methylmercury induced the function-loss by promoting the degradation of Ragulator complex. When autophagy-related gene was inhibited by RNA interference, cultured-cells showed the methylmercury resistance. Taken together, we concluded that methylmercury might be cause the cytotoxicity through the induction of excessive autophagy.

  26. メチル水銀によるＳ－水銀化を介した心血管系障害

    外山 喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 東京理科大学

    2012/04 - 2015/03

    More details Close

    近年の疫学調査から低濃度のメチル水銀 (MeHg) の人体への蓄積と心疾患リスクとの関与が指摘されているが、その機序は不明である。昨年度までの申請者の研究結果から、MeHgは心疾患のイニシエーターというよりもプロモーターとして関与することが示唆されており、そのメカニズムとしてミトコンドリア形態異常の関与が予想された。最終年度である本年度は、この仮説を軸に、心筋においてMeHgが引き起こすミトコンドリア分裂の機構と心不全亢進のメカニズムに関して検討を行った。 MeHg (10 ppm) を10日間自由飲水投与したマウスの心臓を電子顕微鏡により観察した結果、ミトコンドリア小胞化の亢進が示された。ミトコンドリアの小胞化 (分裂) にはDrp1の活性化が重要であり、そのCysの修飾 (S-水銀化) がMeHgによる活性化のトリガーとなることは昨年度に報告した通りであるが、実際にDrp1が活性化しているかは不明であった。そこでGTP-agaroseによるプルダウンアッセイにより、その活性化を検討したところ、NRCMおよびin vivoにおいてMeHgによるDrp1の有意な活性化が示された。MeHgによるS-水銀化の標的部位をMALDI-TOF/MSにより同定したところ、Cys624であることが明らかとなった。GFPタグ付きのDrp1のCys624のSer異体を作成しHela細胞に発現させ、MeHgによる多量体化を観察した結果、本変異体では多量体化が起こらないことが判明した。以上より、MeHgはDrp1のCys624をS-水銀化することで活性化し、ミトコンドリアの小胞化を引き起こすことを見出した。また、Drp1の阻害剤であるMdivi-1を処置した細胞では、ミトコンドリアの小胞化が抑制さると同時に、MeHgによる圧負荷による細胞死は低下した。以上、本研究から、MeHgは心筋中のDrp1のCys624と結合することで、ミトコンドリアの分裂を誘導し、それによって圧感受性が高まった結果、心疾患のプロモーターとして心不全に寄与することが世界に先駆けて明らかとなった

  27. メチル水銀によるタンパク質の翻訳後修飾で生じる神経疾患

    外山 喬士

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 筑波大学

    2010 - 2011

    More details Close

    本研究は、メチル水銀(MeHg)によるユビキチンC末端加水分解酵素L1(UCH-L1)の機能破綻及による神経障害への関与を、分子、細胞から個体レベルで解明を目指したものである。本年度は、MeHgによるタンパク質の翻訳後修飾(S-水銀化)によるUCH-L1の機能破綻のメカニズムを解明したのみに留まらず、それに付随する新たな知見を得ることができた。これは更なる研究の展開に貢献するものである。本年度に得られた成果を下記の通りである。 1. MeHgを曝露した細胞のタンパク質を二次元電気泳動により展開後3mm角のセグメントに分け、ゲル中の水銀濃度を網羅的に測定し、MeHg標的タンパク質をLC/MSにより同定する手法を確立した(Mercuromics解析)。本結果から、UCH-L1はSH-SY5Y細胞中で最もS-水銀化を受けやすいタンパク質の一つであることが示された。 2. モノユビキチンとUCH-L1とのアフィニティーは、MeHgの結合によって顕著に減少した。本結果は、UCH-L1に対するMeHgの結合が、細胞内ユビキチンプールの減少の一因であることを示す。 3. S-水銀化を抑制する生体内因子である硫化水素をSH-SY5Y細胞に処理することで、MeHgによるUCH-L1の機能破綻が抑制せれた。またGSHによってUCH-L1のS-水銀化は解除できることをMALDI-TOF/MSにより明らかにした。 上記知見を前年度の成果と合わせると、UCH-L1はMeHgによるS-水銀化の標的分子であり、Cys151のS-水銀化によって、細胞内およびラット脳中のユビキチン制御系を破綻させることが明らかとなった。またこれらは、生体内の硫化水素やGSH量を制御することで防御できることが示唆された。本成果は、MeHgに起因する神経変性疾患の機構および予防法を模索する上で重要な知見だろう。

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Teaching Experience 12

  1. Advanced Biological Sciences　Tohoku University

  2. GP-Food: Food Science II "Beneficial and Harmful Minerals"　東北大学

  3. Global Issues and Global Society - Environmental Pollution & Health Effects　University of Tsukuba

  4. 基礎ゼミ・学問論演習「くすりを探る」　東北大学

  5. 生命薬学実習　東北大学

  6. 環境衛生学　東北大学

  7. 食品衛生学　東北大学

  8. Environmental Molecular Toxicology　Tokushima Bunri University

  9. 自然科学総合実習　東北大学

  10. 化学概論　東北大学

  11. 環境科学実習　筑波大学

  12. 予防環境医学　筑波大学

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Social Activities 12

  1. 東北大学 未来型医療創造卓越大学院プログラム ファシリテーター教員

    2026/04/01 - Present

  2. Representative Secretariat: The Joint Meeting of the 8th Japanese Selenium Research Society and the 13th International Symposium on Selenium in Biology and Medicine (Se2025)

    2025/10/31 -

  3. 知って安心！日常生活に潜む化学物質とその健康影響 (市民公開講座)

    2025/07 -

  4. JSOT 2025 年会事務局

    2025/07 -

  5. 衛生薬学・環境トキシコロジー 若手研究者の会 フォーラム 2024 プレシンポジウム

    2024/09/02 -

  6. 衛生薬学・環境トキシコロジー 若手研究者の会 フォーラム 2023 プレシンポジウム

    2023/09/11 -

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