Details of the Researcher

PHOTO

Takaaki Akaike
Section
Graduate School of Medicine
Job title
Professor
Degree

  • 医学博士（熊本大学）

e-Rad No.
20231798

Research History 12

  • 2024 - Present
    東北大学超硫黄生命科学研究所　センター長

  • 2013 - Present
    Tohoku University　Graduate School of Medicine

  • 2019 - 2023
    Tohoku University　Graduate School of Medicine

  • 2011 - 2013
    Kumamoto University　School of Medicine, School of Medicine

  • 2010 - 2013
    Kumamoto University　Faculty of Life Sciences

  • 2005 - 2010
    熊本大学大学院医学薬学研究部　教授

  • 2003 - 2005
    Ministry of Education,Culture,Sports,Science and Technology

  • 1994 - 2005
    Kumamoto University　School of Medicine

  • 2001 -
    米国アラバマ大学バーミングハム校　客員教授

  • 1993 -
    米国トーマスジェファーソン医科大学　客員教授

  • 1992 -
    Kumamoto University　School of Medicine

  • 1991 -
    Kumamoto University　School of Medicine

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Education 2

  • Kumamoto University　Kumamoto University

    1991 -

  • Kumamoto University　School of Medicine

    1984 -

Committee Memberships 12

  • 日本酸化ストレス学会　理事長

    2024/04 - Present

  • 分子予防環境医学研究会　理事長

    2018 - Present

  • Federation of Microbiological Societies Japan (FMS Japan)　Vice President

    2021 - 2024

  • Japanese Society for Bacteriology　President

    2018 - 2023

  • Japanese Society for Host Defense Research　President

    2018 - 2020

  • Nitric Oxide Society of Japan　President

    2008 - 2011

  • Nitric Oxide Society　President

    2008 - 2010

  • Redox Week in Sendai 2022　Chair (TFC)

    2022/10 -

  • 第１回硫黄代謝の医学生物学に関する国際会議　運営委員長

    2019/09 -

  • 第90回日本細菌学会総会 総会長

    2017/03 -

  • 第69回日本酸化ストレス学会学術集会 大会長

    2016/08 -

  • 第24回日本生体防御学会学術総会学術 総会長

    2013/07 -

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Professional Memberships 9

  • がん予防研究会

  • THE JAPANESE SOCIETY OF INTERNAL MEDICINE

  • THE JAPANESE CANCER ASSOCIATION

  • THE JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES

  • THE JAPANESE SOCIETY FOR VIROLOGY

  • THE JAPANESE BIOCHEMICAL SOCIETY

  • 日本NO学会

  • 日本生体防御学会

  • JAPANESE SOCIETY FOR BACTERIOLOGY

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Research Areas 2

  • Life sciences / Bacteriology /

  • Life sciences / Medical biochemistry /

Awards 4

  1. 第３回太田原豊一賞

    2022

  2. 日本細菌学会浅川賞

    2015

  3. 日本酸化ストレス学会学会賞

    2014

  4. 日本細菌学会小林六造記念賞

    2001

Papers 478

  1. Oxygen needs sulfur, sulfur needs oxygen: a relationship of interdependence. International-journal

    Hiroki Sekine, Takaaki Akaike, Hozumi Motohashi

    The EMBO journal　44　(12)　3307-3326　2025/06

    DOI： 10.1038/s44318-025-00464-7 　

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    Oxygen and sulfur, both members of the chalcogen group (group 16 elements), play fundamental roles in life. Ancient organisms primarily utilized sulfur for energy metabolism, while the rise in atmospheric oxygen facilitated the evolution of aerobic organisms, enabling highly efficient energy production. Nevertheless, all modern organisms, both aerobes and anaerobes, must protect themselves from oxygen toxicity. Interestingly, aerobes still rely on sulfur for survival. This dependence has been illuminated by the recent discovery of supersulfides, a novel class of biomolecules, made possible through advancements in technology and analytical methods. These breakthroughs are reshaping our understanding of biological processes and emphasizing the intricate interplay between oxygen and sulfur in regulating essential redox reactions. This review summarizes the latest insights into the biological roles of sulfur and oxygen, their interdependence in key processes, and their contributions to adaptive responses to environmental stressors. By exploring these interactions, we aim to provide a comprehensive perspective on how these elements drive survival strategies across diverse life forms, highlighting their indispensable roles in both human health and the sustenance of life.

  2. Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation International-journal

    Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Hibiki Suzuki, Jing Li, Ziying Yang, Ryoji Mitsuwaka, Akihisa Kawajiri, Kosuke Sato, Feng Gao, Taku Nakai, Yuko Okuyama, Tadahisa Numakura, Mitsuhiro Yamada, Tomoaki Ida, Masanobu Morita, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii

    Frontiers in Immunology　16　1506580-1506580　2025/04/15

    Publisher: Frontiers Media SA

    DOI： 10.3389/fimmu.2025.1506580 　

    eISSN： 1664-3224

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    Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation where CD4+ T lymphocytes play an essential role. Accumulating evidence suggests that immune responses driven by CD4+ T cells are critically regulated by various metabolic pathways including oxidative phosphorylation and glycolysis. Here we show that CARS2/CPERS-dependent supersulfide metabolism restrains CD4+ T cell proliferation in a cell-intrinsic manner. Under steady state, Cars2+/- mice exhibited spontaneous accumulation of effector/memory CD4+ T cells in the colon with age. In lymphopenic conditions, Cars2+/- CD4+ T cells showed enhanced cell cycle entry with reduced expression of a cell cycle inhibitor Trp53 and triggered an exacerbated form of colitis, the response being rescued by treatment with a supersulfide donor glutathione trisulfide (GSSSG). Furthermore, re-analysis of publicly available gene datasets of human colonic CD4+ T lymphocytes revealed that downregulation of CARS2 was associated with pathogenesis of IBD, and indeed, addition of GSSSG inhibited human CD4+ T cell proliferation in vitro. Together these observations reveal that CARS2/CPERS-dependent supersulfide metabolism is essential for homeostasis of intestinal effector/memory CD4+ T cells, and further suggest that dysregulation of the same metabolic pathway can lead to development of gut inflammation both in mice and humans.

  3. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis. International-journal

    Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa

    Science advances　11　(8)　eadu3011　2025/02/21

    DOI： 10.1126/sciadv.adu3011 　

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    Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.

  4. Supersulfides: A Promising Therapeutic Approach for Autoinflammatory Diseases. International-journal

    Tianli Zhang, Touya Toyomoto, Tomohiro Sawa, Takaaki Akaike, Tetsuro Matsunaga

    Microbiology and immunology　69　(4)　191-202　2025/02/16

    DOI： 10.1111/1348-0421.13205 　

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    Supersulfides are molecular species characterized by catenated sulfur moieties, including low-molecular-weight and protein-bound supersulfides. Emerging evidence suggests that these molecules, abundantly present in diverse organisms, play essential roles far beyond their chemical properties, such as functions in energy metabolism, protein stabilization, and antiviral defense. Recent studies highlight their regulatory effects on pattern-recognition receptors (PRRs) and associated signaling pathways-such as nucleotide oligomerization domain-like receptor signaling, toll-like receptor signaling, and type I interferon receptor signaling-critical for innate immunity and inflammatory responses. Dysregulation of these pathways is implicated in a heterogeneous group of autoinflammatory diseases, including inflammasomopathies, relopathies, and type I interferonopathies, respectively. Notably, both endogenous and synthetic supersulfide donors have recently shown promising inhibitory effects on PRR signaling, offering their potential as targeted therapies for managing autoinflammatory conditions. This review summarizes the fundamental biology of supersulfides and typical autoinflammatory diseases, focusing on their roles in innate immune and inflammatory responses, while exploring their therapeutic potential in these diseases.

  5. Supersulfides contribute to joint homeostasis and bone regeneration. International-journal

    Miki Maemura, Masanobu Morita, Seiryo Ogata, Yoichi Miyamoto, Tomoaki Ida, Kazuhiro Shibusaka, Soichiro Negishi, Masahiro Hosonuma, Taku Saito, Jun Yoshitake, Tsuyoshi Takata, Tetsuro Matsunaga, Eikan Mishima, Uladzimir Barayeu, Takaaki Akaike, Fumiko Yano

    Redox biology　81　103545-103545　2025/02/11

    DOI： 10.1016/j.redox.2025.103545 　

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    The physiological functions of supersulfides, inorganic and organic sulfides with sulfur catenation, have been extensively studied. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulfide synthase. This study aimed to investigate the role of supersulfides in joint homeostasis and bone regeneration. Using Cars2AINK/+ mutant mice, in which the KIIK motif of CARS2 essential for supersulfide production was replaced with AINK, we evaluated the role of supersulfides in fracture healing and cartilage homeostasis during osteoarthritis (OA). Tibial fracture surgery was performed on the wild-type (Cars2+/+) and Cars2AINK/+ mice littermates. Bulk RNA-seq analysis for the osteochondral regeneration in the fracture model showed increased inflammatory markers and reduced osteogenic factors, indicative of impaired bone regeneration, in Cars2AINK/+ mice. Destabilization of the medial meniscus (DMM) surgery was performed to produce the mouse OA model. Histological analyses with Osteoarthritis Research Society International and synovitis scores revealed accelerated OA progression in Cars2AINK/+ mice compared with that in Cars2+/+ mice. To assess the effects of supersulfides on OA progression, glutathione trisulfide (GSSSG) or saline was periodically injected into the mouse knee joints after the DMM surgery. Thus, supersulfides derived from CARS2 and GSSSG exogenously administered significantly inhibited inflammation and lipid peroxidation of the joint cartilage, possibly through suppression of ferroptosis, during OA development. This study represents a significant advancement in understanding anti-inflammatory and anti-oxidant functions of supersulfides in skeletal tissues and may have a clinical relevance for the bone healing and OA therapeutics.

  6. Supersulfide metabolome of exhaled breath condensate applied as diagnostic biomarkers for esophageal cancer. International-journal

    Seji Asamitsu, Yohei Ozawa, Hiroshi Okamoto, Seiryo Ogata, Tetsuro Matsunaga, Jun Yoshitake, Kazuki Fusegawa, Yusuke Taniyama, Chiaki Sato, Hirotaka Ishida, Takaaki Abe, Hozumi Motohashi, Takaaki Akaike, Takashi Kamei

    Cancer science　116　(4)　1023-1033　2025/02/02

    DOI： 10.1111/cas.16430 　

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    Early detection of esophageal cancer is essential for esophagogastroduodenoscopy and histopathological diagnosis. However, endoscopic examinations are sometimes invasive, which limits their clinical application and compliance, and traditional blood tumor markers are unsuitable for cancer screening. The current study aimed to evaluate the usefulness of sulfur metabolites as new biomarkers for esophageal cancer using blood samples and exhaled breath condensate (EBC), which can be readily obtained and is non-invasive. We collected EBC and plasma samples from 50 patients with esophageal cancer and 30 healthy controls. Sulfur metabolome analysis using tandem mass spectrometry was performed to compare the metabolic profile between the two groups. Supersulfide metabolic profiles were different between the two cohorts. Supersulfide metabolome analysis showed that cysteine hydropersulfide (CysSSH) and homocysteine hydropersulfide (HomoCysSSH) were increased in the plasma of patients with esophageal cancer. Elevated levels of HomoCysSSH could distinguish patients with esophageal cancer from healthy subjects (area under the curve [AUC]: 0.93, sensitivity: 89%, specificity: 96%). Interestingly, we also detected an elevation of supersulfides in the EBC analysis. CysSSH levels significantly increased in the EBC recovered from patients with esophageal cancer (AUC: 0.71, sensitivity: 60%, specificity: 96%). In addition, the observed level was correlated with that of HomoCysSSH in the plasma (r = 0.27). Supersulfides, such as CysSSH and HomoCysSSH, are potential biomarkers for detecting esophageal cancer. CysSSH from EBC may serve as a valuable non-invasive biomarker with similar detection ability but with superior precision and convenience compared with the currently available blood biomarkers.

  7. Non-thermal atmospheric pressure plasma-irradiated cysteine protects cardiac ischemia/reperfusion injury by preserving supersulfides International-journal

    Akiyuki Nishimura, Tomohiro Tanaka, Kakeru Shimoda, Tomoaki Ida, Shota Sasaki, Keitaro Umezawa, Hiromi Imamura, Yasuteru Urano, Fumito Ichinose, Toshiro Kaneko, Takaaki Akaike, Motohiro Nishida

    Redox Biology　79　103445-103445　2025/02

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2024.103445 　

    ISSN： 2213-2317

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    Ischemic heart disease is the main global cause of death in the world. Abnormal sulfide catabolism, especially hydrogen sulfide accumulation, impedes mitochondrial respiration and worsens the prognosis after ischemic insults, but the substantial therapeutic strategy has not been established. Non-thermal atmospheric pressure plasma irradiation therapy is attracted attention as it exerts beneficial effects by producing various reactive molecular species. Growing evidence has suggested that supersulfides, formed by catenation of sulfur atoms, contribute to various biological processes involving electron transfer in cells. Here, we report that non-thermal plasma-irradiated cysteine (Cys∗) protects mouse hearts against ischemia/reperfusion (I/R) injury by preventing supersulfide catabolism. Cys∗ has a weak but long-lasting supersulfide activity, and the treatment of rat cardiomyocytes with Cys∗ prevents mitochondrial dysfunction after hypoxic stress. Cys∗ increases sulfide-quinone oxidoreductase (SQOR), and silencing SQOR abolishes Cys∗-induced supersulfide formation and cytoprotection. Local administration of mouse hearts with Cys∗ significantly reduces infarct size with preserving supersulfide levels after I/R. These results suggest that maintaining supersulfide formation through SQOR underlies cardioprotection by Cys∗ against I/R injury.

  8. The Therapeutic Potential of Supersulfides in Oxidative Stress-Related Diseases International-journal Peer-reviewed

    Yuexuan Pan, Tetsuro Matsunaga, Tianli Zhang, Takaaki Akaike

    Biomolecules　15　(2)　2025/01/23

    DOI： 10.3390/biom15020172 　

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    Oxidation-reduction (redox) reactions are fundamental to sustaining life, with reactive oxygen and nitrogen species playing pivotal roles in cellular signaling and homeostasis. However, excessive oxidative stress disrupts redox balance, contributing to a wide range of diseases, including inflammatory and pulmonary disorders, neurodegeneration, and cancer. Although numerous antioxidant therapies have been developed and tested for oxidative stress-related diseases, their clinical efficacy remains limited. Here, we introduce the emerging concept of 'supersulfides', a class of redox molecule species with unique antioxidant and nucleophilic properties, which have recently been recognized as crucial regulators of cellular redox homeostasis. Unlike traditional antioxidants, supersulfides offer novel mechanisms of action that directly target the underlying processes of oxidative stress. This review summarizes current knowledge on supersulfides, highlighting their roles in oxidative stress and associated diseases, as well as the mechanisms underlying oxidative stress-related pathology. The therapeutic potential of synthetic supersulfides for treating oxidative stress-related diseases is also discussed. A comprehensive understanding of the molecular and cellular basis of redox biology can help to guide the development of innovative redox-based therapeutic strategies aimed at preventing and treating diseases associated with disturbed redox regulation.

  9. Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice. International-journal

    Akiyuki Nishimura, Seiryo Ogata, Xiaokang Tang, Kowit Hengphasatporn, Keitaro Umezawa, Makoto Sanbo, Masumi Hirabayashi, Yuri Kato, Yuko Ibuki, Yoshito Kumagai, Kenta Kobayashi, Yasunari Kanda, Yasuteru Urano, Yasuteru Shigeta, Takaaki Akaike, Motohiro Nishida

    Nature communications　16　(1)　276-276　2025/01/02

    DOI： 10.1038/s41467-024-55661-5 　

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    The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body's primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1). In healthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highly S-glutathionylated. Nearly 40% of Cys644 is normally polysulfidated, which is a preferential target for GSSG-mediated S-glutathionylation. Cys644 S-glutathionylation is resistant to Drp1 depolysulfidation-dependent mitochondrial hyperfission and myocardial dysfunction caused by hypoxic stress. MD simulation of Drp1 structure and site-directed mutagenetic analysis reveal a functional interaction between Cys644 and a critical phosphorylation site Ser637, through Glu640. Bulky modification at Cys644 via polysulfidation or S-glutathionylation reduces Drp1 activity by disrupting Ser637-Glu640-Cys644 interaction. Disruption of Cys644 S-glutathionylation nullifies the cardioprotective effect of GSSG against heart failure after myocardial infarction. Our findings suggest a therapeutic potential of supersulfide-based Cys bulking on Drp1 for ischemic heart disease.

  10. Supersulfide donors and their therapeutic targets in inflammatory diseases. International-journal

    Tianli Zhang, Yuexuan Pan, Tomohiro Sawa, Takaaki Akaike, Tetsuro Matsunaga

    Frontiers in immunology　16　1581385-1581385　2025

    DOI： 10.3389/fimmu.2025.1581385 　

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    Inflammation is one defense mechanism of the body that has multiple origins, ranging from physical agents to infectious agents including viruses and bacteria. The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation, which can become chronic. Failure of the inflammation resolution is a key pathological mechanism that drives the progression of numerous inflammatory diseases. Owing to the various side effects of currently available drugs to control inflammation, novel therapeutic agents that can prevent or suppress inflammation are needed. Supersulfides are highly reactive and biologically potent molecules that function as antioxidants, redox regulators, and modulators of cell signaling. The catenation state of individual sulfur atoms endows supersulfides with unique biological activities. Great strides have recently been made in achieving a molecular understanding of these sulfur species, which participate in various physiological and pathological pathways. This review mainly focuses on the anti-inflammatory effects of supersulfides. The review starts with an overview of supersulfide biology and highlights the roles of supersulfides in both immune and inflammatory responses. The various donors used to generate supersulfides are assessed as research tools and potential therapeutic agents. Deeper understanding of the molecular and cellular bases of supersulfide-driven biology can help guide the development of innovative therapeutic strategies to prevent and treat diseases associated with various immune and inflammatory responses.

  11. Author Correction: PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity. International-journal

    Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

    Nature metabolism　6　(12)　2391-2391　2024/12

    DOI： 10.1038/s42255-024-01183-9 　

  12. Phototriggered Hydrogen Persulfide Donors via Hydrosulfide Radical Formation Enhancing the Reactive Sulfur Metabolome in Cells. International-journal

    Biswajit Roy, Meg Shieh, Tsuyoshi Takata, Minkyung Jung, Eshani Das, Shi Xu, Takaaki Akaike, Ming Xian

    Journal of the American Chemical Society　146　(44)　30502-30509　2024/11/06

    DOI： 10.1021/jacs.4c11540 　

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    Hydrogen persulfide (H2S2) is an important sulfur-containing signaling molecule that plays a crucial role in the homeostasis of various organ systems, such as the renal, cardiovascular, liver, and gastrointestinal systems. However, research on H2S2 in biological settings is still challenging due to its instability and high reactivity. Compounds that can controllably release H2S2 (also known as donors) are thus crucial research tools. Currently, available H2S2 donors are still very limited, with most of them relying on modified disulfide templates. These templates possess an unavoidable limitation of being susceptible to cellular disulfide exchange which can compromise their efficacy. In this work, we explored nondisulfide-based and nonoxidation-dependent templates for the design of H2S2 donors. We found that tertiary naphthacyl thiols could undergo phototriggered C-S homolytic cleavage to form H2S2 via hydrosulfide (HS) radicals. In addition, the release of H2S2 was associated with the formation of a product with strong blue fluorescence, which allowed for real-time monitoring of the release process. This reaction was demonstrated to proceed effectively in both buffers and cells, with the ability to enhance intracellular production of persulfides, including GSSH, CysSSH, H2S2, H2S3, etc. It provides a unique photocontrolled H2S2 donor system with distinct advantages compared to known H2S2 donors due to its good stability and spatiotemporal control ability.

  13. Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes.

    Moe Kondo, Yuya Nakamura, Yuri Kato, Akiyuki Nishimura, Mitsuhiro Fukata, Shohei Moriyama, Tomoya Ito, Keitaro Umezawa, Yasuteru Urano, Takaaki Akaike, Koichi Akashi, Yasunari Kanda, Motohiro Nishida

    Journal of Pharmacological Sciences　156　(2)　69-76　2024/10

    DOI： 10.1016/j.jphs.2024.07.007 　

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    Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.

  14. Supersulfide formation in the sinus mucosa of chronic rhinosinusitis. International-journal

    Jun Suzuki, Tomotaka Hemmi, Tomoaki Ida, Seiryo Ogata, Jun Yoshitake, Tetsuro Matsunaga, Tomoyasu Ishida, Yuki Numano, Yusuke Kusano, Ryoukichi Ikeda, Kazuhiro Nomura, Mitsuru Sugawara, Nobuo Ohta, Takaaki Akaike, Yukio Katori

    Laryngoscope Investigative Otolaryngology　9　(4)　e1261　2024/08

    DOI： 10.1002/lio2.1261 　

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    OBJECTIVES: Disruption of the oxidative stress defense system is involved in developing various diseases. Sulfur compounds such as glutathione (GSH) and cysteine (CysSH) are representative antioxidants in the body. Recently, supersulfides, including reactive persulfide and polysulfide species, have gained attention as potent antioxidants regulating oxidative stress and redox signaling. However, their involvement in the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. METHODS: To clarify the changes in sulfur compounds within the sinus mucosa of each CRS subtype, we measured sulfur compound levels in the sinus mucosa of control individuals (n = 9), patients with eosinophilic CRS (ECRS) (n = 13), and those with non-ECRS (nECRS) (n = 11) who underwent sinus surgery using mass spectrometry. RESULTS: GSH and CysSH levels were significantly reduced, and the glutathione disulfide (GSSG)/GSH ratio, an oxidative stress indicator, was increased in patients with ECRS. Despite the absence of notable variations in supersulfides, patients with ECRS and nECRS exhibited a significant reduction in glutathione trisulfide (GSSSG), which serves as the precursor for supersulfides. CONCLUSIONS: This study is the first quantitative assessment of supersulfides in normal and inflamed sinus mucosa, suggesting that sulfur compounds contribute to the pathogenesis of CRS. LEVEL OF EVIDENCE: N/A.

  15. New aspects of redox signaling mediated by supersulfides in health and disease. International-journal

    Takaaki Akaike, Masanobu Morita, Seiryo Ogata, Jun Yoshitake, Minkyung Jung, Hiroki Sekine, Hozumi Motohashi, Uladzimir Barayeu, Tetsuro Matsunaga

    Free Radical Biology & Medicine　222　539-551　2024/07/09

    DOI： 10.1016/j.freeradbiomed.2024.07.007 　

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    Oxygen molecules accept electrons from the respiratory chain in the mitochondria and are responsible for energy production in aerobic organisms. The reactive oxygen species formed via these oxygen reduction processes undergo complicated electron transfer reactions with other biological substances, which leads to alterations in their physiological functions and cause diverse biological and pathophysiological consequences (e.g., oxidative stress). Oxygen accounts for only a small proportion of the redox reactions in organisms, especially under aerobic or hypoxic conditions but not under anaerobic and hypoxic conditions. This article discusses a completely new concept of redox biology, which is governed by redox-active supersulfides, i.e., sulfur-catenated molecular species. These species are present in abundance in all organisms but remain largely unexplored in terms of redox biology and life science research. In fact, accumulating evidence shows that supersulfides have extensive redox chemical properties and that they can be readily ionized or radicalized to participate in energy metabolism, redox signaling, and oxidative stress responses in cells and in vivo. Thus, pharmacological intervention and medicinal modulation of supersulfide activities have been shown to benefit the regulation of disease pathogenesis as well as disease control.

  16. Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function. International-journal

    Tomas Majtan, Thomas Olsen, Jitka Sokolova, Jakub Krijt, Michaela Křížková, Tomoaki Ida, Tamás Ditrói, Hana Hansikova, Ondrej Vit, Jiri Petrak, Ladislav Kuchař, Warren D Kruger, Péter Nagy, Takaaki Akaike, Viktor Kožich

    Redox Biology　73　103222-103222　2024/06/04

    DOI： 10.1016/j.redox.2024.103222 　

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    BACKGROUND: Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). METHODS: We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. RESULTS: In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. CONCLUSION: The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

  17. PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity. International-journal Peer-reviewed

    Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

    Nature Metabolism　6　(6)　1108-1127　2024/05

    DOI： 10.1038/s42255-024-01053-4 　

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    Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

  18. PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis. International-journal Peer-reviewed

    Hiroaki Fujita, Yu-Ki Tanaka, Seiryo Ogata, Noriyuki Suzuki, Sota Kuno, Uladzimir Barayeu, Takaaki Akaike, Yasumitsu Ogra, Kazuhiro Iwai

    Nature Structural & Molecular Biology　31　(8)　1277-1285　2024/05

    DOI： 10.1038/s41594-024-01329-z 　

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    Ferroptosis is a form of regulated cell death induced by iron-dependent accumulation of lipid hydroperoxides. Selenoprotein glutathione peroxidase 4 (GPX4) suppresses ferroptosis by detoxifying lipid hydroperoxides via a catalytic selenocysteine (Sec) residue. Sec, the genetically encoded 21st amino acid, is biosynthesized from a reactive selenium donor on its cognate tRNA[Ser]Sec. It is thought that intracellular selenium must be delivered 'safely' and 'efficiently' by a carrier protein owing to its high reactivity and very low concentrations. Here, we identified peroxiredoxin 6 (PRDX6) as a novel selenoprotein synthesis factor. Loss of PRDX6 decreases the expression of selenoproteins and induces ferroptosis via a reduction in GPX4. Mechanistically, PRDX6 increases the efficiency of intracellular selenium utilization by transferring selenium between proteins within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, leading to efficient synthesis of selenocysteyl-tRNA[Ser]Sec. These findings highlight previously unidentified selenium metabolic systems and provide new insights into ferroptosis.

  19. Supersulfide catabolism participates in maladaptive remodeling of cardiac cells Peer-reviewed

    Liuchenzi Zhou, Akiyuki Nishimura, Keitaro Umezawa, Yuri Kato, Xinya Mi, Tomoya Ito, Yasuteru Urano, Takaaki Akaike, Motohiro Nishida

    Journal of Pharmacological Sciences　155　(4)　121-130　2024/05

    Publisher: Elsevier BV

    DOI： 10.1016/j.jphs.2024.05.002 　

    ISSN： 1347-8613

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    The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5'-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (H2S), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while H2S accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.

  20. Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism. International-journal Peer-reviewed

    Kanemaru E, Marutani E, Morita M, Miranda M, Miyazaki Y, Bloch D, Akaike T, Ichinose F

    Journal of Clinical Investigation　134　(15)　2024/05

    DOI： 10.1172/JCI170994 　

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    Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.

  21. Human hair keratin responds to oxidative stress via reactive sulfur and supersulfides

    Takeru Hirai, Mayumi Ikeda-Imafuku, Nanami Tasaka, Victor Tuan Giam Chuang, Ming Xian, Tatsuhiro Ishida, Takaaki Akaike, Yu Ishima

    Advances in Redox Research　10　2024/04

    DOI： 10.1016/j.arres.2023.100091 　

    eISSN： 2667-1379

  22. 2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels. International-journal

    Qi Cui, Meg Shieh, Tony W Pan, Akiyuki Nishimura, Tetsuro Matsunaga, Shane S Kelly, Shi Xu, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Jun Yoshitake, Xiaoyan Chen, Jerome R Robinson, Wei-Jun Qian, Motohiro Nishida, Takaaki Akaike, Ming Xian

    Nature Communications　15　(1)　2453-2453　2024/03/19

    DOI： 10.1038/s41467-024-46652-7 　

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    Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

  23. Essential role of ROS - 8-Nitro-cGMP signaling in long-term memory of motor learning and cerebellar synaptic plasticity. International-journal

    Sho Kakizawa, Tomoko Arasaki, Ayano Yoshida, Ayami Sato, Yuka Takino, Akihito Ishigami, Takaaki Akaike, Shuichi Yanai, Shogo Endo

    Redox Biology　70　103053-103053　2024/02/01

    DOI： 10.1016/j.redox.2024.103053 　

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    Although reactive oxygen species (ROS) are known to have harmful effects in organisms, recent studies have demonstrated expression of ROS synthases at various parts of the organisms and the controlled ROS generation, suggesting possible involvement of ROS signaling in physiological events of individuals. However, physiological roles of ROS in the CNS, including functional roles in higher brain functions or neuronal activity-dependent ROS production, remain to be elucidated. Here, we demonstrated involvement of ROS - 8-NO2-cGMP signaling in motor learning and synaptic plasticity in the cerebellum. In the presence of inhibitors of ROS signal or ROS synthases, cerebellar motor learning was impaired, and the stimulus inducing long-term depression (LTD), cellular basis for the motor learning, failed to induce LTD but induced long-term potentiation (LTP)-like change at cerebellar synapses. Furthermore, ROS was produced by LTD-inducing stimulus in enzyme-dependent manner, and excess administration of the antioxidant vitamin E impaired cerebellar motor learning, suggesting beneficial roles of endogenous ROS in the learning. As a downstream signal, involvement of 8-NO2-cGMP in motor learning and cerebellar LTD were also revealed. These findings indicate that ROS - 8-NO2-cGMP signal is activated by neuronal activity and is essential for cerebellum-dependent motor learning and synaptic plasticity, demonstrating involvement of the signal in physiological function of brain systems.

  24. Regulation of innate immune and inflammatory responses by supersulfides. International-journal

    Hiroyasu Tsutsuki, Tianli Zhang, Takaaki Akaike, Tomohiro Sawa

    International Immunology　36　(4)　143-154　2024/01/05

    DOI： 10.1093/intimm/dxad057 　

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    Innate immunity plays an important role in host defense against microbial infections. It also participates in activation of acquired immunity through cytokine production and antigen presentation. Pattern recognition receptors such as Toll-like receptors and nucleotide oligomerization domain-like receptors sense invading pathogens and associated tissue injury, after which inflammatory mediators such as pro-inflammatory cytokines and nitric oxide are induced. Supersulfides are molecular species possessing catenated sulfur atoms such as persulfide and polysulfide moieties. They have recently been recognized as important regulators in cellular redox homeostasis by acting as potent antioxidants and nucleophiles. In addition, recent studies suggested that supersulfides are critically involved in the regulation of innate immune and inflammatory responses. In this review, we summarize current knowledge of the chemistry and biology of supersulfides, with particular attention to their roles in regulation of innate immune and inflammatory responses. Studies with animal models of infection and inflammation demonstrated the potent anti-inflammatory functions of supersulfides such as blocking pro-inflammatory signaling cascades, reducing oxidative stresses, and inhibiting replication of microbial pathogens including severe acute respiratory syndrome coronavirus 2. Precise understanding of how supersulfides regulate innate immune responses is the necessary requirement for developing supersulfide-based diagnostic as well as therapeutic strategies against inflammatory disorders.

  25. Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality. International-journal

    Akira Nishimura, Sunghyeon Yoon, Tetsuro Matsunaga, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Jun Yoshitake, Yuka Unno, Uladzimir Barayeu, Tsuyoshi Takata, Hiroshi Takagi, Hozumi Motohashi, Albert van der Vliet, Takaaki Akaike

    Redox Biology　69　103018-103018　2024/01/03

    DOI： 10.1016/j.redox.2023.103018 　

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    Supersulfides, which are defined as sulfur species with catenated sulfur atoms, are increasingly being investigated in biology. We recently identified pyridoxal phosphate (PLP)-dependent biosynthesis of cysteine persulfide (CysSSH) and related supersulfides by cysteinyl-tRNA synthetase (CARS). Here, we investigated the physiological role of CysSSH in budding yeast (Saccharomyces cerevisiae) by generating a PLP-binding site mutation K109A in CRS1 (the yeast ortholog of CARS), which decreased the synthesis of CysSSH and related supersulfides and also led to reduced chronological aging, effects that were associated with an increased endoplasmic reticulum stress response and impaired mitochondrial bioenergetics. Reduced chronological aging in the K109A mutant could be rescued by using exogenous supersulfide donors. Our findings indicate important roles for CARS in the production and metabolism of supersulfides-to mediate mitochondrial function and to regulate longevity.

  26. Quantitative profiling of supersulfides naturally occurring in dietary meats and beans. International-journal

    Shingo Kasamatsu, Ayaka Kinno, Chiharu Miura, Jun-Ichi Hishiyama, Kensuke Fukui, Shoji Kure, Kazunobu Tsumura, Tomoaki Ida, Tetsuro Matsunaga, Takaaki Akaike, Hideshi Ihara

    Analytical Biochemistry　685　115392-115392　2023/11/13

    DOI： 10.1016/j.ab.2023.115392 　

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    Sulfur is essential in the inception of life and crucial for maintaining human health. This mineral is primarily supplied through the intake of proteins and is used for synthesizing various sulfur-containing biomolecules. Recent research has highlighted the biological significance of endogenous supersulfides, which include reactive persulfide species and sulfur catenated residues in thiol and proteins. Ingestion of exogenous sulfur compounds is essential for endogenous supersulfide production. However, the content and composition of supersulfides in foods remain unclear. This study investigated the supersulfide profiles of protein-rich foods, including edible animal meat and beans. Quantification of the supersulfide content revealed that natto, chicken liver, and bean sprouts contained abundant supersulfides. In general, the supersulfide content in beans and their derivatives was higher than that in animal meat. The highest proportion (2.15 %) was detected in natto, a traditional Japanese fermented soybean dish. These results suggest that the abundance of supersulfides, especially in foods like natto and bean sprouts, may contribute to their health-promoting properties. Our findings may have significant biological implications and warrant developing novel dietary intervention for the human health-promoting effects of dietary supersulfides abundantly present in protein-rich foods such as natto and bean sprouts.

  27. Supersulfides support bone growth by promoting chondrocyte proliferation in the growth plates International-journal

    Yuji Sasama, Kentaro Yoshimura, Marie Hoshino, Kiyohito Sasa, Takaaki Akaike, Masanobu Morita, Kazuyoshi Baba, Tatsuo Shirota, Yoichi Miyamoto

    Journal of Oral Biosciences　66　(1)　76-81　2023/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.job.2023.11.004 　

    ISSN： 1349-0079

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    OBJECTIVES: While chondrocytes have mitochondria, they receive little O2 from the bloodstream. Sulfur respiration, an essential energy production system in mitochondria, uses supersulfides instead of O2. Supersulfides are inorganic and organic sulfides with catenated sulfur atoms and are primarily produced by cysteinyl tRNA synthetase-2 (CARS2). Here, we investigated the role of supersulfides in chondrocyte proliferation and bone growth driven by growth plate chondrocyte proliferation. METHODS: We examined the effects of NaHS, an HS-/H2S donor, and cystine, the cellular source of cysteine, on the proliferation of mouse primary chondrocytes and growth of embryonic mouse tibia in vitro. We also examined the effect of RNA interference acting on the Cars2 gene on chondrocyte proliferation in the presence of cystine. RESULTS: NaHS (30 μmol/L) enhanced tibia longitudinal growth in vitro with expansion of the proliferating zone of their growth plates. While NaHS (30 μmol/L) also promoted chondrocyte proliferation only under normoxic conditions (20 % O2), cystine (0.5 mmol/L) promoted it under both normoxic and hypoxic (2 % O2) conditions. Cars2 gene knockdown abrogated the ability of cystine (0.5 mmol/L) to promote chondrocyte proliferation under normoxic conditions, indicating that supersulfides produced by CARS2 were responsible for the cystine-dependent promotion of bone growth. CONCLUSIONS: The presented results indicate that supersulfides play a vital role in bone growth achieved by chondrocyte proliferation in the growth plates driven by sulfur respiration.

  28. Alkyl gallates inhibit serine O-acetyltransferase in bacteria and enhance susceptibility of drug-resistant Gram-negative bacteria to antibiotics International-journal

    Touya Toyomoto, Katsuhiko Ono, Tomoo Shiba, Kenta Momitani, Tianli Zhang, Hiroyasu Tsutsuki, Takeshi Ishikawa, Kanae Hoso, Koma Hamada, Azizur Rahman, Liping Wen, Yosuke Maeda, Keiichi Yamamoto, Masao Matsuoka, Kenjiro Hanaoka, Takuro Niidome, Takaaki Akaike, Tomohiro Sawa

    Frontiers in Microbiology　14　1276447-1276447　2023/10/27

    Publisher: Frontiers Media SA

    DOI： 10.3389/fmicb.2023.1276447 　

    eISSN： 1664-302X

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    A principal concept in developing antibacterial agents with selective toxicity is blocking metabolic pathways that are critical for bacterial growth but that mammalian cells lack. Serine O-acetyltransferase (CysE) is an enzyme in many bacteria that catalyzes the first step in l-cysteine biosynthesis by transferring an acetyl group from acetyl coenzyme A (acetyl-CoA) to l-serine to form O-acetylserine. Because mammalian cells lack this l-cysteine biosynthesis pathway, developing an inhibitor of CysE has been thought to be a way to establish a new class of antibacterial agents. Here, we demonstrated that alkyl gallates such as octyl gallate (OGA) could act as potent CysE inhibitors in vitro and in bacteria. Mass spectrometry analyses indicated that OGA treatment markedly reduced intrabacterial levels of l-cysteine and its metabolites including glutathione and glutathione persulfide in Escherichia coli to a level similar to that found in E. coli lacking the cysE gene. Consistent with the reduction of those antioxidant molecules in bacteria, E. coli became vulnerable to hydrogen peroxide-mediated bacterial killing in the presence of OGA. More important, OGA treatment intensified susceptibilities of metallo-β-lactamase-expressing Gram-negative bacteria (E. coli and Klebsiella pneumoniae) to carbapenem. Structural analyses showed that alkyl gallate bound to the binding site for acetyl-CoA that limits access of acetyl-CoA to the active site. Our data thus suggest that CysE inhibitors may be used to treat infectious diseases caused by drug-resistant Gram-negative bacteria not only via direct antibacterial activity but also by enhancing therapeutic potentials of existing antibiotics.

  29. Supersulfide biology and translational medicine for disease control. International-journal

    Uladzimir Barayeu, Tomohiro Sawa, Motohiro Nishida, Fan-Yan Wei, Hozumi Motohashi, Takaaki Akaike

    British Journal of Pharmacology　2023/10/23

    DOI： 10.1111/bph.16271 　

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    For decades, the major focus of redox biology has been oxygen, the most abundant element on Earth. Molecular oxygen functions as the final electron acceptor in the mitochondrial respiratory chain, contributing to energy production in aerobic organisms. In addition, oxygen-derived reactive oxygen species including hydrogen peroxide and nitrogen free radicals, such as superoxide, hydroxyl radical and nitric oxide radical, undergo a complicated sequence of electron transfer reactions with other biomolecules, which lead to their modified physiological functions and diverse biological and pathophysiological consequences (e.g. oxidative stress). What is now evident is that oxygen accounts for only a small number of redox reactions in organisms and knowledge of biological redox reactions is still quite limited. This article reviews a new aspects of redox biology which is governed by redox-active sulfur-containing molecules-supersulfides. We define the term 'supersulfides' as sulfur species with catenated sulfur atoms. Supersulfides were determined to be abundant in all organisms, but their redox biological properties have remained largely unexplored. In fact, the unique chemical properties of supersulfides permit them to be readily ionized or radicalized, thereby allowing supersulfides to actively participate in redox reactions and antioxidant responses in cells. Accumulating evidence has demonstrated that supersulfides are indispensable for fundamental biological processes such as energy production, nucleic acid metabolism, protein translation and others. Moreover, manipulation of supersulfide levels was beneficial for pathogenesis of various diseases. Thus, supersulfide biology has opened a new era of disease control that includes potential applications to clinical diagnosis, prevention and therapeutics of diseases.

  30. NRF2 signalling in cytoprotection and metabolism. International-journal

    Shohei Murakami, Yusuke Kusano, Keito Okazaki, Takaaki Akaike, Hozumi Motohashi

    British Journal of Pharmacology　2023/09/15

    DOI： 10.1111/bph.16246 　

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    The KEAP1-NRF2 system plays a central role in cytoprotection in defence mechanisms against oxidative stress. The KEAP1-NRF2 system has been regarded as a sulfur-utilizing cytoprotective mechanism, because KEAP1 serves as a biosensor for electrophiles by using its reactive thiols and NRF2 is a transcriptional factor regulating genes involved in sulfur-mediated redox reactions. NRF2 is a key regulator of cytoprotective genes, such as antioxidant and detoxification genes, and also possesses potent anti-inflammatory activity. Recently NRF2 has been the focus of attention as a regulator of cellular metabolism and mitochondrial function. The NRF2-mediated regulatory mechanisms of metabolites and mitochondria have been considered diverse, but have not yet been fully clarified. This review article provides an overview of molecular mechanisms that regulate NRF2 signalling and its cytoprotective roles, and highlights NRF2 contribution to cellular metabolism, particularly in the context of mitochondrial function and newly-found sulfur metabolism.

  31. Untargeted polysulfide omics analysis of alternations in polysulfide production during the germination of broccoli sprouts International-journal Peer-reviewed

    Shingo Kasamatsu, Takuma Owaki, Somei Komae, Ayaka Kinno, Tomoaki Ida, Takaaki Akaike, Hideshi Ihara

    Redox Biology　67　102875-102875　2023/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2023.102875 　

    ISSN： 2213-2317

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    Higher consumption of broccoli (Brassica oleracea var. italica) is associated with a reduced risk of cardiometabolic diseases, neurological disorders, diabetes, and cancer. Broccoli is rich in various phytochemicals, including glucosinolates, and isothiocyanates. Moreover, it has recently reported the endogenous production of polysulfides, such as cysteine hydropersulfide (CysS2H) and glutathione hydropersulfide (GS2H), in mammals including humans, and that these bioactive substances function as potent antioxidants and important regulators of redox signaling in vivo. However, few studies have focused on the endogenous polysulfide content of broccoli and the impact of germination on the polysulfide content and composition in broccoli. In this study, we investigated the alternations in polysulfide biosynthesis in broccoli during germination by performing untargeted polysulfide omics analysis and quantitative targeted polysulfide metabolomics through liquid chromatography-electrospray ionization-tandem mass spectrometry. We also performed 2,2-diphenyl-1-picrylhydrazyl radical-scavenging assay to determine the antioxidant properties of the polysulfides. The results revealed that the total polysulfide content of broccoli sprouts significantly increased during germination and growth; CysS2H and cysteine hydrotrisulfide were the predominant organic polysulfide metabolites. Furthermore, we determined that novel sulforaphane (SFN) derivatives conjugated with CysS2H and GS2H were endogenously produced in the broccoli sprouts, and the novel SFN conjugated with CysS2H exhibited a greater radical scavenging capacity than SFN and cysteine. These results suggest that the abundance of polysulfides in broccoli sprouts contribute to their health-promoting properties. Our findings have important biological implications for the development of novel pharmacological targets for the health-promoting effects of broccoli sprouts in humans.

  32. Hypoxic erythrocytes mediate cardioprotection through activation of soluble guanylate cyclase and release of cyclic GMP. International-journal Peer-reviewed

    Jiangning Yang, Michaela L Sundqvist, Xiaowei Zheng, Tong Jiao, Aida Collado, Yahor Tratsiakovich, Ali Mahdi, John Tengbom, Evanthia Mergia, Sergiu-Bogdan Catrina, Zhichao Zhou, Mattias Carlström, Takaaki Akaike, Miriam M Cortese-Krott, Eddie Weitzberg, Jon O Lundberg, John Pernow

    Journal of Clinical Investigation　133　(17)　e167693　2023/09/01

    Publisher: American Society for Clinical Investigation

    DOI： 10.1172/JCI167693 　

    eISSN： 1558-8238

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    Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.

  33. Persulfide Biosynthesis Conserved Evolutionarily in All Organisms International-journal

    Seiryo Ogata, Tetsuro Matsunaga, Minkyung Jung, Uladzimir Barayeu, Masanobu Morita, Takaaki Akaike

    Antioxidants & Redox Signaling　39　(13-15)　983-999　2023/08/11

    Publisher: Mary Ann Liebert Inc

    DOI： 10.1089/ars.2023.0405 　

    ISSN： 1523-0864

    eISSN： 1557-7716

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    SIGNIFICANCE: Persulfides/polysulfides are sulfur-catenated molecular species (i.e., R-Sn-R', n > 2; R-Sn-H, n > 1, with R = cysteine, glutathione, and proteins), such as cysteine persulfide (CysSSH). These species are abundantly formed as endogenous metabolites in mammalian and human cells and tissues. However, the persulfide synthesis mechanism has yet to be thoroughly discussed. RECENT ADVANCES: We used β-(4-hydroxyphenyl)ethyl iodoacetamide and mass spectrometry to develop sulfur metabolomics, a highly precise, quantitative analytical method for sulfur metabolites. CRITICAL ISSUES: With this method, we detected appreciable amounts of different persulfide species in biological specimens from various organisms, from the domains Bacteria, Archaea, and Eukarya. By using our rigorously quantitative approach, we identified cysteinyl-tRNA synthetase (CARS) as a novel persulfide synthase, and we found that the CysSSH synthase activity of CARS is highly conserved from the domains Bacteria to Eukarya. Because persulfide synthesis is found not only with CARS but also with other sulfotransferase enzymes in many organisms, persulfides/polysulfides are expected to contribute as fundamental elements to substantially diverse biological phenomena. In fact, persulfide generation in higher organisms-i.e., plants and animals-demonstrated various physiological functions that are mediated by redox signaling, such as regulation of energy metabolism, infection, inflammation, and cell death including ferroptosis. FUTURE DIRECTIONS: Investigating CARS-dependent persulfide production may clarify various pathways of redox signaling in physiological and pathophysiological conditions and may thereby promote the development of preventive and therapeutic measures for oxidative stress as well as different inflammatory, metabolic, and neurodegenerative diseases.

  34. Supersulfide catalysis for nitric oxide and aldehyde metabolism. International-journal Peer-reviewed

    Kasamatsu S, Nishimura A, Alam MM, Morita M, Shimoda K, Matsunaga T, Jung M, Ogata S, Barayeu U, Ida T, Nishida M, Nishimura A, Motohashi H, Akaike T

    Science Advance　9　(33)　eadg8631　2023/08

    DOI： 10.1126/sciadv.adg8631 　

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    Abundant formation of endogenous supersulfides, which include reactive persulfide species and sulfur catenated residues in thiols and proteins (supersulfidation), has been observed. We found here that supersulfides catalyze S-nitrosoglutathione (GSNO) metabolism via glutathione-dependent electron transfer from aldehydes by exploiting alcohol dehydrogenase 5 (ADH5). ADH5 is a highly conserved bifunctional enzyme serving as GSNO reductase (GSNOR) that down-regulates NO signaling and formaldehyde dehydrogenase (FDH) that detoxifies formaldehyde in the form of glutathione hemithioacetal. C174S mutation significantly reduced the supersulfidation of ADH5 and almost abolished GSNOR activity but spared FDH activity. Notably, Adh5C174S/C174S mice manifested improved cardiac functions possibly because of GSNOR elimination and consequent increased NO bioavailability. Therefore, we successfully separated dual functions (GSNOR and FDH) of ADH5 (mediated by the supersulfide catalysis) through the biochemical analysis for supersulfides in vitro and characterizing in vivo phenotypes of the GSNOR-deficient organisms that we established herein. Supersulfides in ADH5 thus constitute a substantial catalytic center for GSNO metabolism mediating electron transfer from aldehydes.

  35. Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop. International-journal

    Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi

    Redox Biology　65　102834-102834　2023/07/29

    DOI： 10.1016/j.redox.2023.102834 　

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    The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.

  36. Supersulphides provide airway protection in viral and chronic lung diseases. International-journal Peer-reviewed

    Matsunaga T, Sano H, Takita K, Morita M, Yamanaka S, Ichikawa T, Numakura T, Ida T, Jung M, Ogata S, Yoon S, Fujino N, Kyogoku Y, Sasaki Y, Koarai A, Tamada T, Toyama A, Nakabayashi T, Kageyama L, Kyuwa S, Inaba K, Watanabe S, Nagy P, Sawa T, Oshiumi H, Ichinose M, Yamada M, Sugiura H, Wei FY, Motohashi H, Akaike T

    Nature Communications　14　(1)　4476-4476　2023/07/25

    DOI： 10.1038/s41467-023-40182-4 　

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    Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease.

  37. Glutathione trisulfide prevents lipopolysaccharide-induced retinal inflammation via inhibition of proinflammatory cytokine production in glial cells. International-journal Peer-reviewed

    Hiroshi Tawarayama, Kota Umeki, Maki Inoue-Yanagimachi, Naoki Takahashi, Hirokazu Hasegawa, Noriko Himori, Satoru Tsuda, Hiroshi Kunikata, Takaaki Akaike, Toru Nakazawa

    Scientific Reports　13　(1)　11513-11513　2023/07/17

    DOI： 10.1038/s41598-023-38696-4 　

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    We aimed to investigate the impact of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammation in retinal glia. Inflammatory responses in mouse-derived glial cells and Wistar rat retinas were stimulated with administration of LPS. Cell survival and proinflammatory cytokine production were examined using the Calcein-AM assay, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Retinal microglia were visualized with immunohistochemistry for Iba1. Administration of LPS (10 µg/mL) or GSSSG (less than 100 µM) did not affect survival of cultured primary Müller cells and established microglial cells (BV-2). RT-qPCR and ELISA indicated that GSSSG inhibited LPS-induced gene upregulation and protein secretion of proinflammatory cytokines in these glial cells and rat retinas. GSSSG inhibited LPS-induced activation of TGF-β-activated kinase 1 (TAK1), which is an upstream kinase of NF-κB, in BV-2 cells. Finally, in vivo experiments indicated that intravitreal administration of GSSSG but not its relative glutathione disulfide (GSSG) inhibited LPS (500 ng)-induced accumulation of Iba1-immunopositive microglia in rat retinas. Taken together, GSSSG has the potential to prevent pathogenesis of inflammation-associated ocular diseases by inhibiting proinflammatory cytokine expression in retinal glial cells.

  38. Development of methods for quantitative determination of the total and reactive polysulfides: Reactive polysulfide profiling in vegetables. International-journal Peer-reviewed

    Shingo Kasamatsu, Ayaka Kinno, Jun-Ichi Hishiyama, Takaaki Akaike, Hideshi Ihara

    Food Chemistry　413　135610-135610　2023/07/01

    DOI： 10.1016/j.foodchem.2023.135610 　

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    Alliaceous and cruciferous vegetables are rich in bioactive organosulfur compounds, including polysulfides, which exhibit a broad spectrum of potential health benefits. Here, we developed novel, accurate, and reproducible methods to quantify the total polysulfide content (TPsC) and the reactive polysulfide content (RPsC) using liquid chromatography-electrospray ionization-tandem mass spectrometry, and analyzed the reactive polysulfide profiles of 22 types of fresh vegetables, including onions, garlic, and broccoli. Quantitative analyses revealed that onions contained the largest amounts of polysulfides, followed by broccoli, Chinese chive, and garlic. A strong positive correlation was observed between the TPsC and RPsC, whereas only a moderate positive correlation was found between the total sulfur content and TPsC. These results suggest that reactive polysulfide profiling can be a novel criterion for evaluating the beneficial functions of vegetables and their derivatives, which may lead to an understanding of the detailed mechanisms underlying their bioactivities.

  39. Presence of Helicobacter cinaedi in atherosclerotic abdominal aortic aneurysmal wall.

    Shinichiro Horii, Hirofumi Sugawara, Hitoshi Goto, Munetaka Hashimoto, Tetsuro Matsunaga, Daijirou Akamatsu, Yuta Tajima, Michihisa Umetsu, Takaaki Akaike, Takashi Kamei

    The Tohoku Journal of Experimental Medicine　261　(1)　35-41　2023/06/15

    DOI： 10.1620/tjem.2023.J049 　

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    Recently, the relationship between Helicobacter cinaedi (H. cinaedi) infection and several diseases, including cardiovascular and central nervous system disorders, bone and soft tissue disorders, and infectious abdominal aortic aneurysms (AAAs), has been reported. Moreover, H. cinaedi may be associated with arteriosclerosis. In the present study, we investigated the association between H. cinaedi infection and clinically uninfected AAAs. Genetic detection of H. cinaedi in the abdominal aneurysm wall was attempted in 39 patients with AAA undergoing elective open surgery between June 2019 and June 2020. DNA samples extracted from the arterial wall obtained during surgery were analyzed using nested polymerase chain reaction (PCR). The target gene region was the H. cinaedi-specific cytolethal distending toxin subunit B (cdtB). Nine (23.1%) of 39 patients showed positive bands corresponding to H. cinaedi, and further sequencing analyses demonstrated the presence of H. cinaedi DNAs in their aneurysm walls. In contrast, all the non-aneurysm arterial walls in our patients were negative for H. cinaedi. In conclusion, this is the first report of the detection of H. cinaedi in the walls of a clinically non-infectious AAA.

  40. Cystathionine γ-lyase self-inactivates by polysulfidation during cystine metabolism. International-journal Peer-reviewed

    Shoma Araki, Tsuyoshi Takata, Katsuhiko Ono, Tomohiro Sawa, Shingo Kasamatsu, Hideshi Ihara, Yoshito Kumagai, Takaaki Akaike, Yasuo Watanabe, Yukihiro Tsuchiya

    International Journal of Molecular Sciences　24　(12)　2023/06/10

    DOI： 10.3390/ijms24129982 　

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    Cystathionine γ-lyase (CSE) is an enzyme responsible for the biosynthesis of cysteine from cystathionine in the final step of the transsulfuration pathway. It also has β-lyase activity toward cystine, generating cysteine persulfide (Cys-SSH). The chemical reactivity of Cys-SSH is thought to be involved in the catalytic activity of particular proteins via protein polysulfidation, the formation of -S-(S)n-H on their reactive cysteine residues. The Cys136/171 residues of CSE have been proposed to be redox-sensitive residues. Herein, we investigated whether CSE polysulfidation occurs at Cys136/171 during cystine metabolism. Transfection of wild-type CSE into COS-7 cells resulted in increased intracellular Cys-SSH production, which was significantly increased when Cys136Val or Cys136/171Val CSE mutants were transfected, instead of the wild-type enzyme. A biotin-polyethylene glycol-conjugated maleimide capture assay revealed that CSE polysulfidation occurs at Cys136 during cystine metabolism. In vitro incubation of CSE with CSE-enzymatically synthesized Cys-SSH resulted in the inhibition of Cys-SSH production. In contrast, the mutant CSEs (Cys136Val and Cys136/171Val) proved resistant to inhibition. The Cys-SSH-producing CSE activity of Cys136/171Val CSE was higher than that of the wild-type enzyme. Meanwhile, the cysteine-producing CSE activity of this mutant was equivalent to that of the wild-type enzyme. It is assumed that Cys-SSH-producing CSE activity could be auto-inactivated via the polysulfidation of the enzyme during cystine metabolism. Thus, the polysulfidation of CSE at the Cys136 residue may be an integral feature of cystine metabolism, which functions to down-regulate Cys-SSH synthesis by the enzyme.

  41. Redox regulation of xenobiotics by reactive sulfur and supersulfide species. International-journal Peer-reviewed

    Tianli Zhang, Takaaki Akaike, Tomohiro Sawa

    Antioxidants & Redox Signaling　40　(10-12)　679-690　2023/06/09

    Publisher: Mary Ann Liebert Inc

    DOI： 10.1089/ars.2022.0172 　

    ISSN： 1523-0864

    eISSN： 1557-7716

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    SIGNIFICANCE: Routine exposure to xenobiotics is unavoidable during our lifetimes. Certain xenobiotics are hazardous to human health, and are metabolized in the body to render them less toxic. During this process, several detoxification enzymes cooperatively metabolize xenobiotics. Glutathione (GSH) conjugation plays an important role in the metabolism of electrophilic xenobiotics. RECENT ADVANCES: Recent advances in reactive sulfur and supersulfide (RSS) analyses showed that persulfides and polysulfides bound to low-molecular-weight thiols, such as GSH and to protein thiols are abundant in both eukaryotes and prokaryotes. The highly nucleophilic nature of hydropersulfides and hydropolysulfides contributes to cell protection against oxidative stress and electrophilic stress. CRITICAL ISSUES: In contrast to GSH conjugation to electrophiles that is aided by glutathione S-transferase (GST), persulfides and polysulfides can directly form conjugates with electrophiles without the catalytic actions of GST. The polysulfur bonds in the conjugates are further reduced by perthioanions and polythioanions derived from RSS to form sulfhydrated metabolites that are no longer electrophilic but rather nucleophilic and differ from metabolites that are formed via GSH conjugation. FUTURE DIRECTIONS: In view of the abundance of RSS in cells and tissues, metabolism of xenobiotics that is mediated by RSS warrants additional investigations, such as studies of the impact of microbiota-derived RSS on xenobiotic metabolism. Metabolites formed from reactions between electrophiles and RSS may be potential biomarkers for monitoring exposure to electrophiles and for studying their metabolism by RSS.

  42. Reactive sulfur species omics analysis in the brain tissue of the 5xFAD mouse model of Alzheimer's disease. International-journal Peer-reviewed

    Ayaka Kinno, Shingo Kasamatsu, Takaaki Akaike, Hideshi Ihara

    Antioxidants (Basel, Switzerland)　12　(5)　2023/05/16

    DOI： 10.3390/antiox12051105 　

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    Alzheimer's disease (AD) is a progressive neurodegenerative disorder whereby oxidative stress augmentation results in mitochondrial dysfunction and cell death by apoptosis. Emerging evidence indicates that reactive sulfur species (RSS), such as glutathione hydropersulfide (GSSH), is endogenously produced, functions as potent antioxidants, and regulate redox signaling through the formation of protein polysulfides. However, the relationship between RSS and AD pathogenesis is not fully understood. In this study, we analyzed endogenous RSS production in the brain tissue of a familial AD model (5xFAD) mouse using multiple RSS-omics approaches. Memory impairment, increased amyloid plaques, and neuroinflammation have been confirmed in 5xFAD mice. Quantitative RSS omics analysis revealed that the total polysulfide content was significantly decreased in the brains of 5xFAD mice, whereas there was no significant difference in the levels of glutathione, GSSH, or hydrogen sulfide between wild-type and 5xFAD mice. In contrast, a significant decline in the protein polysulfide status was observed in the brains of 5xFAD mice, suggesting that RSS production and subsequent redox signaling might be altered during the onset and progression of AD. Our findings have important implications for understanding the significance of RSS in the development of preventive and therapeutic strategies for AD.

  43. Synthesis of sulfides and persulfides is not impeded by disruption of three canonical enzymes in sulfur metabolism. International-journal

    Qamarul Hafiz Zainol Abidin, Tomoaki Ida, Masanobu Morita, Tetsuro Matsunaga, Akira Nishimura, Minkyung Jung, Naim Hassan, Tsuyoshi Takata, Isao Ishii, Warren Kruger, Rui Wang, Hozumi Motohashi, Masato Tsutsui, Takaaki Akaike

    Antioxidants (Basel, Switzerland)　12　(4)　2023/04/03

    DOI： 10.3390/antiox12040868 　

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    Reactive sulfur species, or persulfides and polysulfides, such as cysteine hydropersulfide and glutathione persulfide, are endogenously produced in abundance in both prokaryotes and eukaryotes, including mammals. Various forms of reactive persulfides occur in both low-molecular-weight and protein-bound thiols. The chemical properties and great supply of these molecular species suggest a pivotal role for reactive persulfides/polysulfides in different cellular regulatory processes (e.g., energy metabolism and redox signaling). We demonstrated earlier that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase (CPERS) and is responsible for the in vivo production of most reactive persulfides (polysulfides). Some researchers continue to suggest that 3-mercaptopyruvate sulfurtransferase (3-MST), cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) may also produce hydrogen sulfide and persulfides that may be generated during the transfer of sulfur from 3-mercaptopyruvate to the cysteine residues of 3-MST or direct synthesis from cysteine by CBS/CSE, respectively. We thus used integrated sulfur metabolome analysis, which we recently developed, with 3-MST knockout (KO) mice and CBS/CSE/3-MST triple-KO mice, to elucidate the possible contribution of 3-MST, CBS, and CSE to the production of reactive persulfides in vivo. We therefore quantified various sulfide metabolites in organs derived from these mutant mice and their wild-type littermates via this sulfur metabolome, which clearly revealed no significant difference between mutant mice and wild-type mice in terms of reactive persulfide production. This result indicates that 3-MST, CBS, and CSE are not major sources of endogenous reactive persulfide production; rather, CARS/CPERS is the principal enzyme that is actually involved in and even primarily responsible for the biosynthesis of reactive persulfides and polysulfides in vivo in mammals.

  44. Polysulfide metabolizing enzymes influence SqrR-mediated sulfide-induced transcription by impacting intracellular polysulfide dynamics International-journal Peer-reviewed

    Takayuki Shimizu, Tomoaki Ida, Giuliano T Antelo, Yuta Ihara, Joseph N Fakhoury, Shinji Masuda, David P Giedroc, Takaaki Akaike, Daiana A Capdevila, Tatsuru Masuda

    PNAS Nexus　2　(3)　pgad048　2023/02/10

    DOI： 10.1093/pnasnexus/pgad048 　

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    Sulfide plays essential roles in controlling various physiological activities in almost all organisms. Although recent evidence has demonstrated that sulfide is endogenously generated and metabolized into polysulfides inside the cells, the relationship between polysulfide metabolism and polysulfide-sensing mechanisms is not well understood. To better define this interplay between polysulfide metabolism and sensing in cells, we investigated the role of polysulfide-metabolizing enzymes such as sulfide:quinone oxidoreductase (SQR) on the temporal dynamics of cellular polysulfide speciation and on the transcriptional regulation by the persulfide-responsive transcription factor SqrR in Rhodobacter capsulatus. We show that disruption of the sqr gene resulted in the loss of SqrR repression by exogenous sulfide at longer culture times, which impacts the speciation of intracellular polysulfides of Δsqr vs. wild-type strains. Both the attenuated response of SqrR and the change in polysulfide dynamics of the Δsqr strain is fully reversed by the addition to cells of cystine-derived polysulfides, but not by glutathione disulfide (GSSG)-derived polysulfides. Furthermore, cysteine persulfide (CysSSH) yields a higher rate of oxidation of SqrR relative to glutathione persulfide (GSSH), which leads to DNA dissociation in vitro. The oxidation of SqrR was confirmed by a mass spectrometry-based kinetic profiling strategy that showed distinct polysulfide-crosslinked products obtained with CysSSH vs. GSSH. Taken together, these results establish a novel association between the metabolism of polysulfides and the mechanisms for polysulfide sensing inside the cells.

  45. Contribution of NRF2 to sulfur metabolism and mitochondrial activity. International-journal Peer-reviewed

    Md Morshedul Alam, Akihiro Kishino, Eunkyu Sung, Hiroki Sekine, Takaaki Abe, Shohei Murakami, Takaaki Akaike, Hozumi Motohashi

    Redox Biology　60　102624-102624　2023/02/02

    DOI： 10.1016/j.redox.2023.102624 　

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    NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation.

  46. Echinochrome prevents sulfide catabolism-associated chronic heart failure after myocardial infarction in mice. International-journal Peer-reviewed

    Xiaokang Tang, Akiyuki Nishimura, Kohei Ariyoshi, Kazuhiro Nishiyama, Yuri Kato, Elena A Vasileva, Natalia P Mishchenko, Sergey A Fedoreyev, Valentin A Stonik, Hyoung-Kyu Kim, Jin Han, Yasunari Kanda, Keitaro Umezawa, Yasuteru Urano, Takaaki Akaike, Motohiro Nishida

    Marine drugs　21　(1)　2023/01/12

    DOI： 10.3390/md21010052 　

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    Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

  47. Cysteine hydropersulfide reduces lipid peroxidation and protects against myocardial ischaemia-reperfusion injury - Are endogenous persulfides mediators of ischaemic preconditioning? International-journal Peer-reviewed

    Kayleigh Griffiths, Tomoaki Ida, Masanobu Morita, Reece J Lamb, Jordan J Lee, Michael P Frenneaux, Jon M Fukuto, Takaaki Akaike, Martin Feelisch, Melanie Madhani

    Redox Biology　60　102605-102605　2023/01/10

    DOI： 10.1016/j.redox.2023.102605 　

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    Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and oxidant properties, modulates redox-dependent signal transduction and has been shown to mitigate oxidative stress. However, its functional relevance in the setting of myocardial ischaemia-reperfusion injury (IRI) remains unknown. The present study was undertaken to (1) study the dynamics of production and consumption of persulfides under normoxic and hypoxic conditions in the heart, and (2) determine whether exogenous administration of the CysSSH donor, cysteine trisulfide (Cys-SSS-Cys) at the onset of reperfusion rescues functional impairment and myocardial damage by interfering with lipid peroxidation. Utilising a well-established ex vivo Langendorff murine model, we here demonstrate that endogenous tissue concentrations of CysSSH are upregulated when oxygen supply is compromised (global myocardial ischaemia) and rapidly restored to baseline levels upon reperfusion, suggestive of active regulation. In a separate set of experiments, exogenous administration of Cys-SSS-Cys for 10 min at the onset of reperfusion was found to decrease malondialdehyde (MDA) concentrations, formation of 4-hydroxynonenal (4-HNE) protein adducts and rescue the heart from injury. Cys-SSS-Cys also restored post-ischaemic cardiac function, improving both coronary flow and left ventricular developed pressure (LVDP). Taken together, these results support the notion that endogenous CysSSH plays an important role as a "redox preconditioning" agent to combat the oxidative insult in myocardial IRI.

  48. A persulfide shield

    Hisyam Abdul Hamid, Tsuyoshi Takata, Tetsuro Matsunaga, Takaaki Akaike

    Sulfurtransferases　101-117　2023

    Publisher: Elsevier

    DOI： 10.1016/b978-0-443-18827-5.00001-7 　

  49. 8-Nitro-cGMP suppresses mineralization by mouse osteoblasts. Peer-reviewed

    Kotaro Kaneko, Yoichi Miyamoto, Tomoaki Ida, Masanobu Morita, Kentaro Yoshimura, Kei Nagasaki, Kazuki Toba, Risa Sugisaki, Hozumi Motohashi, Takaaki Akaike, Daichi Chikazu, Ryutaro Kamijo

    Journal of Clinical Biochemistry and Nutrition　71　(3)　191-197　2022/11

    DOI： 10.3164/jcbn.21-129 　

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    Nitric oxide and reactive oxygen species regulate bone remodeling, which occurs via bone formation and resorption by osteoblasts and osteoclasts, respectively. Recently, we found that 8-nitro-cGMP, a second messenger of nitric oxide and reactive oxygen species, promotes osteoclastogenesis. Here, we investigated the formation and function of 8-nitro-cGMP in osteoblasts. Mouse calvarial osteoblasts were found to produce 8-nitro-cGMP, which was augmented by tumor necrosis factor-α (10 ng/ml) and interleukin-1β (1 ng/ml). These cytokines suppressed osteoblastic differentiation in a NO synthase activity-dependent manner. Exogenous 8-nitro-cGMP (30 μmol/L) suppressed expression of osteoblastic phenotypes, including mineralization, in clear contrast to the enhancement of mineralization by osteoblasts induced by 8-bromo-cGMP, a cell membrane-permeable analog of cGMP. It is known that reactive sulfur species denitrates and degrades 8-nitro-cGMP. Mitochondrial cysteinyl-tRNA synthetase plays a crucial role in the endogenous production of RSS. The expression of osteoblastic phenotypes was suppressed by not only exogenous 8-nitro-cGMP but also by silencing of the Cars2 gene, indicating a role of endogenous 8-nitro-cGMP in suppressing the expression of osteoblastic phenotypes. These results suggest that 8-nitro-cGMP is a negative regulator of osteoblastic differentiation.

  50. Cystine-dependent antiporters buffer against excess intracellular reactive sulfur species-induced stress. International-journal Peer-reviewed

    Masahiro Akiyama, Takamitsu Unoki, Hanako Aoki, Akiyuki Nishimura, Yasuhiro Shinkai, Eiji Warabi, Kazuhiro Nishiyama, Yuka Furumoto, Naohiko Anzai, Takaaki Akaike, Motohiro Nishida, Yoshito Kumagai

    Redox Biology　57　102514-102514　2022/10/17

    DOI： 10.1016/j.redox.2022.102514 　

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    Reactive sulfur species (RSS) play a role in redox homeostasis; however, adaptive cell responses to excessive intracellular RSS are not well understood. Therefore, in this study, we generated transgenic (Tg) mice overexpressing cystathionine gamma-lyase (CSE) to produce excessive RSS. Contrary to expectations, tissue concentrations of RSS, such as cysteine persulfide (CysSSH), were comparable in both wild-type and CSE Tg mice, but the plasma concentrations of CysSSH were significantly higher in CSE Tg mice than in wild-type mice. This export of surplus intracellular RSS was also observed in primary hepatocytes of CSE Tg mice. Exposure of primary hepatocytes to the RSS generator sodium tetrasulfide (Na2S4) resulted in an initial increase in the intracellular concentration of RSS, which later returned to basal levels after export into the extracellular space. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during Na2S4 exposure, suggesting that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout and overexpression of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by Na2S4 exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity. These results suggest the presence of a cellular response to excess intracellular RSS that involves the extracellular efflux of excess CysSSH by a cystine-dependent transporter to maintain intracellular redox homeostasis.

  51. Development of an anti-oxidative intraocular irrigating solution based on reactive persulfides. International-journal Peer-reviewed

    Hiroshi Kunikata, Hiroshi Tawarayama, Satoru Tsuda, Takaaki Akaike, Toru Nakazawa

    Scientific reports　12　(1)　19243-19243　2022/10

    DOI： 10.1038/s41598-022-21677-4 　

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    Anti-oxidative intraocular irrigating solutions (IISs) based on reactive persulfides, such as oxidized glutathione disulfide (GSSG), are commonly used worldwide. However, even with GSSG-based IISs, it has been shown that oxidative stress can occur during surgery, posing a risk to intraocular tissues. This study compared two IISs: one containing GSSG and one containing an oxidized glutathione trisulfide (GSSSG). Experimental in vivo irrigation with the IISs in rabbits showed that there was less leakage into the anterior chamber of rabbit serum albumin during perfusion with a 300-μM GSSSG IIS than with a 300-μM GSSG IIS. Experimental in vivo cataract surgery in rabbits showed that aqueous flare was suppressed 3 days after surgery with a 600-μM GSSSG IIS, but not with a 300-μM GSSSG or 300-μM GSSG IIS. Furthermore, an in vitro experiment, without any live tissue, showed that reactive oxygen species were suppressed more strongly with a 600-μM GSSSG IIS than with a 300-μM GSSG IIS. Thus, this study found that novel IISs based on GSSSG had anti-inflammatory and anti-oxidative effects during and after intraocular surgery and may decrease the rate of complications after surgery.

  52. Coupled discrete phase model and Eulerian wall film model for numerical simulation of respiratory droplet generation during coughing International-journal Peer-reviewed

    Hitomi Anzai, Yugo Shindo, Yutaro Kohata, Masahiro Hasegawa, Hidemasa Takana, Tetsuro Matsunaga, Takaaki Akaike, Makoto Ohta

    Scientific Reports　12　(1)　14849-14849　2022/09/01

    DOI： 10.1038/s41598-022-18788-3 　

    eISSN： 2045-2322

  53. Shining a light on SSP4: A comprehensive analysis and biological applications for the detection of sulfane sulfurs. International-journal Peer-reviewed

    Meg Shieh, Xiang Ni, Shi Xu, Stephen P Lindahl, Moua Yang, Tetsuro Matsunaga, Robert Flaumenhaft, Takaaki Akaike, Ming Xian

    Redox Biology　56　102433-102433　2022/08/09

    DOI： 10.1016/j.redox.2022.102433 　

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    Fluorescent probes are useful tools for the detection of sulfane sulfurs in biological systems. In this work, we report the development of SSP4, a widely used probe generated in our laboratory. We describe its evolution, preparation, and physical/chemical properties. Fluorescence analyses of SSP4 determined its high selectivity and sensitivity to sulfane sulfurs, even with the interfering presence of other species, such as amino acids and metal ions. Protocols for using SSP4 in a relatively quick and simple manner for the detection of persulfidated proteins, including papain, BSA, and GAPDH were developed. The method was then applied to human protein disulfide isomerase (PDI), leading to the discovery that persulfidation can occur at PDI's non-active site cysteines, and that PDI reductase activity is affected by sulfane sulfur treatment. Protocols for using SSP4 for the bioimaging of exogenous and endogenous sulfane sulfurs in different -cell lines were also established. These results should guide further applications of SSP4.

  54. Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection. International-journal

    Hiroyasu Tsutsuki, Tianli Zhang, Kinnosuke Yahiro, Katsuhiko Ono, Yukio Fujiwara, Sunao Iyoda, Fan-Yan Wei, Kazuaki Monde, Kazuko Seto, Makoto Ohnishi, Hiroyuki Oshiumi, Takaaki Akaike, Tomohiro Sawa

    iScience　25　(4)　104050-104050　2022/04/15

    DOI： 10.1016/j.isci.2022.104050 　

    eISSN： 2589-0042

  55. Regulation of nitric oxide/reactive oxygen species redox signaling by nNOS splicing variants. International-journal

    Shingo Kasamatsu, Hiroyasu Tsutsuki, Tomoaki Ida, Tomohiro Sawa, Yasuo Watanabe, Takaaki Akaike, Hideshi Ihara

    Nitric oxide : biology and chemistry　120　44-52　2022/03/01

    DOI： 10.1016/j.niox.2022.01.004 　

    ISSN： 1089-8603

    eISSN： 1089-8611

  56. What triggers inflammation in COVID-19? International-journal

    Tomohiro Sawa, Takaaki Akaike

    eLife　11　2022/01/20

    DOI： 10.7554/eLife.76231 　

    eISSN： 2050-084X

  57. Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression. International-journal

    Kazuhiro Nishiyama, Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Yuri Kato, Takahiro Shibata, Hiroshi Tanaka, Hitoshi Kurose, Yasu-Taka Azuma, Hideshi Ihara, Yoshito Kumagai, Takaaki Akaike, Philip Eaton, Koji Uchida, Motohiro Nishida

    Science Signaling　15　(716)　eabj0644　2022/01/11

    DOI： 10.1126/scisignal.abj0644 　

    ISSN： 1945-0877

    eISSN： 1937-9145

  58. Virucidal effect of monogalactosyl diacylglyceride from a green microalga, Coccomyxa sp. KJ, against clinical isolates of SARS-CoV-2 as assessed by a plaque assay. International-journal

    Kyoko Hayashi, Satomi Asai, Kazuo Umezawa, Hidehumi Kakizoe, Hayato Miyachi, Masanobu Morita, Takaaki Akaike, Hitoshi Kuno, Satoko Komatsu, Takumi Watanabe, Toshio Kawahara

    Journal of Clinical Laboratory Analysis　36　(1)　e24146　2022/01

    DOI： 10.1002/jcla.24146 　

    ISSN： 0887-8013

    eISSN： 1098-2825

  59. GRIM-19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation. International-journal

    Tomomi Kurane, Tetsuro Matsunaga, Tomoaki Ida, Kazuko Sawada, Akira Nishimura, Masayuki Fukui, Masayuki Umemura, Masaaki Nakayama, Naoya Ohara, Sohkichi Matsumoto, Takaaki Akaike, Goro Matsuzaki, Giichi Takaesu

    FASEB Journal　36　(1)　e22096　2022/01

    DOI： 10.1096/fj.202101074RR 　

    ISSN： 0892-6638

    eISSN： 1530-6860

  60. Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation. International-journal

    Katalin Erdélyi, Tamás Ditrói, Henrik J Johansson, Ágnes Czikora, Noémi Balog, Laxmi Silwal-Pandit, Tomoaki Ida, Judit Olasz, Dorottya Hajdú, Zoltán Mátrai, Orsolya Csuka, Koji Uchida, József Tóvári, Olav Engebraten, Takaaki Akaike, Anne-Lise Børresen Dale, Miklós Kásler, Janne Lehtiö, Péter Nagy

    Proceedings of the National Academy of Sciences of the United States of America　118　(45)　2021/11/09

    DOI： 10.1073/pnas.2100050118 　

    ISSN： 0027-8424

    eISSN： 1091-6490

  61. Methods in sulfide and persulfide research. International-journal

    Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Tomoaki Ida, Masanobu Morita, Hozumi Motohashi, Xinggui Shen, Christopher G Kevil, Jon M Fukuto, Takaaki Akaike

    Nitric Oxide : Biology and Chemistry　116　47-64　2021/11/01

    DOI： 10.1016/j.niox.2021.09.002 　

    ISSN： 1089-8603

    eISSN： 1089-8611

  62. Chemical biology of reactive sulfur species: Hydrolysis-driven equilibrium of polysulfides as a determinant of physiological functions. International-journal

    Tomohiro Sawa, Tsuyoshi Takata, Tetsuro Matsunaga, Hideshi Ihara, Hozumi Motohashi, Takaaki Akaike

    Antioxidants & Redox Signaling　36　(4-6)　327-336　2021/08/19

    DOI： 10.1089/ars.2021.0170 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  63. Corrigendum to ‟On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity" [Redox Biol. 41 (2021) 101926]. International-journal

    Kazufumi Honda, Takako Hishiki, Sohei Yamamoto, Takehiro Yamamoto, Nami Miura, Akiko Kubo, Mai Itoh, Wei-Yu Chen, Masashi Takano, Tomoyuki Yoshikawa, Takahiro Kasamatsu, Shinichiro Sonoda, Hirotoshi Yoshizawa, Seigo Nakamura, Yuichiro Itai, Megumi Shiota, Daisuke Koike, Masayuki Naya, Noriyo Hayakawa, Yoshiko Naito, Tomomi Matsuura, Keiko Iwaisako, Toshihiko Masui, Shinji Uemoto, Kengo Nagashima, Yoshinori Hashimoto, Tomohiro Sakuma, Osamu Matsubara, Wilber Huang, Tomoaki Ida, Takaaki Akaike, Yohei Masugi, Michiie Sakamoto, Tomoyasu Kato, Yoshinori Ino, Hiroshi Yoshida, Hitoshi Tsuda, Nobuyoshi Hiraoka, Yasuaki Kabe, Makoto Suematsu

    Redox Biology　44　102028-102028　2021/08

    DOI： 10.1016/j.redox.2021.102028 　

    ISSN： 2213-2317

  64. Sulfide catabolism ameliorates hypoxic brain injury. International-journal

    Eizo Marutani, Masanobu Morita, Shuichi Hirai, Shinichi Kai, Robert M H Grange, Yusuke Miyazaki, Fumiaki Nagashima, Lisa Traeger, Aurora Magliocca, Tomoaki Ida, Tetsuro Matsunaga, Daniel R Flicker, Benjamin Corman, Naohiro Mori, Yumiko Yamazaki, Annabelle Batten, Rebecca Li, Tomohiro Tanaka, Takamitsu Ikeda, Akito Nakagawa, Dmitriy N Atochin, Hideshi Ihara, Benjamin A Olenchock, Xinggui Shen, Motohiro Nishida, Kenjiro Hanaoka, Christopher G Kevil, Ming Xian, Donald B Bloch, Takaaki Akaike, Allyson G Hindle, Hozumi Motohashi, Fumito Ichinose

    Nature Communications　12　(1)　3108-3108　2021/05/25

    DOI： 10.1038/s41467-021-23363-x 　

    eISSN： 2041-1723

  65. Cysteine hydropersulfide inactivates β-lactam antibiotics with formation of ring-opened carbothioic S-acids in bacteria. International-journal

    Katsuhiko Ono, Yusuke Kitamura, Tianli Zhang, Hiroyasu Tsutsuki, Azizur Rahman, Toshihiro Ihara, Takaaki Akaike, Tomohiro Sawa

    ACS chemical Biology　16　(4)　731-739　2021/04/16

    DOI： 10.1021/acschembio.1c00027 　

    ISSN： 1554-8929

    eISSN： 1554-8937

  66. Comment on "Evidence that the ProPerDP method is inadequate for protein persulfidation detection due to lack of specificity". International-journal

    Éva Dóka, Elias S J Arnér, Edward E Schmidt, Tobias P Dick, Albert van der Vliet, Jing Yang, Réka Szatmári, Tamás Ditrói, John L Wallace, Giuseppe Cirino, Kenneth Olson, Hozumi Motohashi, Jon M Fukuto, Michael D Pluth, Martin Feelisch, Takaaki Akaike, David A Wink, Louis J Ignarro, Péter Nagy

    Science Advances　7　(17)　2021/04

    DOI： 10.1126/sciadv.abe7006 　

    eISSN： 2375-2548

  67. ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation. International-journal

    Tianli Zhang, Hiroyasu Tsutsuki, Waliul Islam, Katsuhiko Ono, Kohsuke Takeda, Takaaki Akaike, Tomohiro Sawa

    Redox Biology　41　101930-101930　2021/03/10

    DOI： 10.1016/j.redox.2021.101930 　

    ISSN： 2213-2317

  68. On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity. International-journal

    Kazufumi Honda, Takako Hishiki, Sohei Yamamoto, Takehiro Yamamoto, Nami Miura, Akiko Kubo, Mai Itoh, Wei-Yu Chen, Masashi Takano, Tomoyuki Yoshikawa, Takahiro Kasamatsu, Shinichiro Sonoda, Hirotoshi Yoshizawa, Seigo Nakamura, Yuichiro Itai, Megumi Shiota, Daisuke Koike, Masayuki Naya, Noriyo Hayakawa, Yoshiko Naito, Tomomi Matsuura, Keiko Iwaisako, Toshihiko Masui, Shinji Uemoto, Kengo Nagashima, Yoshinori Hashimoto, Tomohiro Sakuma, Osamu Matsubara, Wilber Huang, Tomoaki Ida, Takaaki Akaike, Yohei Masugi, Michiie Sakamoto, Tomoyasu Kato, Yoshinori Ino, Hiroshi Yoshida, Hitoshi Tsuda, Nobuyoshi Hiraoka, Yasuaki Kabe, Makoto Suematsu

    Redox Biology　41　101926-101926　2021/03/02

    DOI： 10.1016/j.redox.2021.101926 　

    ISSN： 2213-2317

  69. Loss of cell wall integrity genes cpxA and mrcB causes flocculation in Escherichia coli. International-journal

    Keita Sugawara, Hayato Toyoda, Mami Kimura, Shunsuke Hayasaka, Hiromi Saito, Hiroshi Kobayashi, Kunio Ihara, Tomoaki Ida, Takaaki Akaike, Eiji Ando, Mamoru Hyodo, Yoshihiro Hayakawa, Shin Hamamoto, Nobuyuki Uozumi

    The Biochemical Journal　478　(1)　41-59　2021/01/15

    DOI： 10.1042/BCJ20200723 　

    ISSN： 0264-6021

    eISSN： 1470-8728

  70. High-Precision Sulfur Metabolomics Innovated by a New Specific Probe for Trapping Reactive Sulfur Species. International-journal

    Shingo Kasamatsu, Tomoaki Ida, Taisei Koga, Kosho Asada, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike

    Antioxidants & Redox Signaling　34　(18)　1407-1419　2021/01/04

    DOI： 10.1089/ars.2020.8073 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  71. Antioxidative and anti-inflammatory actions of reactive cysteine persulfides.

    Tianli Zhang, Hiroyasu Tsutsuki, Katushiko Ono, Takaaki Akaike, Tomohiro Sawa

    Journal of Clinical Biochemistry and Nutrition　68　(1)　5-8　2021/01

    DOI： 10.3164/jcbn.20-13 　

    ISSN： 0912-0009

  72. Measuring Reactive Sulfur Species and Thiol Oxidation States: Challenges and Cautions in Relation to Alkylation-Based Protocols. International-journal Peer-reviewed

    Péter Nagy, Éva Dóka, Tomoaki Ida, Takaaki Akaike

    Antioxidants & Redox Signaling　33　(16)　1174-1189　2020/12/01

    DOI： 10.1089/ars.2020.8077 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  73. Glutathione Trisulfide Prevents Lipopolysaccharide-induced Inflammatory Gene Expression in Retinal Pigment Epithelial Cells. International-journal

    Hiroshi Tawarayama, Noriyuki Suzuki, Maki Inoue-Yanagimachi, Noriko Himori, Satoru Tsuda, Kota Sato, Tomoaki Ida, Takaaki Akaike, Hiroshi Kunikata, Toru Nakazawa

    Ocular immunology and inflammation　1-12　2020/11/20

    DOI： 10.1080/09273948.2020.1833224 　

    More details Close

    We investigated the effects of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammatory gene expression in immortalized ARPE-19, and primary human and mouse retinal pigment epithelial (RPE) cells. Sulfane sulfur molecules were significantly increased in GSSSG-treated ARPE-19 cells. GSSSG prevented the LPS-induced upregulation of interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 2 (CCL2) in ARPE-19/primary RPE cells. Moreover, GSSSG prevented the activation of the nuclear factor-kappa B p65 subunit, and promoted the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LPS-treated ARPE-19 cells. ERK1/2 inhibition prevented the GSSSG-mediated inhibition of LPS-induced IL-6 and CCL2 upregulation. Additionally, ERK1/2 activation prevented the upregulation of these genes in the absence of GSSSG. Knockdown of HMOX1 or NRF2, known as anti-oxidative genes, did not affect the activity of GSSSG in the context of LPS stimulation. These findings suggest that GSSSG attenuates LPS-induced inflammatory gene expression via ERK signaling hyperactivation, independently of the NRF2/HMOX1 pathway.

  74. Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides. International-journal

    Tomohiro Sawa, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike

    Biomolecules　10　(9)　1-13　2020/08/27

    DOI： 10.3390/biom10091245 　

    eISSN： 2218-273X

  75. Erratum: Environmental electrophile-mediated toxicity in mice lacking nrf2, CSE, or both (Environ Health Perspect, (2019) 127, 6, 10.1289/EHP4949)

    Masahiro Akiyama, Takamitsu Unoki, Yasuhiro Shinkai, Isao Ishii, Tomoaki Ida, Takaaki Akaike, Masayuki Yamamoto, Yoshito Kumagai

    Environmental Health Perspectives　128　(6)　1　2020/06

    DOI： 10.1289/EHP7480 　

    ISSN： 0091-6765

    eISSN： 1552-9924

  76. 8-Nitro-cGMP modulates exocytosis in adrenal chromaffin cells. International-journal Peer-reviewed

    Hiroyasu Tsutsuki, Shingo Kasamatsu, Kohei Kunieda, Tomoaki Ida, Tomohiro Sawa, Nobuyuki Sasakawa, Takaaki Akaike, Hideshi Ihara

    Biochemical and biophysical research communications　526　(1)　225-230　2020/05/21

    DOI： 10.1016/j.bbrc.2020.03.045 　

    More details Close

    Nitric oxide (NO)-mediated production of cyclic guanosine 3',5'-monophosphate (cGMP) is a crucial signaling pathway that controls a wide array of neuronal functions, including exocytotic neurotransmitter release. A novel nitrated derivative of cGMP, 8-nitro-cGMP, not only activates cGMP-dependent protein kinase (PKG), but also has membrane permeability and redox activity to produce superoxide and S-guanylated protein. To date, no studies have addressed the effects of 8-nitro-cGMP on exocytotic kinetics. Here, we aimed to assess the 8-nitro-cGMP-mediated modulation of the depolarization-evoked catecholamine release from bovine chromaffin cells. 8-Nitro-cGMP was produced in bovine chromaffin cells dependent on NO donor. Amperometric analysis revealed that 8-nitro-cGMP modulated the kinetic parameters of secretory spikes from chromaffin cells, particularly decreased the speed of individual spikes, resulting in a reduced amperometric spike height, slope β, and absolute value of slope γ. The modulatory effects were independent of the PKG signal and superoxide production. This is the first study to demonstrate that 8-nitro-cGMP modulates exocytosis and provide insights into a novel regulatory mechanism of exocytosis.

  77. Control of protein function through oxidation and reduction of persulfidated states International-journal Peer-reviewed

    Dóka, T. Ida, M. Dagnell, Y. Abiko, N. C. Luong, N. Balog, T. Takata, B. Espinosa, A. Nishimura, Q. Cheng, Y. Funato, H. Miki, J. M. Fukuto, J. R. Prigge, E. E. Schmidt, E. S.J. Arnér, Y. Kumagai, T. Akaike, P. Nagy

    Science Advances　6　(1)　eaax8358　2020/01/01

    DOI： 10.1126/sciadv.aax8358 　

    eISSN： 2375-2548

  78. Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling

    Martin Feelisch, Takaaki Akaike, Kayleigh Griffiths, Tomoaki Ida, Oleksandra Prysyazhna, Joanna J. Goodwin, Nicholas D. Gollop, Bernadette O. Fernandez, Magdalena Minnion, Miriam M. Cortese-Krott, Alessandra Borgognone, Rosie M. Hayes, Philip Eaton, Michael P. Frenneaux, Melanie Madhani

    Cardiovascular Research　116　(1)　51-62　2020/01/01

    Publisher: Oxford University Press ({OUP})

    DOI： 10.1093/cvr/cvz202 　

    ISSN： 0008-6363

    eISSN： 1755-3245

  79. AUTACs: Cargo-Specific Degraders Using Selective Autophagy. International-journal Peer-reviewed

    Daiki Takahashi, Jun Moriyama, Tomoe Nakamura, Erika Miki, Eriko Takahashi, Ayami Sato, Takaaki Akaike, Kaori Itto-Nakama, Hirokazu Arimoto

    Molecular cell　76　(5)　797-810　2019/12/05

    DOI： 10.1016/j.molcel.2019.09.009 　

    ISSN： 1097-2765

    eISSN： 1097-4164

  80. Rational Design of a Dual-Reactivity-Based Fluorescent Probe for Visualizing Intracellular HSNO. International-journal Peer-reviewed

    Wei Chen, Tetsuro Matsunaga, Deshka L Neill, Chun-Tao Yang, Takaaki Akaike, Ming Xian

    Angewandte Chemie (International ed. in English)　58　(45)　16067-16070　2019/11/04

    Publisher: Wiley

    DOI： 10.1002/anie.201908950 　

    ISSN： 1433-7851

    eISSN： 1521-3773

  81. Nitrosative stress in patients with asthma–chronic obstructive pulmonary disease overlap Peer-reviewed

    Yorihiko Kyogoku, Hisatoshi Sugiura, Tomohiro Ichikawa, Tadahisa Numakura, Akira Koarai, Mitsuhiro Yamada, Naoya Fujino, Yutaka Tojo, Katsuhiro Onodera, Rie Tanaka, Kei Sato, Hirohito Sano, Shun Yamanaka, Koji Itakura, Ayumi Mitsune, Tsutomu Tamada, Takaaki Akaike, Masakazu Ichinose

    Journal of Allergy and Clinical Immunology　144　(4)　972-983.e14　2019/10

    DOI： 10.1016/j.jaci.2019.04.023 　

    ISSN： 0091-6749

    eISSN： 1097-6825

  82. Data-Driven Identification of Hydrogen Sulfide Scavengers Peer-reviewed

    Chun tao Yang, Yingying Wang, Eizo Marutani, Tomoaki Ida, Xiang Ni, Shi Xu, Wei Chen, Hui Zhang, Takaaki Akaike, Fumito Ichinose, Ming Xian

    Angewandte Chemie - International Edition　58　(32)　10898-10902　2019/08/05

    Publisher: Wiley

    DOI： 10.1002/anie.201905580 　

    ISSN： 1433-7851

    eISSN： 1521-3773

  83. Titelbild: Data‐Driven Identification of Hydrogen Sulfide Scavengers (Angew. Chem. 32/2019) Peer-reviewed

    Chun-tao Yang, Yingying Wang, Eizo Marutani, Tomoaki Ida, Xiang Ni, Shi Xu, Wei Chen, Hui Zhang, Takaaki Akaike, Fumito Ichinose, Ming Xian

    Angewandte Chemie　131　(32)　10877　2019/08

    Publisher: Wiley

    DOI： 10.1002/ange.201908294 　

  84. Environmental electrophile-mediated toxicity in mice lacking Nrf2, CSE, or both Peer-reviewed

    Masahiro Akiyama, Takamitsu Unoki, Yasuhiro Shinkai, Isao Ishii, Tomoaki Ida, Takaaki Akaike, Masayuki Yamamoto, Yoshito Kumagai

    Environmental Health Perspectives　127　(6)　67002　2019/06

    DOI： 10.1289/EHP4949 　

    ISSN： 0091-6765

    eISSN： 1552-9924

  85. Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension. Peer-reviewed

    Rudyk O, Rowan A, Prysyazhna O, Krasemann S, Hartmann K, Zhang M, Shah AM, Ruppert C, Weiss A, Schermuly RT, Ida T, Akaike T, Zhao L, Eaton P

    Proceedings of the National Academy of Sciences of the United States of America　116　(26)　13016-13025　2019/06

    DOI： 10.1073/pnas.1904064116 　

    ISSN： 0027-8424

    eISSN： 1091-6490

  86. Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock Peer-reviewed

    Tianli Zhang, Katsuhiko Ono, Hiroyasu Tsutsuki, Hideshi Ihara, Waliul Islam, Takaaki Akaike, Tomohiro Sawa

    Cell Chemical Biology　26　(5)　686-698.e4　2019/05/16

    DOI： 10.1016/j.chembiol.2019.02.003 　

    ISSN： 2451-9456

    eISSN： 2451-9448

  87. The active-site cysteine residue of Ca 2+ /calmodulin-dependent protein kinase I is protected from irreversible modification via generation of polysulfidation Peer-reviewed

    Tsuyoshi Takata, Ayaka Tsukuda, Yukihiro Tsuchiya, Takaaki Akaike, Yasuo Watanabe

    Nitric Oxide - Biology and Chemistry　86　68-75　2019/05/01

    DOI： 10.1016/j.niox.2019.02.008 　

    ISSN： 1089-8603

    eISSN： 1089-8611

  88. Distribution of Polysulfide in Human Biological Fluids and Their Association with Amylase and Sperm Activities. International-journal Peer-reviewed

    Mayumi Ikeda, Yu Ishima, Victor T G Chuang, Maki Sakai, Hiroki Osafune, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Hiroshi Watanabe, Toru Maruyama, Masaki Otagiri, Takaaki Akaike, Tatsuhiro Ishida

    Molecules (Basel, Switzerland)　24　(9)　2019/04/30

    DOI： 10.3390/molecules24091689 　

    More details Close

    Intracellular polysulfide could regulate the redox balance via its anti-oxidant activity. However, the existence of polysulfide in biological fluids still remains unknown. Recently, we developed a quantitative analytical method for polysulfide and discovered that polysulfide exists in plasma and responds to oxidative stress. In this study, we confirmed the presence of polysulfide in other biological fluids, such as semen and nasal discharge. The levels of polysulfide in these biological fluids from healthy volunteers (n = 9) with identical characteristics were compared. Additionally, the circadian rhythm of plasma polysulfide was also investigated. The polysulfide levels detected from nasal discharge and seminal fluid were approximately 400 and 600 μM, respectively. No correlation could be found between plasma polysulfide and the polysulfide levels of tear, saliva, and nasal discharge. On the other hand, seminal polysulfide was positively correlated with plasma polysulfide, and almost all polysulfide contained in semen was found in seminal fluid. Intriguingly, saliva and seminal polysulfide strongly correlated with salivary amylase and sperm activities, respectively. These results provide a foundation for scientific breakthroughs in various research areas like infertility and the digestive system process.

  89. 8-Nitro-cGMP attenuates context-dependent fear memory in mice Peer-reviewed

    Yusuke Kishimoto, Shingo Kasamatsu, Shuichi Yanai, Shogo Endo, Takaaki Akaike, Hideshi Ihara

    Biochemical and Biophysical Research Communications　511　(1)　141-147　2019/03/26

    Publisher: Elsevier {BV}

    DOI： 10.1016/j.bbrc.2019.01.138 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  90. The Uptake and Release of Polysulfur Cysteine Species by Cells: Physiological and Toxicological Implications Peer-reviewed

    Joseph Lin, Masahiro Akiyama, Iris Bica, Faith T. Long, Catherine F. Henderson, Robert N. Goddu, Valeria Suarez, Blaine Baker, Tomoaki Ida, Yasuhiro Shinkai, Peter Nagy, Takaaki Akaike, Jon M. Fukuto, Yoshito Kumagai

    Chemical Research in Toxicology　32　(3)　447-455　2019/03/18

    DOI： 10.1021/acs.chemrestox.8b00340 　

    ISSN： 0893-228X

    eISSN： 1520-5010

  91. Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells

    Shigemoto Fujii, Tomohiro Sawa, Hozumi Motohashi, Takaaki Akaike

    British Journal of Pharmacology　176　(4)　607-615　2019/02

    Publisher: Wiley

    DOI： 10.1111/bph.14356 　

    ISSN： 0007-1188

    eISSN： 1476-5381

  92. The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems Peer-reviewed

    Christopher L. Bianco, Takaaki Akaike, Tomoaki Ida, Peter Nagy, Virag Bogdandi, John P. Toscano, Yoshito Kumagai, Catherine F. Henderson, Robert N. Goddu, Joseph Lin, Jon M. Fukuto

    British Journal of Pharmacology　176　(4)　671-683　2019/02

    DOI： 10.1111/bph.14372 　

    ISSN： 0007-1188

    eISSN： 1476-5381

  93. Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell? Peer-reviewed

    Virág Bogdándi, Tomoaki Ida, Thomas R. Sutton, Christopher Bianco, Tamás Ditrói, Grielof Koster, Hillary A. Henthorn, Magda Minnion, John P. Toscano, Albert van der Vliet, Michael D. Pluth, Martin Feelisch, Jon M. Fukuto, Takaaki Akaike, Péter Nagy

    British Journal of Pharmacology　176　(4)　646-670　2019/02

    DOI： 10.1111/bph.14394 　

    ISSN： 0007-1188

    eISSN： 1476-5381

  94. Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis Peer-reviewed

    Hisyam Abdul Hamid, Akira Tanaka, Tomoaki Ida, Akira Nishimura, Tetsuro Matsunaga, Shigemoto Fujii, Masanobu Morita, Tomohiro Sawa, Jon M. Fukuto, Péter Nagy, Ryouhei Tsutsumi, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike

    Redox Biology　21　101096　2019/02

    DOI： 10.1016/j.redox.2019.101096 　

    ISSN： 2213-2317

  95. Production of 8-nitro-cGMP in osteocytic cells and its upregulation by parathyroid hormone and prostaglandin E <inf>2</inf> Peer-reviewed

    Kazuhiro Nagayama, Yoichi Miyamoto, Kotaro Kaneko, Kentaro Yoshimura, Kiyohito Sasa, Takaaki Akaike, Shigemoto Fujii, Eri Izumida, Risa Uyama, Daichi Chikazu, Koutaro Maki, Ryutaro Kamijo

    In Vitro Cellular and Developmental Biology - Animal　55　(1)　45-51　2019/01/15

    DOI： 10.1007/s11626-018-0304-0 　

    ISSN： 1071-2690

  96. SNAP-25 S-guanylation and SNARE complex formation Peer-reviewed

    Yusuke Kishimoto, Takaaki Akaike, Hideshi Ihara

    Methods in Molecular Biology　1860　163-173　2019

    DOI： 10.1007/978-1-4939-8760-3_9 　

    ISSN： 1064-3745

  97. Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload 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

    DOI： 10.1126/scisignal.aaw1920 　

    ISSN： 1945-0877

    eISSN： 1937-9145

  98. Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells Peer-reviewed

    Akira Nishimura, Ryo Nasuno, Yuki Yoshikawa, Minkyung Jung, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hiroshi Takagi, Hozumi Motohashi, Takaaki Akaike

    Journal of Biological Chemistry　294　(37)　13781-13788　2019

    Publisher: American Society for Biochemistry {\&} Molecular Biology ({ASBMB})

    DOI： 10.1074/jbc.RA119.009203 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  99. Mitochondria-specific SQR deficiency in mice causes lethal impairment of sulfur respiration Peer-reviewed

    Morita Masanobu, Ida Tomoaki, Tanaka Tomohiro, Matsunaga Tetsuro, Nishimura Akira, Fujii Shigemoto, Nishida Motohiro, Motohashi Hozumi, Akaike Takaaki

    FREE RADICAL BIOLOGY AND MEDICINE　128　S90-S90　2018/11/20

    DOI： 10.1016/j.freeradbiomed.2018.10.209 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  100. Emerging role of glutathione in the activation of NLRP3 inflammasome Peer-reviewed

    Zhang Tianli, Tsutsuki Hiroyasu, Ono Katsuhiko, Akaike Takaaki, Sawa Tomohiro

    FREE RADICAL BIOLOGY AND MEDICINE　128　S114　2018/11/20

    DOI： 10.1016/j.freeradbiomed.2018.10.278 　

    ISSN： 0891-5849

  101. Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling Peer-reviewed

    Shahzada Khan, Shigemoto Fujii, Tetsuro Matsunaga, Akira Nishimura, Katsuhiko Ono, Tomoaki Ida, Khandaker Ahtesham Ahmed, Tatsuya Okamoto, Hiroyasu Tsutsuki, Tomohiro Sawa, Takaaki Akaike

    Cell Chemical Biology　25　(11)　1403-1413.e4　2018/11/15

    DOI： 10.1016/j.chembiol.2018.08.007 　

    ISSN： 2451-9456

    eISSN： 2451-9448

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

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    Science signaling　11　(556)　2018/11/13

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  104. Biological hydropersulfides and related polysulfides – a new concept and perspective in redox biology Peer-reviewed

    Jon M. Fukuto, Louis J. Ignarro, Peter Nagy, David A. Wink, Christopher G. Kevil, Martin Feelisch, Miriam M. Cortese-Krott, Christopher L. Bianco, Yoshito Kumagai, Adrian J. Hobbs, Joseph Lin, Tomoaki Ida, Takaaki Akaike

    FEBS Letters　592　(12)　2140-2152　2018/06/01

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  105. Cysteinyl-tRNA synthetase (CARS) controls endogenous hydropersulfide production and mitochondrial respiration Peer-reviewed

    Akaike Takaaki, Motohashi Hozumi, Fukuto Jon, Nagy Peter

    FREE RADICAL BIOLOGY AND MEDICINE　120　S21　2018/05/20

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  106. Bright and dark sides of KEAP1-NRF2 system in carcinogenesis Peer-reviewed

    Motohashi Hozumi, Ida Tomoaki, Alam Md. Morshedul, Kitamura Hiroshi, Akaike Takaaki

    FREE RADICAL BIOLOGY AND MEDICINE　120　S18　2018/05/20

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  107. Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling? Peer-reviewed

    David E. Heppner, Milena Hristova, Tomoaki Ida, Ana Mijuskovic, Christopher M. Dustin, Virág Bogdándi, Jon M. Fukuto, Tobias P. Dick, Péter Nagy, Jianing Li, Takaaki Akaike, Albert van der Vliet

    Redox Biology　14　379-385　2018/04/01

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  108. 8-Nitro-cGMP Attenuates the Interaction between SNARE Complex and Complexin through S-Guanylation of SNAP-25 Peer-reviewed

    Yusuke Kishimoto, Kohei Kunieda, Atsushi Kitamura, Yuki Kakihana, Takaaki Akaike, Hideshi Ihara

    ACS Chemical Neuroscience　9　(2)　217-223　2018/02/21

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  109. Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against Nitric oxide-mediated nitrative stress in microcirculation in mice Peer-reviewed

    Hiroki Saito, Shigeo Godo, Saori Sato, Akiyo Ito, Yosuke Ikumi, Shuhei Tanaka, Tomoaki Ida, Shigemoto Fujii, Takaaki Akaike, Hiroaki Shimokawa

    Journal of Cardiovascular Pharmacology　71　(2)　113-126　2018/02/01

    Publisher: Lippincott Williams and Wilkins

    DOI： 10.1097/FJC.0000000000000552 　

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  110. Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against Nitric oxide-mediated nitrative stress in microcirculation in mice Peer-reviewed

    Hiroki Saito, Shigeo Godo, Saori Sato, Akiyo Ito, Yosuke Ikumi, Shuhei Tanaka, Tomoaki Ida, Shigemoto Fujii, Takaaki Akaike, Hiroaki Shimokawa

    Journal of Cardiovascular Pharmacology　71　(2)　113-126　2018/02/01

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  111. 8-Nitro-cGMP is a promoter of osteoclast differentiation induced by RANKL Peer-reviewed

    K. Kaneko, Y. Miyamoto, R. Tsukuura, K. Sasa, T. Akaike, S. Fujii, K. Yoshimura, K. Nagayama, M. Hoshino, S. Inoue, K. Maki, K. Baba, D. Chikazu, R. Kamijo

    Nitric Oxide - Biology and Chemistry　72　46-51　2018/01/30

    Publisher: Academic Press Inc.

    DOI： 10.1016/j.niox.2017.11.006 　

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  112. Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons. International-journal Peer-reviewed

    Kumiko Masuda, Hiroyasu Tsutsuki, Shingo Kasamatsu, Tomoaki Ida, Tsuyoshi Takata, Kikuya Sugiura, Motohiro Nishida, Yasuo Watanabe, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara

    Biochemical and biophysical research communications　495　(3)　2165-2170　2018/01/15

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  113. Reactive persulfide-mediated energy metabolism: sulfur respiration and its potential implication for tumor biology Peer-reviewed

    Akaike Takaaki

    CANCER SCIENCE　109　144　2018/01

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  114. Reactive Cysteine Persulphides: Occurrence, Biosynthesis, Antioxidant Activity, Methodologies, and Bacterial Persulphide Signalling Peer-reviewed

    Tomohiro Sawa, Katsuhiko Ono, Hiroyasu Tsutsuki, Tianli Zhang, Tomoaki Ida, Motohiro Nishida, Takaaki Akaike

    Advances in Microbial Physiology　72　1-28　2018/01/01

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  115. Production of reactive persulfide species in chronic obstructive pulmonary disease Peer-reviewed

    Tadahisa Numakura, Hisatoshi Sugiura, Takaaki Akaike, Tomoaki Ida, Shigemoto Fujii, Akira Koarai, Mitsuhiro Yamada, Katsuhiro Onodera, Yuichiro Hashimoto, Rie Tanaka, Kei Sato, Yutaka Shishikura, Taizou Hirano, Satoru Yanagisawa, Naoya Fujino, Tatsuma Okazaki, Tsutomu Tamada, Yasushi Hoshikawa, Yoshinori Okada, Masakazu Ichinose

    THORAX　72　(12)　1074-1083　2017/12

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  116. Moonlighting Functions of Cysteinyl-tRNA Synthetases: Cycteine Hydropersulfide Production and Regulation of Mitochondrial Biogenesis and Bioenergetics Peer-reviewed

    Takaaki Akaike, Akira Nishimura, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hozumi Motohashi

    FREE RADICAL BIOLOGY AND MEDICINE　112　182-183　2017/11

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  117. Cysteine Hydropersulfide Production Catalyzed by Cysteinyl-tRNA Synthetases Peer-reviewed

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    FREE RADICAL BIOLOGY AND MEDICINE　112　189-190　2017/11

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  118. Altered Glutathione Homeostasis in NLRP3 Inflammasome Activation Mediated by ATP-P2X7 Receptor Signaling Peer-reviewed

    Tomohiro Sawa, Tianli Zhang, Hiroyasu Tsutsuki, Katsuhiko Ono, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　112　210-211　2017/11

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  119. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. International-journal Peer-reviewed

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    Nature communications　8　(1)　1177-1177　2017/10/27

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  120. Chemical Biology of Hydropersulfides and Related Species: Possible Roles in Cellular Protection and Redox Signaling Peer-reviewed

    Lucia Alvarez, Christopher L. Bianco, John P. Toscano, Joseph Lin, Takaaki Akaike, Jon M. Fukuto

    ANTIOXIDANTS & REDOX SIGNALING　27　(10)　622-633　2017/10

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  121. Diversity and microevolution of CRISPR loci in Helicobacter cinaedi Peer-reviewed

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    PLOS ONE　12　(10)　e0186241　2017/10

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  122. 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage Peer-reviewed

    Marie Hoshino, Kotaro Kaneko, Yoichi Miyamoto, Kentaro Yoshimura, Dai Suzuki, Takaaki Akaike, Tomohiro Sawa, Tomoaki Ida, Shigemoto Fujii, Hideshi Ihara, Junichi Tanaka, Risa Tsukuura, Daichi Chikazu, Kenji Mishima, Kazuyoshi Baba, Ryutaro Kamijo

    FREE RADICAL BIOLOGY AND MEDICINE　110　63-71　2017/09

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  123. 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

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  124. Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells Peer-reviewed

    Motohiro Nishida, Akiyuki Nishimura, Tetsuro Matsunaga, Hozumi Motohashi, Shingo Kasamatsu, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　109　132-140　2017/08

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  125. Disruption of the structural and functional features of surfactant protein A by acrolein in cigarette smoke Peer-reviewed

    Rina Takamiya, Koji Uchida, Takahiro Shibata, Toshitaka Maeno, Masaki Kato, Yoshiki Yamaguchi, Shigeru Ariki, Yoshihiro Hasegawa, Atsushi Saito, Soichi Miwa, Hiroki Takahashi, Takaaki Akaike, Yoshio Kuroki, Motoko Takahashi

    SCIENTIFIC REPORTS　7　(1)　8304　2017/08

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  126. Reactive sulfur species inactivate Ca2+/calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue. International-journal Peer-reviewed

    Tsuyoshi Takata, Hideshi Ihara, Naoya Hatano, Yukihiro Tsuchiya, Takaaki Akaike, Yasuo Watanabe

    The Biochemical journal　474　(15)　2547-2562　2017/07/17

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  127. Synthesis of L-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome Peer-reviewed

    Katsuhiko Ono, Minkyung Jung, Tianli Zhang, Hiroyasu Tsutsuki, Hiroshi Sezaki, Hideshi Ihara, Fan-Yan Wei, Kazuhito Tomizawa, Takaaki Akaike, Tomohiro Sawa

    FREE RADICAL BIOLOGY AND MEDICINE　106　69-79　2017/05

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  128. Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach Peer-reviewed

    Mayumi Ikeda, Yu Ishima, Akitomo Shibata, Victor T. G. Chuang, Tomohiro Sawa, Hideshi Ihara, Hiroshi Watanabe, Ming Xian, Yuya Ouchi, Taro Shimizu, Hidenori Ando, Masami Ukawa, Tatsuhiro Ishida, Takaaki Akaike, Masaki Otagiri, Toru Maruyama

    ANALYTICA CHIMICA ACTA　969　18-25　2017/05

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  129. Superoxide generation from nNOS splice variants and its potential involvement in redox signal regulation. International-journal Peer-reviewed

    Hideshi Ihara, Atsushi Kitamura, Shingo Kasamatsu, Tomoaki Ida, Yuki Kakihana, Hiroyasu Tsutsuki, Tomohiro Sawa, Yasuo Watanabe, Takaaki Akaike

    The Biochemical journal　474　(7)　1149-1162　2017/03/15

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  130. Synthesis and Characterization of 8-Nitroguanosine 3',5'-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase Gl alpha Peer-reviewed

    Khandaker Ahtesham Ahmed, Tianli Zhang, Katsuhiko Ono, Hiroyasu Tsutsuki, Tomoaki Ida, Soichiro Akashi, Keishi Miyata, Yuichi Oike, Takaaki Akaike, Tomohiro Sawa

    BIOLOGICAL & PHARMACEUTICAL BULLETIN　40　(3)　365-374　2017/03

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  131. Synthesis and Characterization of 8-Nitroguanosine 3',5'-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase Gl alpha Peer-reviewed

    Khandaker Ahtesham Ahmed, Tianli Zhang, Katsuhiko Ono, Hiroyasu Tsutsuki, Tomoaki Ida, Soichiro Akashi, Keishi Miyata, Yuichi Oike, Takaaki Akaike, Tomohiro Sawa

    BIOLOGICAL & PHARMACEUTICAL BULLETIN　40　(3)　365-374　2017/03

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  132. 1,4-Naphthoquinone activates the HSP90/HSF1 pathway through the S-arylation of HSP90 in A431 cells: Negative regulation of the redox signal transduction pathway by persulfides/polysulfides. International-journal Peer-reviewed

    Yumi Abiko, Liang Sha, Yasuhiro Shinkai, Takamitsu Unoki, Nho Cong Luong, Yukihiro Tsuchiya, Yasuo Watanabe, Reiko Hirose, Takaaki Akaike, Yoshito Kumagai

    Free radical biology & medicine　104　118-128　2017/03

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  133. Metabolomic profiling of reactive persulfides and polysulfides in the aqueous and vitreous humors Peer-reviewed

    Hiroshi Kunikata, Tomoaki Ida, Kota Sato, Naoko Aizawa, Tomohiro Sawa, Hiroshi Tawarayama, Namie Murayama, Shigemoto Fujii, Takaaki Akaike, Toru Nakazawa

    SCIENTIFIC REPORTS　7　41984　2017/02

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  134. Regulation of Redox Signaling by a Nitrated Nucleotide and Reactive Cysteine Persulfides Peer-reviewed

    Tomohiro Sawa, Yoshito Kumagai, Takaaki Akaike

    Nitric Oxide: Biology and Pathobiology: Third Edition　231-235　2017/01/01

    Publisher: Elsevier Inc.

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  135. Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion Peer-reviewed

    Nozomu Takahashi, Fan-Yan Wei, Sayaka Watanabe, Mayumi Hirayama, Yuya Ohuchi, Atsushi Fujimura, Taku Kaitsuka, Isao Ishii, Tomohiro Sawa, Hideki Nakayama, Takaaki Akaike, Kazuhito Tomizawa

    NUCLEIC ACIDS RESEARCH　45　(1)　435-445　2017/01

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  136. Redox Signaling Regulated by Cysteine Persulfide and Protein Polysulfidation Peer-reviewed

    Shingo Kasamatsu, Akira Nishimura, Masanobu Morita, Tetsuro Matsunaga, Hisyam Abdul Hamid, Takaaki Akaike

    MOLECULES　21　(12)　2016/12

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  137. Degradation of bradykinin by a metalloendopeptidase from Streptococcus pyogenes Peer-reviewed

    Yoichi Miyamoto, Takaaki Akaike, Shigetada Kawabata, Teruo Akuta, Chiho Taruki, Jun Yoshitake, Shigeyuki Hamada, Fusao Ota, Hideo Igarashi, Kentaro Yoshimura, Ryutaro Kamijo, Hiroshi Maeda

    Journal of Oral Biosciences　58　(4)　167-172　2016/11/01

    Publisher: Japanese Association for Oral Biology

    DOI： 10.1016/j.job.2016.07.003 　

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  138. Degradation of bradykinin by a metalloendopeptidase from Streptococcus pyogenes Peer-reviewed

    Miyamoto Yoichi, Akaike Takaaki, Kawabata Shigetada, Akuta Teruo, Taruki Chiho, Yoshitake Jun, Hamada Shigeyuki, Ota Fusao, Igarashi Hideo, Yoshimura Kentaro, Kamijo Ryutaro, Maeda Hiroshi

    Journal of Oral Biosciences　58　(4)　167-172　2016/11

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  139. Protein polysulfidation-dependent persulfide dioxygenase activity of ethylmalonic encephalopathy protein 1 Peer-reviewed

    Minkyung Jung, Shingo Kasamatsu, Tetsuro Matsunaga, Soichiro Akashi, Katsuhiko Ono, Akira Nishimura, Masanobu Morita, Hisyam Abdul Hamid, Shigemoto Fujii, Hiroshi Kitamura, Tomohiro Sawa, Tomoaki Ida, Hozumi Motohashi, Takaaki Akaike

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　480　(2)　180-186　2016/11

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  140. Modification of Tau by 8-Nitroguanosine 3,5-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION Peer-reviewed

    Jun Yoshitake, Yoshiyuki Soeda, Tomoaki Ida, Akio Sumioka, Misato Yoshikawa, Kenji Matsushita, Takaaki Akaike, Akihiko Takashima

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(43)　22714-22720　2016/10

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  141. Mice Deficient in Angiopoietin-like Protein 2 (Angptl2) Gene Show Increased Susceptibility to Bacterial Infection Due to Attenuated Macrophage Activity Peer-reviewed

    Masaki Yugami, Haruki Odagiri, Motoyoshi Endo, Hiroyasu Tsutsuki, Shigemoto Fujii, Tsuyoshi Kadomatsu, Tetsuro Masuda, Keishi Miyata, Kazutoyo Terada, Hironori Tanoue, Hitoshi Ito, Jun Morinaga, Haruki Horiguchi, Taichi Sugizaki, Takaaki Akaike, Tomomi Gotoh, Toshiyuki Takai, Tomohiro Sawa, Hiroshi Mizuta, Yuichi Oike

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(36)　18843-18852　2016/09

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  142. Endogenous occurrence of protein S-guanylation in Escherichia coli: Target identification and genetic regulation Peer-reviewed

    Hiroyasu Tsutsuki, Minkyung Jung, Tianli Zhang, Katsuhiko Ono, Tomoaki Ida, Kohei Kunieda, Hideshi Ihara, Takaaki Akaike, Tomohiro Sawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　478　(1)　7-11　2016/09

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  143. The chemical biology of protein hydropersulfides: Studies of a possible protective function of biological hydropersulfide generation Peer-reviewed

    Robert Millikin, Christopher L. Bianco, Corey White, Simran S. Saund, Stephanie Henriquez, Victor Sosa, Takaaki Akaike, Yoshito Kumagai, Shuhei Soeda, John P. Toscano, Joseph Lin, Jon M. Fukuto

    FREE RADICAL BIOLOGY AND MEDICINE　97　136-147　2016/08

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  144. Proposal of Helicobacter canicola sp nov., previously identified as Helicobacter cinaedi, isolated from canines Peer-reviewed

    Yoshiaki Kawamura, Junko Tomida, Tohru Miyoshi-Akiyama, Tatsuya Okamoto, Masashi Narita, Katsuhiko Hashimoto, Margo Cnockaert, Peter Vandamme, Yuji Morita, Tomohiro Sawa, Takaaki Akaike

    SYSTEMATIC AND APPLIED MICROBIOLOGY　39　(5)　307-312　2016/07

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  145. [Re-emerging reactive sulfur-containing compounds and their unique biological functions]. Peer-reviewed

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    Nihon yakurigaku zasshi. Folia pharmacologica Japonica　147　(5)　278-284　2016/05

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  146. [Reactive sulfur species-modified protein thiols: new methods for polysulfurated protein analysis]. Peer-reviewed

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    Nihon yakurigaku zasshi. Folia pharmacologica Japonica　147　(5)　299-302　2016/05

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  147. Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides Peer-reviewed

    Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Hideshi Ihara, Tomoaki Ida, Hozumi Motohashi, Takaaki Akaike

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　595　140-146　2016/04

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  148. Formation mechanisms and redox-regulatory functions of reactive persulfide and protein polysulfur species Peer-reviewed

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    JOURNAL OF PHARMACOLOGICAL SCIENCES　130　(3)　S29　2016/03

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  149. Redox signaling regulated by electrophiles and reactive sulfur species Peer-reviewed

    Motohiro Nishida, Yoshito Kumagai, Hideshi Ihara, Shigemoto Fujii, Hozumi Motohashi, Takaaki Akaike

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION　58　(2)　91-98　2016/03

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  150. Persistent Activation of cGMP-Dependent Protein Kinase by a Nitrated Cyclic Nucleotide via Site Specific Protein S-Guanylation Peer-reviewed

    Soichiro Akashi, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Katsuhiko Ono, Hiroyasu Tsutsuki, Joseph R. Burgoyne, Tomoaki Ida, Eiji Horio, Oleksandra Prysyazhna, Yuichi Oike, Mizanur Md. Rahaman, Philip Eaton, Shigemoto Fujii, Takaaki Akaike

    BIOCHEMISTRY　55　(5)　751-761　2016/02

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  151. The chemical biology of hydropersulfides (RSSH): Chemical stability, reactivity and redox roles Peer-reviewed

    Simran S. Saund, Victor Sosa, Stephanie Henriquez, Q. Nhu N. Nguyen, Christopher L. Bianco, Shuhei Soeda, Robert Millikin, Corey White, Henry Le, Katsuhiko Ono, Dean J. Tantillo, Yoshito Kumagai, Takaaki Akaike, Joseph Lin, Jon M. Fukuto

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　588　15-24　2015/12

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  152. The Development of Fluorescent Probes for Visualizing Intracellular Hydrogen Polysulfides Peer-reviewed

    Wei Chen, Ethan W. Rosser, Tetsuro Matsunaga, Armando Pacheco, Takaaki Akaike, Ming Xian

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION　54　(47)　13961-13965　2015/11

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  153. Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide Against Neuronal Ischemia Peer-reviewed

    Eizo Marutani, Marina Yamada, Tomoaki Ida, Kentaro Tokuda, Kohei Ikeda, Shinichi Kai, Kazuhiro Shirozu, Kei Hayashida, Shizuko Kosugi, Kenjiro Hanaoka, Masao Kaneki, Takaaki Akaike, Fumito Ichinose

    JOURNAL OF THE AMERICAN HEART ASSOCIATION　4　(11)　2015/11

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  154. 8-Nitro-cGMP Enhances SNARE Complex Formation through S-Guanylation of Cys90 in SNAP25 Peer-reviewed

    Kohei Kunieda, Hiroyasu Tsutsuki, Tomoaki Ida, Yusuke Kishimoto, Shingo Kasamatsu, Tomohiro Sawa, Naoki Goshima, Makoto Itakura, Masami Takahashi, Takaaki Akaike, Hideshi Ihara

    ACS CHEMICAL NEUROSCIENCE　6　(10)　1715-1725　2015/10

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  155. Formation of sulfur adducts of N-acetyl-p-benzoquinoneimine, an electrophilic metabolite of acetaminophen in vivo: participation of reactive persulfides. International-journal Peer-reviewed

    Yumi Abiko, Isao Ishii, Shotaro Kamata, Yukihiro Tsuchiya, Yasuo Watanabe, Hideshi Ihara, Takaaki Akaike, Yoshito Kumagai

    Chemical research in toxicology　28　(9)　1796-802　2015/09/21

    DOI： 10.1021/acs.chemrestox.5b00245 　

    ISSN： 0893-228X

  156. Decreased levels of bis-S-bimane in exhaled breath condensate of COPD Peer-reviewed

    Onodera Katsuhiro, Sugiura Hisatoshi, Hashimoto Yuichiro, Numakura Tadahisa, Abe Kyoko, Koarai Akira, Yamada Mitsuhiro, Ida Tomoaki, Akaike Takaaki, Ichinose Masakazu

    EUROPEAN RESPIRATORY JOURNAL　46　2015/09/01

    DOI： 10.1183/13993003.congress-2015.PA2087 　

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  157. Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions Peer-reviewed

    Shintaro Nakano, Isao Ishii, Ken Shinmura, Kayoko Tamaki, Takako Hishiki, Noriyuki Akahoshi, Tomoaki Ida, Tsuyoshi Nakanishi, Shotaro Kamata, Yoshito Kumagai, Takaaki Akaike, Keiichi Fukuda, Motoaki Sano, Makoto Suematsu

    JOURNAL OF MOLECULAR MEDICINE-JMM　93　(8)　879-889　2015/08

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  158. 8-Mercapto-Cyclic GMP Mediates Hydrogen Sulfide-Induced Stomatal Closure in Arabidopsis Peer-reviewed

    Kenji Honda, Naotake Yamada, Riichiro Yoshida, Hideshi Ihara, Tomohiro Sawa, Takaaki Akaike, Sumio Iwai

    PLANT AND CELL PHYSIOLOGY　56　(8)　1481-1489　2015/08

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  159. Different activation state between microglia and astrocyte in a mouse model of hyperactivity Peer-reviewed

    Kajiwara Yuto, Kurauchi Yuki, Yoshimaru Yuko, Hisatsune Akinori, Seki Takahiro, Sawa Tomohiro, Akaike Takaaki, Katsuki Hiroshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES　128　(3)　S162　2015/07

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  160. Reactive sulfur-containing compounds reversibly inactivate Ca2+/calmodulin-dependent protein kinase IV Peer-reviewed

    Takata Tsuyoshi, Tsuchiya Yukihiro, Ida Tomoaki, Sawa Tomohiro, Akaike Takaaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES　128　(3)　S208-S208　2015/07

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  161. Discovery of re-emerging reactive sulfur-containing compounds and their unique biological functions Peer-reviewed

    Ida Tomoaki, Akaike Takaaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES　128　(3)　S64　2015/07

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  162. Na+, K+-ATPase inhibition induces protein S-guanylation during cerebrovascular endothelial cell injury Peer-reviewed

    Kurauchi Yuki, Sawa Tomohiro, Hisatsune Akinori, Seki Takahiro, Akaike Takaaki, Katsuki Hiroshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES　128　(3)　S224　2015/07

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  163. Involvement of Reactive Persulfides in Biological Bismethylmercury Sulfide Formation Peer-reviewed

    Yumi Abiko, Eiko Yoshida, Isao Ishii, Jon M. Fukuto, Takaaki Akaike, Yoshito Kumagai

    CHEMICAL RESEARCH IN TOXICOLOGY　28　(6)　1301-1306　2015/06

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  164. Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress Peer-reviewed

    Yasuhiro Shinkai, Yumi Abiko, Tomoaki Ida, Takashi Miura, Hidenao Kakehashi, Isao Ishii, Motohiro Nishida, Tomohiro Sawa, Takaaki Akaike, Yoshito Kumagai

    CHEMICAL RESEARCH IN TOXICOLOGY　28　(5)　838-847　2015/05

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  165. Mesenchymal Stem Cells Correct Inappropriate Epithelial-mesenchyme Relation in Pulmonary Fibrosis Using Stanniocalcin-1 Peer-reviewed

    Manabu Ono, Shinya Ohkouchi, Masahiko Kanehira, Naoki Tode, Makoto Kobayashi, Masahito Ebina, Toshihiro Nukiwa, Toshiya Irokawa, Hiromasa Ogawa, Takaaki Akaike, Yoshinori Okada, Hajime Kurosawa, Toshiaki Kikuchi, Masakazu Ichinose

    MOLECULAR THERAPY　23　(3)　549-560　2015/03

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  166. [Host defense and oxidative stress signaling in bacterial infection ]. Peer-reviewed

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    Nihon saikingaku zasshi. Japanese journal of bacteriology　70　(3)　339-349　2015

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  167. Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: Implications of their possible biological activity and utility Peer-reviewed

    Katsuhiko Ono, Takaaki Akaike, Tomohiro Sawa, Yoshito Kumagai, David A. Wink, Dean J. Tantillo, Adrian J. Hobbs, Peter Nagy, Ming Xian, Joseph Lin, Jon M. Fukuto

    FREE RADICAL BIOLOGY AND MEDICINE　77　82-94　2014/12

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  168. Helicobacter cinaedi meningitis: A case report and review of previous cases Peer-reviewed

    Hatsumi Okubo, Masahide Goto, Miori Sato, Teruyuki Sugiyama, Mikihiko Kawano, Tetsuro Matsunaga, Takaaki Akaike

    JOURNAL OF THE NEUROLOGICAL SCIENCES　347　(1-2)　396-397　2014/12

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  169. Role of reactive sulfur species in detoxification of methylmercury: Phase zero reaction for electrophile trapping and detoxification Peer-reviewed

    Yoshito Kumagai, Eiko Yoshida, Yasuhiro Shinkai, Jon Fukuto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　100-100　2014/11

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  170. 8-Nitro-cGMP-mediated autophagy in host defense and its regulation by hydrogen sulfide produced by bacteria Peer-reviewed

    Shigemoto Fujii, Shahzada Khan, Tomoaki Ida, Tomohiro Sawa, Tetsuro Matsunaga, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　122-122　2014/11

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  171. Metabolism of 8-nitro-cGMP and regulation of electrophilic signaling by reactive sulfur species Peer-reviewed

    Tomoaki Ida, Tomohiro Sawa, Hideshi Ihara, Yukihiro Tsuchiya, Yasuo Watanabe, Yoshito Kumagai, Hozumi Motohashi, Shigemoto Fujii, Tetsuro Matsunaga, Masayuki Yamamoto, Katsuhiko Ono, Jon Fukuto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　126-127　2014/11

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  172. Redox signal regulation via nNOS phosphorylation at Ser847 in PC12 cells and rat cerebellar granule neurons Peer-reviewed

    Hideshi Ihara, Shingo Kasamatsu, Yasuo Watanabe, Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　127-127　2014/11

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  173. Persistent activation of protein kinase G by a nitrated cyclic nucleotide via site specific S-guanylation and its implication for vascular hyporeactivity in endotoxin shock Peer-reviewed

    Tomohiro Sawa, Ahtesham Ahmed, Katsuhiko Ono, Tomoaki Ida, Shigemoto Fujii, Philip Eaton, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　140-140　2014/11

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  174. Reversible inactivation of Ca2+/calmodulin-dependent protein kinase IV by reactive cysteine persulfides generated from cystathionine gamma-lyase and cystine Peer-reviewed

    Tsuyoshi Takata, Yukihiro Tsuchiya, Tomoaki Ida, Tomohiro Sawa, Takaaki Akaike, Yasuo Watanabe

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　42　142-142　2014/11

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  175. Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by an Electrophile through Sulfenic Acids Formation under Oxidative Stress Peer-reviewed

    Yoshito Kumagai, Yasuhiro Shinkai, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　76　S149-S150　2014/11

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  176. Clinical and bacteriological characteristics of Helicobacter cinaedi infection Peer-reviewed

    Yoshiaki Kawamura, Junko Tomida, Yuji Morita, Shigemoto Fujii, Tatsuya Okamoto, Takaaki Akaike

    JOURNAL OF INFECTION AND CHEMOTHERAPY　20　(9-10)　517-526　2014/09

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  177. 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

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  178. Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. International-journal Peer-reviewed

    Tomoaki Ida, Tomohiro Sawa, Hideshi Ihara, Yukihiro Tsuchiya, Yasuo Watanabe, Yoshito Kumagai, Makoto Suematsu, Hozumi Motohashi, Shigemoto Fujii, Tetsuro Matsunaga, Masayuki Yamamoto, Katsuhiko Ono, Nelmi O Devarie-Baez, Ming Xian, Jon M Fukuto, Takaaki Akaike

    Proceedings of the National Academy of Sciences of the United States of America　111　(21)　7606-11　2014/05/27

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  179. Redox signal regulation via nNOS phosphorylation at Ser847 in PC12 cells and rat cerebellar granule neurons. International-journal Peer-reviewed

    Shingo Kasamatsu, Yasuo Watanabe, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara

    The Biochemical journal　459　(2)　251-63　2014/04/15

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  180. Reactive Oxygen Species Signaling and Redox Homeostasis Regulated by 8-Nitro-cGMP Peer-reviewed

    Takaaki Akaike

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN　134　(4)　515-519　2014/04

    DOI： 10.1248/yakushi.13-00251-3 　

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  181. SIRT7 Controls Hepatic Lipid Metabolism by Regulating the Ubiquitin-Proteasome Pathway Peer-reviewed

    Tatsuya Yoshizawa, Md. Fazlul Karim, Yoshifumi Sato, Takafumi Senokuchi, Keishi Miyata, Takaichi Fukuda, Chisa Go, Masayoshi Tasaki, Kohei Uchimura, Tsuyoshi Kadomatsu, Zhe Tian, Christian Smolka, Tomohiro Sawa, Motohiro Takeya, Kazuhito Tomizawa, Yukio Ando, Eiichi Araki, Takaaki Akaike, Thomas Braun, Yuichi Oike, Eva Bober, Kazuya Yamagata

    CELL METABOLISM　19　(4)　712-721　2014/04

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  182. Promotion of atherosclerosis by Helicobacter cinaedi infection that involves macrophage-driven proinflammatory responses Peer-reviewed

    Shahzada Khan, H. N. Ashiqur Rahman, Tatsuya Okamoto, Tetsuro Matsunaga, Yukio Fujiwara, Tomohiro Sawa, Jun Yoshitake, Katsuhiko Ono, Khandaker Ahtesham Ahmed, Md Mizanur Rahaman, Kohta Oyama, Motohiro Takeya, Tomoaki Ida, Yoshiaki Kawamura, Shigemoto Fujii, Takaaki Akaike

    SCIENTIFIC REPORTS　4　4680　2014/04

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  183. Angiopoietin-like protein 2 accelerates carcinogenesis by activating chronic inflammation and oxidative stress. International-journal Peer-reviewed

    Jun Aoi, Motoyoshi Endo, Tsuyoshi Kadomatsu, Keishi Miyata, Aki Ogata, Haruki Horiguchi, Haruki Odagiri, Tetsuro Masuda, Satoshi Fukushima, Masatoshi Jinnin, Satoshi Hirakawa, Tomohiro Sawa, Takaaki Akaike, Hironobu Ihn, Yuichi Oike

    Molecular cancer research : MCR　12　(2)　239-49　2014/02

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  184. S-Guanylation Proteomics for Redox-Based Mitochondrial Signaling Peer-reviewed

    Md. Mizanur Rahaman, Tomohiro Sawa, Ahmed Khandaker Ahtesham, Shahzada Khan, Hirofumi Inoue, Atsuhi Irie, Shigemoto Fujii, Takaaki Akaike

    ANTIOXIDANTS & REDOX SIGNALING　20　(2)　295-307　2014/01

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  185. Endogenous Nitrated Nucleotide Is a Key Mediator of Autophagy and Innate Defense against Bacteria Peer-reviewed

    Chiaki Ito, Yohei Saito, Takashi Nozawa, Shigemoto Fujii, Tomohiro Sawa, Hirofumi Inoue, Tetsuro Matsunaga, Shahzada Khan, Soichiro Akashi, Ryota Hashimoto, Chihiro Aikawa, Eriko Takahashi, Hiroshi Sagara, Masaaki Komatsu, Keiji Tanaka, Takaaki Akaike, Ichiro Nakagawa, Hirokazu Arimoto

    MOLECULAR CELL　52　(6)　794-804　2013/12

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  186. Inhibition of H3K18 deacetylation of Sirt7 by Myb-binding protein 1a (Mybbp1a) Peer-reviewed

    Md Fazlul Karim, Tatsuya Yoshizawa, Yoshifumi Sato, Tomohiro Sawa, Kazuhito Tomizawa, Takaaki Akaike, Kazuya Yamagata

    Biochemical and Biophysical Research Communications　441　(1)　157-163　2013/11/08

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  187. Formation, signaling functions, and metabolisms of nitrated cyclic nucleotide Peer-reviewed

    Tomohiro Sawa, Hideshi Ihara, Tomoaki Ida, Shigemoto Fujii, Motohiro Nishida, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　34　10-18　2013/11

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  188. Redox signaling by 8-nitro-cyclic guanosine monophosphate: Nitric oxide-and reactive oxygen species-derived electrophilic messenger Peer-reviewed

    Shigemoto Fujii, Takaaki Akaike

    Antioxidants and Redox Signaling　19　(11)　1236-1246　2013/10/10

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  189. Fluorescent Probes for Live Cell Imaging of Endogenous Guanine Nitration Peer-reviewed

    Yohei Saito, Chiaki Ito, Shigemoto Fujii, Tomohiro Sawa, Takaaki Akaike, Hirokazu Arimoto

    CHEMBIOCHEM　14　(9)　1068-1071　2013/06

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  190. Comparative evaluation of agar dilution and broth microdilution methods for antibiotic susceptibility testing of Helicobacter cinaedi Peer-reviewed

    Junko Tomida, Ayako Oumi, Tatsuya Okamoto, Yuji Morita, Akihiko Okayama, Naoaki Misawa, Tetsuya Hayashi, Takaaki Akaike, Yoshiaki Kawamura

    MICROBIOLOGY AND IMMUNOLOGY　57　(5)　353-358　2013/05

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  191. Potential role for 8-Nitro-cGMP in nitrite-mediated hypoxic signaling Peer-reviewed

    Benjamin Y. Owusu, Ryan Stapley, Takaaki Akaike, Rakesh P. Patel

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　31　S26-S27　2013/04

    DOI： 10.1016/j.niox.2013.02.034 　

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  192. Nitric oxide/soluble guanylyl cyclase signaling mediates depolarization-induced protection of rat mesencephalic dopaminergic neurons from MPP+ cytotoxicity Peer-reviewed

    Y. Kurauchi, A. Hisatsune, Y. Isohama, T. Sawa, T. Akaike, H. Katsuki

    Neuroscience　231　206-215　2013/02/02

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  193. Regulation of redox signalling by an electrophilic cyclic nucleotide Peer-reviewed

    Takaaki Akaike, Motohiro Nishida, Shigemoto Fujii

    JOURNAL OF BIOCHEMISTRY　153　(2)　131-138　2013/02

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  194. Nitrated cyclic GMP modulates guard cell signaling in Arabidopsis Peer-reviewed

    Takahiro Joudoi, Yudai Shichiri, Nobuto Kamizono, Takaaki Akaike, Tomohiro Sawa, Jun Yoshitake, Naotaka Yamada, Sumio Iwai

    Plant Cell　25　(2)　558-571　2013/02

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  195. S-nitrosated α-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis Peer-reviewed

    Kaori Watanabe, Yu Ishima, Takaaki Akaike, Tomohiro Sawa, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Ayaka Suenaga, Toshiya Kai, Masaki Otagiri, Toru Maruyama

    FASEB Journal　27　(1)　391-398　2013/01

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  196. Electrophilic modification of H-Ras underlies development of chronic heart failure after myocardial infarction Peer-reviewed

    Naoyuki Kitajima, Tomohiro Sawa, Takaaki Akaike, Motohiro Nishida

    JOURNAL OF PHARMACOLOGICAL SCIENCES　121　77P-77P　2013

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  197. S-nitrosated alpha-1-acid glycoprotein kills drug-resistant bacteria and aids survival in sepsis Peer-reviewed

    Kaori Watanabe, Yu Ishima, Takaaki Akaike, Tomohiro Sawa, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Ayaka Suenaga, Toshiya Kai, Masaki Otagiri, Toru Maruyama

    FASEB JOURNAL　27　(1)　391-398　2013/01

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  198. Nucleotide nitration by ROS and NO mediates oxidative and genotoxic stress response Peer-reviewed

    Takaaki Akaike, Tomohiro Sawa

    GENES & GENETIC SYSTEMS　87　(6)　373-373　2012/12

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  199. Identification of and Screening for Human Helicobacter cinaedi Infections and Carriers via Nested PCR Peer-reviewed

    Kohta Oyama, Shahzada Khan, Tatsuya Okamoto, Shigemoto Fujii, Katsuhiko Ono, Tetsuro Matsunaga, Jun Yoshitake, Tomohiro Sawa, Junko Tomida, Yoshiaki Kawamura, Takaaki Akaike

    JOURNAL OF CLINICAL MICROBIOLOGY　50　(12)　3893-3900　2012/12

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  200. Potential Role for 8-Nitro-CGMP and Protein S-Guanylation in Nitrite-Dependent Signaling Peer-reviewed

    Benjamin Y. Owusu, Ryan Stapley, Takaaki Akaike, Rakesh Patel

    FREE RADICAL BIOLOGY AND MEDICINE　53　S184-S184　2012/11

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  201. [Regulation of ROS signaling for targeted cancer chemotherapy]. Peer-reviewed

    Sawa T, Akaike T

    Nihon rinsho. Japanese journal of clinical medicine　70 Suppl 8　273-276　2012/11

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  202. HGF-mediated inhibition of oxidative stress by 8-nitro-cGMP in high glucose-treated rat mesangial cells Peer-reviewed

    Shang Guoguo, Takaaki Akaike, Jiang Tao, Chen Qi, Zhang Nong, Li Hui

    FREE RADICAL RESEARCH　46　(10)　1238-1248　2012/10

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  203. S-guanylation of human serum albumin is a unique posttranslational modification and results in a novel class of antibacterial agents Peer-reviewed

    Yu Ishima, Hitomi Hoshino, Takuya Shinagawa, Kaori Watanabe, Takaaki Akaike, Tomohiro Sawa, Ulrich Kragh-hansen, Toshiya Kai, Hiroshi Watanabe, Toru Maruyama, Masaki Otagiri

    JOURNAL OF PHARMACEUTICAL SCIENCES　101　(9)　3222-3229　2012/09

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  204. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration Peer-reviewed

    Motohiro Nishida, Tomohiro Sawa, Naoyuki Kitajima, Katsuhiko Ono, Hirofumi Inoue, Hideshi Ihara, Hozumi Motohashi, Masayuki Yamamoto, Makoto Suematsu, Hitoshi Kurose, Albert van der Vliet, Bruce A. Freeman, Takahiro Shibata, Koji Uchida, Yoshito Kumagai, Takaaki Akaike

    NATURE CHEMICAL BIOLOGY　8　(8)　714-724　2012/08

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  205. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration Peer-reviewed

    Motohiro Nishida, Tomohiro Sawa, Naoyuki Kitajima, Katsuhiko Ono, Hirofumi Inoue, Hideshi Ihara, Hozumi Motohashi, Masayuki Yamamoto, Makoto Suematsu, Hitoshi Kurose, Albert van der Vliet, Bruce A. Freeman, Takahiro Shibata, Koji Uchida, Yoshito Kumagai, Takaaki Akaike

    NATURE CHEMICAL BIOLOGY　8　(8)　714-724　2012/08

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  206. Keap1 degradation by autophagy for the maintenance of redox homeostasis Peer-reviewed

    Keiko Taguchi, Nanako Fujikawa, Masaaki Komatsu, Tetsuro Ishii, Michiaki Unno, Takaaki Akaike, Hozumi Motohashi, Masayuki Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　109　(34)　13561-13566　2012/08

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  207. S-guanylation proteomics for redox-based mitochondrial signaling Peer-reviewed

    Tomohiro Sawa, Md. M. Rahaman, Ahmed K. Ahtesham, Atsushi Irie, Shigemoto Fujii, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　27　S11-S11　2012/07

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  208. 8-SH-cGMP endogenously formed from 8-nitro-cGMP as a second messenger of hydrogen sulfide Peer-reviewed

    Takaaki Akaike, Hideshi Ihara, Tomohiro Sawa

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　27　S14-S15　2012/07

    DOI： 10.1016/j.niox.2012.04.052 　

    ISSN： 1089-8603

  209. Regulation by mitochondrial superoxide and nadph oxidase of cellular formation of nitrated cyclic GMP: Potential implications for NO and ROS signaling Peer-reviewed

    Shigemoto Fujii, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Hideshi Ihara, Shingo Kasamatsu, Jun Yoshitake, Md Mizanur Rahaman, Tatsuya Okamoto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　27　S20-S20　2012/07

    DOI： 10.1016/j.niox.2012.04.071 　

    ISSN： 1089-8603

  210. nNOS modulates NO-ROS signaling in neurons via phosphorylation at Ser847 Peer-reviewed

    Shingo Kasamatsu, Tomohiro Sawa, Yasuo Watanabe, Takaaki Akaike, Hideshi Ihara

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　27　S24-S24　2012/07

    DOI： 10.1016/j.niox.2012.04.086 　

    ISSN： 1089-8603

  211. Quantification of a novel sulfhydrylated cGMP in mammalian cells and tissues by liquid chromatography tandem mass spectrometry Peer-reviewed

    Hideshi Ihara, Tomoaki Ida, Shingo Kasamatsu, Kouhei Kunieda, Yoshikazu Ikeda, Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　27　S36-S37　2012/07

    DOI： 10.1016/j.niox.2012.04.132 　

    ISSN： 1089-8603

  212. Complete Genome Sequence of Helicobacter cinaedi Strain PAGU611, Isolated in a Case of Human Bacteremia Peer-reviewed

    Takatsugu Goto, Yoshitoshi Ogura, Hideki Hirakawa, Junko Tomida, Yuji Morita, Takaaki Akaike, Tetsuya Hayashi, Yoshiaki Kawamura

    JOURNAL OF BACTERIOLOGY　194　(14)　3744-3745　2012/07

    DOI： 10.1128/JB.00645-12 　

    ISSN： 0021-9193

  213. Anks4b, a Novel Target of HNF4 alpha Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic beta-Cells Peer-reviewed

    Yoshifumi Sato, Mitsutoki Hatta, Md Fazlul Karim, Tomohiro Sawa, Fan-Yan Wei, Shoki Sato, Mark A. Magnuson, Frank J. Gonzalez, Kazuhito Tomizawa, Takaaki Akaike, Tatsuya Yoshizawa, Kazuya Yamagata

    JOURNAL OF BIOLOGICAL CHEMISTRY　287　(27)　23236-23245　2012/06

    DOI： 10.1074/jbc.M112.368779 　

    ISSN： 0021-9258

  214. Potential association of Helicobacter cinaedi with atrial arrhythmias and atherosclerosis Peer-reviewed

    Shahzada Khan, Tatsuya Okamoto, Koji Enomoto, Naomi Sakashita, Kohta Oyama, Shigemoto Fujii, Tomohiro Sawa, Motohiro Takeya, Hisao Ogawa, Hiroshige Yamabe, Takaaki Akaike

    MICROBIOLOGY AND IMMUNOLOGY　56　(3)　145-154　2012/03

    DOI： 10.1111/j.1348-0421.2012.00421.x 　

    ISSN： 0385-5600

  215. Activity-dependent nitric oxide signaling protects dopaminergic neurons via protein S-guanylation Peer-reviewed

    Yuki Kurauchi, Akinori Hisatsune, Yoichiro Isohama, Tomohiro Sawa, Takaaki Akaike, Hiroshi Katsuki

    JOURNAL OF PHARMACOLOGICAL SCIENCES　118　187P-187P　2012

    ISSN： 1347-8613

  216. Regulation by mitochondrial superoxide and NADPH oxidase of cellular formation of nitrated cyclic GMP: potential implications for ROS signalling Peer-reviewed

    Khandaker Ahtesham Ahmed, Tomohiro Sawa, Hideshi Ihara, Shingo Kasamatsu, Jun Yoshitake, Md. Mizanur Rahaman, Tatsuya Okamoto, Shigemoto Fujii, Takaaki Akaike

    BIOCHEMICAL JOURNAL　441　(2)　719-730　2012/01

    DOI： 10.1042/BJ20111130 　

    ISSN： 0264-6021

  217. The critical role of nitrated cyclic guanine nucleotide signaling via protein S-guanylation in the antioxidant adaptive response Peer-reviewed

    Shigemoto Fujii, Takaaki Akaike

    Seikagaku　84　(2)　124-128　2012

    ISSN： 0037-1017

  218. Nitric oxide promotes recycling of 8-nitro-cGMP, a cytoprotective mediator, into intact cGMP in cells Peer-reviewed

    Yohei Saito, Tomohiro Sawa, Jun Yoshitake, Chiaki Ito, Shigemoto Fujii, Takaaki Akaike, Hirokazu Arimoto

    MOLECULAR BIOSYSTEMS　8　(11)　2909-2915　2012

    DOI： 10.1039/c2mb25189b 　

    ISSN： 1742-206X

  219. Nitric oxide regulation of cellular functions Peer-reviewed

    Tomohiro Sawa, Takaaki Akaike

    GENES & GENETIC SYSTEMS　86　(6)　387-387　2011/12

    ISSN： 1341-7568

    eISSN： 1880-5779

  220. Cellular uptake mechanisms and responses to NO transferred from mono- and poly-S-nitrosated human serum albumin Peer-reviewed

    Yu Ishima, Fumika Yoshida, Ulrich Kragh-Hansen, Kaori Watanabe, Naohisa Katayama, Keisuke Nakajou, Takaaki Akaike, Toshiya Kai, Toru Maruyama, Masaki Otagiri

    FREE RADICAL RESEARCH　45　(10)　1196-1206　2011/10

    DOI： 10.3109/10715762.2011.606814 　

    ISSN： 1071-5762

  221. 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

  222. Methodological proof of immunochemistry for specific identification of 8-nitroguanosine 3 &apos;,5 &apos;-cyclic monophosphate formed in glia cells Peer-reviewed

    Hideshi Ihara, Ahmed Khandaker Ahtesham, Tomoaki Ida, Shingo Kasamatsu, Kouhei Kunieda, Tatsuya Okamoto, Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　25　(2)　169-175　2011/08

    DOI： 10.1016/j.niox.2011.04.015 　

    ISSN： 1089-8603

  223. Frontiers in nitric oxide and redox signaling Preface Peer-reviewed

    Takaaki Akaike, Albert van der Vliet, Philip Eaton

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　25　(2)　57-58　2011/08

    DOI： 10.1016/j.niox.2011.05.002 　

    ISSN： 1089-8603

  224. Protein S-guanylation and its unique regulation mechanisms involving cysteine metabolism Peer-reviewed

    Takaaki Akaike

    AMINO ACIDS　41　S77-S77　2011/07

    ISSN： 0939-4451

  225. Antioxidant Effect of a Nitrated Cyclic Nucleotide Functioning as an Endogenous Electrophile Peer-reviewed

    Tomohiro Sawa, Hideshi Ihara, Takaaki Akaike

    CURRENT TOPICS IN MEDICINAL CHEMISTRY　11　(14)　1854-1860　2011/07

    DOI： 10.2174/156802611796235080 　

    ISSN： 1568-0266

  226. Protein cysteine S-guanylation and electrophilic signal transduction by endogenous nitro-nucleotides Peer-reviewed

    Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike

    AMINO ACIDS　41　(1)　123-130　2011/06

    DOI： 10.1007/s00726-010-0535-1 　

    ISSN： 0939-4451

  227. Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice Peer-reviewed

    Yoshiko Tokutomi, Keiichiro Kataoka, Eiichiro Yamamoto, Taishi Nakamura, Masaya Fukuda, Hisato Nako, Kensuke Toyama, Yi-Fei Dong, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike, Shokei Kim-Mitsuyama

    BRITISH JOURNAL OF PHARMACOLOGY　162　(8)　1884-1893　2011/04

    DOI： 10.1111/j.1476-5381.2011.01201.x 　

    ISSN： 0007-1188

  228. Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF Peer-reviewed

    Yuki Kurauchi, Akinori Hisatsune, Yoichiro Isohama, Tomohiro Sawa, Takaaki Akaike, Koichi Shudo, Hiroshi Katsuki

    JOURNAL OF NEUROCHEMISTRY　116　(3)　323-333　2011/02

    DOI： 10.1111/j.1471-4159.2010.06916.x 　

    ISSN： 0022-3042

  229. Retinoid signaling regulates axonal morphology of midbrain dopaminergic neurons Peer-reviewed

    Yuki Kurauchi, Akinori Hisatsune, Yoichiro Isohama, Tomohiro Sawa, Takaaki Akaike, Koichi Shudo, Hiroshi Katsuki

    JOURNAL OF PHARMACOLOGICAL SCIENCES　115　133P-133P　2011

    ISSN： 1347-8613

  230. Retinoic acid receptor-regulated NO/cyclic GMP signaling pathway promotes S-guanylation of beta-tubulin and activation of MEK/ERK signaling pathway resulting in neurite differentiation in SH-SY5Y neuroblastoma cells Peer-reviewed

    Yuki Kurauchi, Akinori Hisatsune, Yoichiro Isohama, Tomohiro Sawa, Takaaki Akaike, Koichi Shudo, Hiroshi Katsuki

    NEUROSCIENCE RESEARCH　71　E115-E115　2011

    DOI： 10.1016/j.neures.2011.07.490 　

    ISSN： 0168-0102

  231. Nucleotides function as endogenous chemical sensors for oxidative stress signaling Peer-reviewed

    Hideshi Ihara, Tomohiro Sawa, Yusaku Nakabeppu, Takaaki Akaike

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION　48　(1)　33-39　2011/01

    DOI： 10.3164/jcbn.11-003FR 　

    ISSN： 0912-0009

    eISSN： 1880-5086

  232. Cell signaling mediated by nitrated cyclic guanine nucleotide Peer-reviewed

    Takaaki Akaike, Shigemoto Fujii, Tomohiro Sawa, Hideshi Ihara

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　23　(3)　166-174　2010/11

    DOI： 10.1016/j.niox.2010.06.006 　

    ISSN： 1089-8603

  233. One-step preparation of S-nitrosated human serum albumin with high biological activities Peer-reviewed

    Yu Ishima, Shuichi Hiroyama, Ulrich Kragh-Hansen, Toru Maruyama, Tomohiro Sawa, Takaaki Akaike, Toshiya Kai, Masaki Otagiri

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　23　(2)　121-127　2010/09

    DOI： 10.1016/j.niox.2010.05.002 　

    ISSN： 1089-8603

  234. Regulation of Redox Signaling Involving Chemical Conjugation of Protein Thiols by Nitric Oxide and Electrophiles Peer-reviewed

    Tomohiro Sawa, Hirokazu Arimoto, Takaaki Akaike

    BIOCONJUGATE CHEMISTRY　21　(7)　1121-1129　2010/07

    DOI： 10.1021/bc900396u 　

    ISSN： 1043-1802

  235. The Critical Role of Nitric Oxide Signaling, via Protein S-Guanylation and Nitrated Cyclic GMP, in the Antioxidant Adaptive Response Peer-reviewed

    Shigemoto Fujii, Tomohiro Sawa, Hideshi Ihara, Kit I. Tong, Tomoaki Ida, Tatsuya Okamoto, Ahmed Khandaker Ahtesham, Yu Ishima, Hozumi Motohashi, Masayuki Yamamoto, Takaaki Akaike

    JOURNAL OF BIOLOGICAL CHEMISTRY　285　(31)　23970-23984　2010/07

    DOI： 10.1074/jbc.M110.145441 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  236. [Nitric oxide (NO) and its related compounds]. Peer-reviewed

    Okamoto T, Sawa T, Akaike T

    Nihon rinsho. Japanese journal of clinical medicine　68 Suppl 7　839-842　2010/07

    ISSN： 0047-1852

  237. Chemical studies on protein modifications by nitronucleotides Peer-reviewed

    Hirokazu Arimoto, Yohei Saito, Eriko Kida, Takashi Tanoi, Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S7-S7　2010/06

    DOI： 10.1016/j.niox.2010.05.012 　

    ISSN： 1089-8603

  238. Nitrated cGMP: a new player in guard cell signaling Peer-reviewed

    Sumio Iwai, Takahiro Joudoi, Yudai Shichiri, Nobuto Kamizonon, Takaaki Akaike, Tomoiro Sawa

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S22-S22　2010/06

    DOI： 10.1016/j.niox.2010.05.061 　

    ISSN： 1089-8603

  239. New nitric oxide signaling via 8-nitro-cyclic GMP formation and protein S-guanylation Peer-reviewed

    Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S34-S34　2010/06

    DOI： 10.1016/j.niox.2010.05.098 　

    ISSN： 1089-8603

  240. Elucidation of metabolite of endogenous nitrated nucleotide using chemical probes Peer-reviewed

    Yohei Saito, Tomohiro Sawa, Takaaki Akaike, Hirokazu Arimoto

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S44-S44　2010/06

    DOI： 10.1016/j.niox.2010.05.126 　

    ISSN： 1089-8603

  241. Chemical basis for mechanism of 8-nitroguanosine 3&apos;,5&apos;-cyclic monophosphate formation in cells Peer-reviewed

    Khandaker Ahtesham Ahmed, Tomohiro Sawa, Tomoaki Ida, Hideshi Ihara, Tatsuya Okamoto, Shigemoto Fujii, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S48-S49　2010/06

    DOI： 10.1016/j.niox.2010.05.139 　

    ISSN： 1089-8603

  242. Live cell imaging using fluorescent probe based on 8-nitroguanosine Peer-reviewed

    Chiaki Ito, Yohei Saito, Shigemoto Fujii, Tatsuya Okamoto, Tomohiro Sawa, Takaaki Akaike, Hirokazu Arimoto

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S49-S49　2010/06

    DOI： 10.1016/j.niox.2010.05.141 　

    ISSN： 1089-8603

  243. Retinoic acid receptor stimulation activates NO/cyclic GMP-dependent MEK/ERK signaling pathway leading to upregulation of BDNF expression in midbrain dopaminergic neurons Peer-reviewed

    Yuki Kurauche, Akinori Hisatsune, Yoichiro Isohama, Tomohiro Sawa, Takaaki Akaike, Koichi Shudo, Hiroshi Katsuki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S54-S54　2010/06

    DOI： 10.1016/j.niox.2010.05.154 　

    ISSN： 1089-8603

  244. Activation of EGFR coupled to reduction of PTP1B activity by nitrated oleic acid: an electrophile signaling Peer-reviewed

    Noriko Iwamoto, Takaaki Akaike, Bruce A. Freeman, Kumagal Yoshito

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S56-S56　2010/06

    DOI： 10.1016/j.niox.2010.05.161 　

    ISSN： 1089-8603

  245. Proteomic identification for sulfhydryl modifications of mitochondrial proteins by 8-nitroguanosine 3&apos;,5&apos;-cyclic monophosphate Peer-reviewed

    Mizanur Rahaman, Tomohlro Sawa, Tatsuya Okamoto, Shigemoto Fujii, Katsuhiko Ono, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S57-S57　2010/06

    DOI： 10.1016/j.niox.2010.05.166 　

    ISSN： 1089-8603

  246. Role of Keap1 S-guanylation in the antioxidant adaptive response in C6 glioma cells Peer-reviewed

    Shigemoto Fujii, Tomohiro Sawa, Hideshi Ihara, Tomoaki Ida, Tatsuya Okamoto, Hozumi Motohashi, Masayuki Yamamoto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S58-S58　2010/06

    DOI： 10.1016/j.niox.2010.05.168 　

    ISSN： 1089-8603

  247. Estrogen receptor-dependent or -independent suppression of NO production and 8-nitroguanosine formation by endocrine-disrupting chemicals Peer-reviewed

    Jun Yoshitake, Katsuaki Kato, Tomohiro Sawa, Takaaki Akaike, Tetsuhiko Yoshimura

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S58-S58　2010/06

    DOI： 10.1016/j.niox.2010.05.167 　

    ISSN： 1089-8603

  248. Activation mechanism of cGMP-dependent protein kinase by a nitrated derivative of cGMP Peer-reviewed

    Kohta Oyama, Ahmed Khandaker Ahtesham, Tomohiro Sawa, Tatsuya Okamoto, Shigemoto Fujii, Philip Eaton, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S57-S57　2010/06

    DOI： 10.1016/j.niox.2010.05.165 　

    ISSN： 1089-8603

  249. Modulation of exocytosis by a novel nitrated second messenger, 8-nitroguanosine 3&apos;,5&apos;-cyclic monophosphate Peer-reviewed

    Hiroyasu Tsutsuki, Tomoaki Ida, Nobuyuki Sasakawa, Mitsuki Hayashi, Konosuke Kumakura, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S56-S57　2010/06

    DOI： 10.1016/j.niox.2010.05.163 　

    ISSN： 1089-8603

  250. Superoxide generation from neuronal nitric oxide synthise splice variants and its potential involvement in NO-ROS signaling Peer-reviewed

    Hideshi Ihara, Tomoaki Ida, Tomohiro Sawa, Yasuo Watanabe, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S58-S58　2010/06

    DOI： 10.1016/j.niox.2010.05.169 　

    ISSN： 1089-8603

  251. Potential involvement of 8-nitro-cGMP in oxidative stress-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Peer-reviewed

    Takashi Aoki, Ono Katuhiko, Nakajima Hidemitsu, Yamaji Ryoichi, Sawa Tomohiro, Ihara Hideshi, Akaike Takaaki

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S59-S59　2010/06

    DOI： 10.1016/j.niox.2010.05.170 　

    ISSN： 1089-8603

  252. S-guanylation of synaptosomal-associated protein of 25 kDa (SNAP25) Peer-reviewed

    Kouhei Kunieda, Tomoaki Ida, Tomohiro Sawa, Takaaki Akaike, Makoto Itakura, Masami Takahashi, Hideshi Ihara

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S70-S70　2010/06

    DOI： 10.1016/j.niox.2010.05.205 　

    ISSN： 1089-8603

  253. Regulatory mechanism of calcium-dependent glutamate release from astrocytes mediated by cytokines via the nitric oxide signal pathway Peer-reviewed

    Tomoaki Ida, Shigemoto Fujii, Tomohiro Sawa, Akaike Takaaki, Ihara Hideshi

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S70-S70　2010/06

    DOI： 10.1016/j.niox.2010.05.204 　

    ISSN： 1089-8603

  254. Nitric oxide promotes odontoblastic differentiation Peer-reviewed

    Yoichi Miyamoto, Rika Yasuhara, Tetsuo Suzawa, Xiaogu Wang, Kentaro Yoshimura, Toshifumi Maruyama, Tomohito Akiyama, Masamichi Takami, Atsushi Yamada, Tomohiro Sawa, Takaaki Akaike, Tetsuhiko Tachikawa, Kazuyoshi Baba, Ryutaro Kamijo

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S76-S77　2010/06

    DOI： 10.1016/j.niox.2010.05.226 　

    ISSN： 1089-8603

  255. Nitration of 3&apos;,5&apos;-cyclic diguanylic acid, a bacterial signaling molecule Peer-reviewed

    Katsuhiko Ono, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S78-S79　2010/06

    DOI： 10.1016/j.niox.2010.05.233 　

    ISSN： 1089-8603

  256. Detection of protein-bound 3-nitrotyrosine in plasma from pediatric patients with fulminant ARDS and avian influenza infection Peer-reviewed

    Tatsuya Okamoto, Tomohiro Sawa, Shigemoto Fujii, Mie Tateyame, Shoji Kawachi, Thuy Thi Pung, Lien Thanh Nguyen, Kazuo Suzuki, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S87-S87　2010/06

    DOI： 10.1016/j.niox.2010.05.259 　

    ISSN： 1089-8603

  257. Guanine nitration and oxidative stress responses during influenza virus pneumonia in mice Peer-reviewed

    Shahzada Khan, Tatsuya Okamoto, Tomohiro Sawa, Shigemoto Fujii, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S85-S85　2010/06

    DOI： 10.1016/j.niox.2010.05.252 　

    ISSN： 1089-8603

  258. Vascular responses to 8-nitroguanosine 3&apos;,5&apos;-cyclic monophosphate in non-diabetic and diabetic mice Peer-reviewed

    Yoshiko Tokutomi, Keiichiro Kataoka, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike, Shokei Kim-Mitsuyama

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　22　S89-S89　2010/06

    DOI： 10.1016/j.niox.2010.05.266 　

    ISSN： 1089-8603

  259. 血中における内因性S-cGMP化血清アルブミンの検出と機能評価 Peer-reviewed

    異島 優, 星野 瞳, 赤池 孝章, 渡邊 博志, 小田切 優樹, 丸山 徹

    日本薬学会年会要旨集　130年会　(3)　143-143　2010/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  260. NO signaling via a unique nucleotide sensing mediated by elctrophilic nitrated cyclic GMP Peer-reviewed

    Takaaki Akaike

    JOURNAL OF PHARMACOLOGICAL SCIENCES　112　21P-21P　2010

    ISSN： 1347-8613

  261. Regulation of SNARE complex formation by 8-nitro-cGMP Peer-reviewed

    Kouhei Kunieda, Tomoaki Ida, Tomohiro Sawa, Takaaki Akaike, Makoto Itakura, Masami Takahashi, Hideshi Ihara

    NEUROSCIENCE RESEARCH　68　E116-E117　2010

    DOI： 10.1016/j.neures.2010.07.2084 　

    ISSN： 0168-0102

  262. Nitric oxide/Reactive oxygen species signaling pathway in astrocytes: Regulation of calcium-dependent glutamate release Peer-reviewed

    Tomoaki Ida, Shigemoto Fujii, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara

    NEUROSCIENCE RESEARCH　68　E125-E125　2010

    DOI： 10.1016/j.neures.2010.07.2125 　

    ISSN： 0168-0102

  263. A New Paradigm for Antimicrobial Host Defense Mediated by a Nitrated Cyclic Nucleotide Peer-reviewed

    Tatsuya Okamoto, Shahzada Khan, Kohta Oyama, Shigemoto Fujii, Tomohiro Sawa, Takaaki Akaike

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION　46　(1)　14-19　2010/01

    DOI： 10.3164/jcbn.SR09-70 　

    ISSN： 0912-0009

    eISSN： 1880-5086

  264. 強力な臓器保護剤としての新規S-ニトロソヒト血清アルブミンの開発 Peer-reviewed

    異島 優, 赤池 孝章, 廣山 秀一, 澤 智裕, 末永 綾香, 丸山 徹, 甲斐 俊哉, 小田切 優樹

    人工血液　17　(3)　119-119　2009/09

    Publisher: 日本血液代替物学会

    ISSN： 1341-1594

  265. Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis Peer-reviewed

    Mohammad Hasan Zaki, Shigemoto Fujii, Tatsuya Okamoto, Sabrina Islam, Shahzada Khan, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike

    JOURNAL OF IMMUNOLOGY　182　(6)　3746-3756　2009/03

    DOI： 10.4049/jimmunol.0803363 　

    ISSN： 0022-1767

  266. THE DETECTION OF ENDOGENOUS S-GUANYLATED HUMAN SERUM ALBUMIN.

    Hoshino Hitomi, Ishima Yu, Akaike Takaaki, Watanabe Hiroshi, Otagiri Masaki, Maruyama Toru

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics　24　160-160　2009

    Publisher: The Japanese Society for the Study of Xenobiotics

    DOI： 10.14896/jssxmeeting.24.0.160.0 　

  267. Effects of 8-nitro-cGMP on vascular responsiveness Peer-reviewed

    Yoshiko Tokutomi, Keiichiro Kataoka, Eiichiro Yamamoto, Taishi Nakamura, Masaya Fukuda, Tomohiro Sawa, Takaaki Akaike, Shokei Kim-Mitsuyama

    JOURNAL OF PHARMACOLOGICAL SCIENCES　109　105P-105P　2009

    ISSN： 1347-8613

  268. New paradigm of host defense against intracellular pathogens by nitric oxide Peer-reviewed

    Takaaki Akaike, Tatsuya Okamoto, Hasan Md Zaki, Shigemoto Fujii, Tomohiro Sawa

    Japanese Journal of Leprosy　78　(1)　41-47　2009

    DOI： 10.5025/hansen.78.41 　

    ISSN： 1342-3681 1884-314X

  269. S-nitrosylated human serum albumin-mediated cytoprotective activity is enhanced by fatty acid binding. International-journal Peer-reviewed

    Yu Ishima, Takaaki Akaike, Ulrich Kragh-Hansen, Shuichi Hiroyama, Tomohiro Sawa, Ayaka Suenaga, Toru Maruyama, Toshiya Kai, Masaki Otagiri

    The Journal of biological chemistry　283　(50)　34966-75　2008/12/12

    DOI： 10.1074/jbc.M807009200 　

    ISSN： 0021-9258

  270. S-Nitrosylated Human Serum Albumin-mediated Cytoprotective Activity Is Enhanced by Fatty Acid Binding Peer-reviewed

    Yu Ishima, Takaaki Akaike, Ulrich Kragh-Hansen, Shuichi Hiroyama, Tomohiro Sawa, Ayaka Suenaga, Toru Maruyama, Toshiya Kai, Masaki Otagiri

    JOURNAL OF BIOLOGICAL CHEMISTRY　283　(50)　34966-34975　2008/12

    DOI： 10.1074/jbc.M807009200 　

    ISSN： 0021-9258

  271. Suppression of NO production and 8-nitroguano sine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: Involvement of estrogen receptor-dependent or -independent pathways Peer-reviewed

    Jun Yoshitake, Katsuaki Kato, Daisuke Yoshioka, Yoshimi Sueishi, Tomohiro Sawa, Takaaki Akaike, Tetsuhiko Yoshimura

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　18　(3)　223-228　2008/05

    DOI： 10.1016/j.niox.2008.01.003 　

    ISSN： 1089-8603

  272. Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2-eNOS-NO pathway in a mouse hind-limb ischemia model Peer-reviewed

    Takashi Urano, Yasuhiro Ito, Masaki Akao, Tomohiro Sawa, Keishi Miyata, Mitsuhisa Tabata, Tohru Morisada, Tai Hato, Masato Yano, Tsuyoshi Kadomatsu, Kunio Yasunaga, Rei Shibata, Toyoaki Murohara, Takaaki Akaike, Hidenobu Tanihara, Toshio Suda, Yuichi Oike

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　28　(5)　827-834　2008/05

    DOI： 10.1161/ATVBAHA.107.149674 　

    ISSN： 1079-5642

  273. Nitric oxide regulation of MMP-9 activation and its relationship to modifications of the cysteine switch Peer-reviewed

    Sean M. McCarthy, Peter F. Bove, Dwight E. Matthews, Takaaki Akaike, Albert van der Vliet

    BIOCHEMISTRY　47　(21)　5832-5840　2008/05

    DOI： 10.1021/bi702496v 　

    ISSN： 0006-2960

  274. Mutagenicity of 8-nitroguanosine, a product of nitrative nucleoside modification by reactive nitrogen oxides, in mammalian cells Peer-reviewed

    Kazuyoshi Kaneko, Teruo Akuta, Tomohiro Sawa, Ha Won Kim, Shigemoto Fujii, Tatsuya Okamoto, Hitoshi Nakayama, Hajime Ohigashi, Akira Murakami, Takaaki Akaike

    CANCER LETTERS　262　(2)　239-247　2008/04

    DOI： 10.1016/j.canlet.2007.12.007 　

    ISSN： 0304-3835

  275. Nitric oxide produced in Peyer's patches exhibits antiapoptotic activity contributing to an antimicrobial effect in murine salmonellosis Peer-reviewed

    Mohammad S. Alam, Mohammad H. Zaki, Tomohiro Sawa, Sabrina Islam, Khandaker A. Ahmed, Shigemoto Fujii, Tatsuya Okamoto, Takaaki Akaike

    MICROBIOLOGY AND IMMUNOLOGY　52　(4)　197-208　2008/04

    DOI： 10.1111/j.1348.0421.2008.00030.x 　

    ISSN： 0385-5600

  276. 細胞膜上での一酸化窒素放出における脂肪酸結合の影響 Peer-reviewed

    異島 優, 廣山 秀一, 赤池 孝章, 澤 智裕, 丸山 徹, 小田切 優樹

    日本薬学会年会要旨集　128年会　(3)　66-66　2008/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  277. Identification of the major antigenic protein of Helicobacter cinaedi and its immunogenicity in humans with H. cinaedi infections Peer-reviewed

    Hirofumi Iwashita, Shigemoto Fujii, Yoshiaki Kawamura, Tatsuya Okamoto, Tomohiro Sawa, Takayuki Masaki, Akira Nishizono, Shuichi Higashi, Toshio Kitamura, Fumio Tamura, Yutaka Sasaki, Takaaki Akaike

    CLINICAL AND VACCINE IMMUNOLOGY　15　(3)　513-521　2008/03

    DOI： 10.1128/CVI.00439-07 　

    ISSN： 1556-6811

  278. FATTY ACIDS COULD BE A NOVEL TYPE OF MEDIATOR OF S-TRANSNITROSATION FROM S-NITROSYLATED HUMAN SERUM ALBUMIN

    Ishima Yu, Akaike Takaaki, Sawa Tomohiro, Suenaga Ayaka, Maruyama toru, Kai Toshiya, Otagiri Masaki

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics　23　191-191　2008

    Publisher: The Japanese Society for the Study of Xenobiotics

    DOI： 10.14896/jssxmeeting.23.0.191.0 　

  279. S-nitrosylated human serum albumin-mediated cytoprotective activity is enhanced by fatty acid binding

    Yu Ishima, Shuichi Hiroyama, Takaaki Akaike, Tomohiro Sawa, Ayaka Suenaga, Toru Maruyama, Ulrich Kragh-Hansen, Toshiya Kai, Masaki Otagiri

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN　128　85-86　2008

    ISSN： 0031-6903

  280. S-NITROSYLATED HUMAN SERUM ALBUMIN-MEDIATED CYTOPROTECTIVE ACTIVITY IS ENHANCED BY FATTY ACIDS BINDING Peer-reviewed

    Yu Ishima, Takaaki Akaike, Ulrich Kragh-Hansen, Shuichi Hiroyama, Tomohiro Sawa, Ayaka Suenaga, Toru Maruyama, Toshiya Kai, Masaki Otagiri

    DRUG METABOLISM REVIEWS　40　112-113　2008

    ISSN： 0360-2532

  281. Protein S-guanylation induced by 8-nitro-cGMP Peer-reviewed

    Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S21-S21　2008

    DOI： 10.1016/j.niox.2008.06.006 　

    ISSN： 1089-8603

  282. Physiological role of Keap1 S-guanylation by 8-nitroguanosine 3&apos;,5&apos;-cyclic monophosphate formed in C6 glioma cells Peer-reviewed

    Shigemoto Fujii, Tomohiro Sawa, Tatsuya Okamoto, Hideshi Ihara, Hozumi Motohashi, Masayuki Yamamoto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S35-S36　2008

    DOI： 10.1016/j.niox.2008.06.069 　

    ISSN： 1089-8603

  283. Guanine nitration and host defense during influenza virus pneumonia Peer-reviewed

    Tatsuya Okamoto, Tomohiro Sawa, Shigernoto Fujii, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S60-S60　2008

    DOI： 10.1016/j.niox.2008.06.173 　

    ISSN： 1089-8603

  284. Nitric oxide-dependent sulfhydryl modification of Keap1 by 8-nitroguanosine 3 ',5 '-cyclic monophosphate Peer-reviewed

    Tomohiro Sawa, Shigemoto Fujii, Atsushi Irie, Tatsuya Okamoto, Hozumi Motohashi, Masayuki Yamamoto, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S61-S61　2008

    DOI： 10.1016/j.niox.2008.06.176 　

    ISSN： 1089-8603

  285. Superoxide production by neuronal nitric oxide synthase (nNOS)-alpha and nNOS-mu Peer-reviewed

    Hideshi Ihara, Yousuke Inui, Tomoaki Ida, Tomohiro Sawa, Yasuo Watanabe, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　19　S64-S64　2008

    DOI： 10.1016/j.niox.2008.06.188 　

    ISSN： 1089-8603

  286. 8-Nitroguanosines as chemical probes of the protein S-guanylation Peer-reviewed

    Yohei Saito, Hirobumi Taguchi, Shigemoto Fujii, Tomohiro Sawa, Eriko Kida, Chizuko Kabuto, Takaaki Akaike, Hirokazu Arimoto

    CHEMICAL COMMUNICATIONS　(45)　5984-5986　2008

    DOI： 10.1039/b810771h 　

    ISSN： 1359-7345

  287. Effects of endogenous ligands on the biological role of human serum albumin in S-nitrosylation Peer-reviewed

    Yu Ishima, Takaaki Akaike, Ulrich Kragh-Hansen, Shuichi Hiroyama, Tomohiro Sawa, Toru Maruyama, Toshiya Kai, Masaki Otagiri

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　364　(4)　790-795　2007/12

    DOI： 10.1016/j.bbrc.2007.10.094 　

    ISSN： 0006-291X

  288. Protein S-guanylation by the biological signal 8-nitroguanosine 3 &apos;,5 &apos;-cyclic monophosphate Peer-reviewed

    Tomohiro Sawa, Mohammad Hasan Zaki, Tatsuya Okamoto, Teruo Akuta, Yoshiko Tokutomi, Shokei Kim-Mitsuyama, Hideshi Ihara, Akira Kobayashi, Masayuki Yamamoto, Shigemoto Fujii, Hirokazu Arimoto, Takaaki Akaike

    NATURE CHEMICAL BIOLOGY　3　(11)　727-735　2007/11

    DOI： 10.1038/nchembio.2007.33 　

    ISSN： 1552-4450

    eISSN： 1552-4469

  289. Nitrative stress in respiratory inflammation caused by influenza virus infection

    Md H. Zaki, T. Okamoto, T. Sawa, S. Fujii, T. Akaike

    Clinical and Experimental Allergy Reviews　7　(1)　19-26　2007/08

    DOI： 10.1111/j.1365-2222.2007.00120.x 　

    ISSN： 1472-9725

  290. 内因性リガンド結合が及ぼすヒト血清アルブミンのS-ニトロソ化効率への影響 Peer-reviewed

    異島 優, 赤池 孝章, 廣山 秀一, 澤 智裕, 丸山 徹, 小田切 優樹

    日本薬学会年会要旨集　127年会　(2)　5-5　2007/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  291. S-nitrosylation of human variant albumin liprizzi (R410C) confers potent antibacterial and cytoprotective properties Peer-reviewed

    Yu Ishima, Tomohiro Sawa, Ulrich Kragh-Hansen, Yoichi Miyamoto, Sadaharu Matsushita, Takaaki Akaike, Masaki Otagiri

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS　320　(3)　969-977　2007/03

    DOI： 10.1124/jpet.106.114959 　

    ISSN： 0022-3565

  292. [NO-induced mutagenesis for microbial pathogen and host defense suppression]. Peer-reviewed

    Okamoto T, Fujii S, Sawa T, Akaike T

    Nihon rinsho. Japanese journal of clinical medicine　65 Suppl 2 Pt. 1　78-84　2007/02

    ISSN： 0047-1852

  293. EFFECT OF NITRIC OXIDE IN TRANSTHYRETIN-RELATED AMYLOIDOSIS Peer-reviewed

    Shiori Saito, Yukio Ando, Mitsuharu Ueda, Masaaki Nakamura, Jaemi Kim, Yu Ishima, Takaaki Akaike, Masaki Otagiri

    DRUG METABOLISM REVIEWS　39　297-298　2007

    ISSN： 0360-2532

  294. Helicobacter cinaedi cellulitis and bacteremia in immunocompetent hosts after orthopedic surgery Peer-reviewed

    Toshio Kitamura, Yoshiaki Kawamura, Kiyofumi Ohkusu, Takayuki Masaki, Hirofumi Iwashita, Tomohiro Sawa, Shigemoto Fujii, Tatsuya Okamoto, Takaaki Akaike

    JOURNAL OF CLINICAL MICROBIOLOGY　45　(1)　31-38　2007/01

    DOI： 10.1128/JCM.01507-06 　

    ISSN： 0095-1137

  295. Effect of nitric oxide on amyloid formation in transthyretin-related amyloidosis

    S. Saito, Y. Ando, M. Ueda, J. Kim, M. Nakamura, T. Yamashita, K. Obayashi, Y. Misumi, S. Shinriki, S. Himeno, W. Meng, Y. Ishima, T. Akaike, M. Otagiri

    AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS　13　57-57　2006/11

    ISSN： 1350-6129

  296. Nitric oxide-induced downregulation of leptin production by 3T3-L1 adipocytes Peer-reviewed

    Yuka Unno, Teruo Akuta, Yu-ichiro Sakamoto, Seikoh Horiuchi, Takaaki Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　15　(2)　125-132　2006/09

    DOI： 10.1016/j.niox.2005.12.002 　

    ISSN： 1089-8603

  297. Guanine nitration in idiopathic pulmonary fibrosis and its implication for carcinogenesis Peer-reviewed

    Yasuhiro Terasaki, Teruo Akuta, Mika Terasaki, Tomohiro Sawa, Takeshi Mori, Tatsuya Okamoto, Masakazu Ozaki, Motohiro Takeya, Takaaki Akaike

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　174　(6)　665-673　2006/09

    DOI： 10.1164/rccm.200510-1580OC 　

    ISSN： 1073-449X

  298. S-ニトロソ化アルブミンの調製と評価 Peer-reviewed

    廣山 秀一, 異島 優, 赤池 孝章, 小田切 優樹

    人工血液　14　(1)　24-24　2006/08

    Publisher: 日本血液代替物学会

    ISSN： 1341-1594

  299. 酸化ストレスと毒作用発現 NOによるニトロ化ストレスとシグナル伝達機構

    赤池 孝章, 澤 智裕

    The Journal of Toxicological Sciences　31　(Suppl.)　S33-S33　2006/06

    Publisher: (一社)日本毒性学会

    ISSN： 0388-1350

  300. Hepatic targeting system of S-nitrosylated human serum albumin enhanced by endogenous ligands binding

    Y Ishima, M Otagiri, S Hiroyama, T Sawa, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　14　(4)　A42-A42　2006/06

    DOI： 10.1016/j.niox.2006.04.144 　

    ISSN： 1089-8603

  301. Guanine nitration in idiopathic pulmonary fibrosis

    Y Terasaki, T Okamoto, T Akuta, T Sawa, M Takeya, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　14　(4)　A63-A63　2006/06

    DOI： 10.1016/j.niox.2006.04.205 　

    ISSN： 1089-8603

  302. Nitrative signal transduction: A unique signaling pathway mediated via NO-dependent nitration of guanosine derivatives

    T Sawa, T Akuta, MH Zaki, K Kaneko, Y Tokutomi, S Mitsuyama, H Arimoto, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　14　(4)　A33-A34　2006/06

    ISSN： 1089-8603

  303. Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage - Critical dimerization of inducible nitric-oxide synthase Peer-reviewed

    K Sakai, H Suzuki, H Oda, T Akaike, Y Azuma, T Murakami, K Sugi, T Ito, H Ichinose, S Koyasu, M Shirai

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(26)　17736-17742　2006/06

    DOI： 10.1074/jbc.M601896200 　

    ISSN： 0021-9258

  304. 8-Nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species: Formation, occurrence, and implications in inflammation and carcinogenesis Peer-reviewed

    Hiroshi Ohshima, Tomohiro Sawa, Takaaki Akaike

    ANTIOXIDANTS & REDOX SIGNALING　8　(5-6)　1033-1045　2006/05

    DOI： 10.1089/ars.2006.8.1033 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  305. 内因性リガンド結合が及ぼすヒト血清アルブミンのS-ニトロソ化反応 Peer-reviewed

    異島 優, 廣山 秀一, 芥 照夫, 赤池 孝章, 小田切 優樹

    日本薬学会年会要旨集　126年会　(3)　59-59　2006/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  306. Nitrative stress through formation of 8-nitroguanosine: Insights into microbial pathogenesis Peer-reviewed

    T Akuta, MH Zaki, J Yoshitake, T Okamoto, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　14　(2)　101-108　2006/03

    DOI： 10.1016/j.niox.2005.10.004 　

    ISSN： 1089-8603

  307. Involvement of Salmonella enterica serovar Typhi RpoS in resistance to NO-mediated host defense against serovar Typhi infection Peer-reviewed

    MS Alam, MH Zaki, J Yoshitake, T Akuta, T Ezaki, T Akaike

    MICROBIAL PATHOGENESIS　40　(3)　116-125　2006/03

    DOI： 10.1016/j.micpath.2005.11.007 　

    ISSN： 0882-4010

  308. Immunocompetent hostに敗血症および蜂窩織炎を引き起こしたHelicobacter cinaediの細菌学的特徴

    河村 好章, 大楠 清文, 正木 孝幸, 岩下 博文, 芥 照夫, 江崎 孝行, 赤池 孝章, 北村 歳男, 山川 慶多

    日本細菌学雑誌　61　(1)　57-57　2006/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

    eISSN： 1882-4110

  309. Analysis of urinary 8-nitroguanine, a marker of nitrative nucleic acid damage, by high-performance liquid chromatography-electrochemical detection coupled with immunoaffinity purification: Association with cigarette smoking Peer-reviewed

    T Sawa, M Tatemichi, T Akaike, A Barbin, H Ohshima

    FREE RADICAL BIOLOGY AND MEDICINE　40　(4)　711-720　2006/02

    DOI： 10.1016/j.freeradbiomed.2005.09.035 　

    ISSN： 0891-5849

  310. NO is not a direct activator of MMP9 Peer-reviewed

    Sean N. Mccarthy, Peter F. Bove, John Heim, Dwight E. Matthews, Takaaki Akaike, Albert Van Der Vliet

    FREE RADICAL BIOLOGY AND MEDICINE　41　S127-S127　2006

    ISSN： 0891-5849

  311. Improved S-nitrosylation of human serum albumin affected by its endogenous free fatty acid ligand Peer-reviewed

    Yu Ishima, Shuichi Hiroyama, Masaki Otagiri, Takaaki Akaike

    DRUG METABOLISM REVIEWS　38　146-147　2006

    ISSN： 0360-2532

  312. 固形腫瘍モデルにおけるNOによるヘムオキシゲナーゼの発現制御と血中CO量変化 Peer-reviewed

    前田 達観, 樽木 千穂, 芥 照夫, 異島 優, 赤池 孝章

    日本癌学会総会記事　64回　475-475　2005/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  313. IL-1-induced chondrocyte death mediated by MOS and NADPH oxidase.

    R Yasuhara, Y Miyamoto, A Yamada, M Takami, T Suzawa, T Akaike, T Akuta, R Kamijo

    JOURNAL OF BONE AND MINERAL RESEARCH　20　(9)　S112-S112　2005/09

    ISSN： 0884-0431

  314. Effect of nitric oxide in amyloid fibril formation on transthyretin-related amyloidosis Peer-reviewed

    S Saito, Y Ando, M Nakamura, M Ueda, J Kim, Y Ishima, T Akaike, M Otagiri

    BIOCHEMISTRY　44　(33)　11122-11129　2005/08

    DOI： 10.1021/bi050327i 　

    ISSN： 0006-2960

  315. [Nitric oxide and its related compounds]. Peer-reviewed

    Akuta T, Akaike T

    Nihon rinsho. Japanese journal of clinical medicine　63 Suppl 8　791-793　2005/08

    ISSN： 0047-1852

  316. Interleukin-1 beta induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner Peer-reviewed

    R Yasuhara, Y Miyamoto, T Akaike, T Akuta, M Nakamura, M Takami, N Morimura, K Yasu, R Kamijo

    BIOCHEMICAL JOURNAL　389　(Pt 2)　315-323　2005/07

    DOI： 10.1042/BJ20041996 　

    ISSN： 0264-6021

  317. Nitric oxide-induced nitrative stress involved in microbial pathogenesis Peer-reviewed

    MH Zaki, T Akuta, T Akaike

    JOURNAL OF PHARMACOLOGICAL SCIENCES　98　(2)　117-129　2005/06

    ISSN： 1347-8613

  318. Influence of membrane fluidity on human immunodeficiency virus type 1 entry Peer-reviewed

    S Harada, K Yusa, K Monde, T Akaike, Y Maeda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　329　(2)　480-486　2005/04

    DOI： 10.1016/j.bbrc.2005.02.007 　

    ISSN： 0006-291X

  319. Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation Peer-reviewed

    T Okamoto, T Akuta, F Tamura, A van der Vliet, T Akaike

    BIOLOGICAL CHEMISTRY　385　(11)　997-1006　2004/11

    DOI： 10.1515/BC.2004.130 　

    ISSN： 1431-6730

  320. Quantitative analysis of 8-nitroguanine in biological fluids by HPLC-electrochemical detection coupled with immunoaffinity purification

    T Sawa, A Barbin, T Akaike, H Tazawa, S Ohnishi, H Ohshima

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　105-105　2004/08

    ISSN： 1089-8603

  321. 8-Nitroguanosine formation and heme oxygenase-1 upregulation during differentiation of 3T3-L1 preadipocytes

    Y Unno, T Akuta, T Akaike, Y Sakamoto, S Horiuchi

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　116-117　2004/08

    ISSN： 1089-8603

  322. 8-Nitroguanosine formation induced by NO and its potential cytoptotective effect

    T Akuta, T Akaike, J Yoshitake, K Kaneko, Y Terasaki, H Maeda

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　98-99　2004/08

    ISSN： 1089-8603

  323. Synthesis of a novel S-nitroso derivative from a human serum albumin variant and analysis for its biological activity

    Y Ishima, T Akaike, S Kanaba, T Akuta, Y Miyamoto, M Otagiri

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　90-90　2004/08

    ISSN： 1089-8603

  324. Formation of 8-nitroguanosine in mouse liver infected with Salmonella typhimurium

    MH Zaki, T Akuta, Y Terasaki, MS Alam, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　100-100　2004/08

    ISSN： 1089-8603

  325. Endothelial Cu,Zn-SOD plays a pivotal role in endothelium-dependent hyperpolarization in mice

    K Morikawa, H Kubota, T Matoba, M Hatanaka, T Fujiki, MAH Talukder, T Akaike, H Maeda, H Shimokawa

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　48-48　2004/08

    DOI： 10.1016/j.niox.2004.07.003 　

    ISSN： 1089-8603

  326. 8-Nitroguanosine formation in hyperoxia-induced lung injury

    Y Terasaki, T Akuta, M Takeya, T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　113-113　2004/08

    ISSN： 1089-8603

  327. 8-Nitroguanosine formation induced by NO in viral pneumonia and its involvement in redox signaling of the host

    T Akaike

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　44-45　2004/08

    ISSN： 1089-8603

  328. Role of nitric oxide in IL-beta-induced chondrocyte death

    R Yasuhara, Y Miyamoto, T Akaike, T Akuta, H Maeda, R Kamijo

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　102-102　2004/08

    ISSN： 1089-8603

  329. Nitric oxide is mutagenic for RNA virus without apparent antiviral activity

    J Ysohitake, T Akaike, T Akuta, F Tamura, T Ogura, H Esumi, H Maeda

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY　11　(1)　100-101　2004/08

    ISSN： 1089-8603

  330. Proapoptotic effect of proteolytic activation of matrix metalloproteinases by Streptococcus pyogenes thiol proteinase (Streptococcus pyrogenic exotoxin B) Peer-reviewed

    F Tamura, R Nakagawa, T Akuta, S Okamoto, S Hamada, H Maeda, S Kawabata, T Akaike

    INFECTION AND IMMUNITY　72　(8)　4836-4847　2004/08

    DOI： 10.1128/IAI.72.8.4836-4847.2004 　

    ISSN： 0019-9567

  331. Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity Peer-reviewed

    J Yoshitake, T Akaike, T Akuta, F Tamura, T Ogura, H Esumi, H Maeda

    JOURNAL OF VIROLOGY　78　(16)　8709-8719　2004/08

    DOI： 10.1128/JVI.78.16.8709-8719.2004 　

    ISSN： 0022-538X

  332. Antioxidative and antimutagenic activities of 4-vinyl-2,6-dimethoxyphenol (Canolol) isolated from canola oil Peer-reviewed

    H Kuwahara, A Kanazawa, D Wakamatu, S Morimura, K Kida, T Akaike, H Maeda

    JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY　52　(14)　4380-4387　2004/07

    DOI： 10.1021/jf040045 　

    ISSN： 0021-8561

  333. SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours Peer-reviewed

    K Greish, T Sawa, J Fang, T Akaike, H Maeda

    JOURNAL OF CONTROLLED RELEASE　97　(2)　219-230　2004/06

    DOI： 10.1016/j.conrel.2004.03.027 　

    ISSN： 0168-3659

  334. Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin Peer-reviewed

    J Fang, T Sawa, T Akaike, K Greish, H Maeda

    INTERNATIONAL JOURNAL OF CANCER　109　(1)　1-8　2004/03

    DOI： 10.1002/ijc.11644 　

    ISSN： 0020-7136

  335. Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment

    J Fang, T Akaike, H Maeda

    APOPTOSIS　9　(1)　27-35　2004/01

    ISSN： 1360-8185

  336. Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice Peer-reviewed

    T Okamoto, K Gohil, EI Finkelstein, P Bove, T Akaike, A van der Vliet

    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY　286　(1)　L198-L209　2004/01

    DOI： 10.1152/ajplung.00136.2003 　

    ISSN： 1040-0605

  337. Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway disease Peer-reviewed

    H Sugiura, M Ichinose, M Tomaki, H Ogawa, A Koarai, T Kitamuro, Y Komaki, T Akita, H Nishino, S Okamoto, T Akaike, T Hattori

    FREE RADICAL RESEARCH　38　(1)　49-57　2004/01

    DOI： 10.1080/10715760310001633817 　

    ISSN： 1071-5762

  338. Adsorption and infectivity of human immunodeficiency virus type 1 are modified by the fluidity of the plasma membrane for multiple-site binding Peer-reviewed

    S Harada, T Akaike, K Yusa, Y Maeda

    MICROBIOLOGY AND IMMUNOLOGY　48　(4)　347-355　2004

    ISSN： 0385-5600

  339. Enhanced chemotherapeutic response of tumor cells by targeted inhibition of heme oxygenase-I in solid tumor.

    H Maeda, J Fang, T Sawa, T Akaike

    CLINICAL CANCER RESEARCH　9　(16)　6073S-6073S　2003/12

    ISSN： 1078-0432

  340. Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization Peer-reviewed

    K Morikawa, H Shimokawa, T Matoba, H Kubota, T Akaike, MAH Talukder, M Hatanaka, T Fujiki, H Maeda, S Takahashi, A Takeshita

    JOURNAL OF CLINICAL INVESTIGATION　112　(12)　1871-1879　2003/12

    DOI： 10.1172/JCI200319351 　

    ISSN： 0021-9738

  341. Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative Peer-reviewed

    T Sawa, T Akaike, K Ichimori, T Akuta, K Kaneko, H Nakayama, DJ Stuehr, H Maeda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　311　(2)　300-306　2003/11

    DOI： 10.1016/j.bbrc.2003.10.003 　

    ISSN： 0006-291X

  342. Pegylated zinc protoporphyrin for cancer therapy: An antitumor strategy by targeted inhibition of heme oxygenase-1 in solid tumor

    J Fang, T Sawa, S Tanaka, T Akaike, G Khaled, H Maeda

    JOURNAL OF CONTROLLED RELEASE　91　(1-2)　265-266　2003/08

    ISSN： 0168-3659

  343. Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels Peer-reviewed

    T Matoba, H Shimokawa, K Morikawa, H Kubota, Kunihiro, I, L Urakami-Harasawa, Y Mukai, Y Hirakawa, T Akaike, A Takeshita

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　23　(7)　1224-1230　2003/07

    DOI： 10.1161/01.ATV.0000078601.79536.6C 　

    ISSN： 1079-5642

  344. In vivo antitumor activity of pegylated zinc protoporphyrin: Targeted inhibition of heme oxygenase in solid tumor Peer-reviewed

    J Fang, T Sawa, T Akaike, T Akuta, SK Sahoo, G Khaled, A Hamada, H Maeda

    CANCER RESEARCH　63　(13)　3567-3574　2003/07

    ISSN： 0008-5472

  345. Antiapoptotic effect of haem oxygenase-I induced by nitric oxide in experimental solid tumour Peer-reviewed

    S Tanaka, T Akaike, J Fang, T Beppu, M Ogawa, F Tamura, Y Miyamoto, H Maeda

    BRITISH JOURNAL OF CANCER　88　(6)　902-909　2003/03

    DOI： 10.1038/sj.bjc.6600830 　

    ISSN： 0007-0920

  346. Heme oxygenase and nitric oxide synthase on tumor growth Peer-reviewed

    K Doi, T Akaike, S Fujii, N Ikebe, T Beppu, M Ogawa, H Maeda

    BIOLOGICAL RESPONSE TO PLANNED AND UNPLANNED INJURIES: CELLULAR, MOLECULAR AND GENETIC ASPECTS　1255　265-268　2003

    DOI： 10.1016/S0531-5131(03)00881-1 　

    ISSN： 0531-5131

  347. Protective function of nitric oxide in murine Salmonella infection Peer-reviewed

    MS Alam, T Akaike, H Maeda

    BIOLOGICAL RESPONSE TO PLANNED AND UNPLANNED INJURIES: CELLULAR, MOLECULAR AND GENETIC ASPECTS　1255　257-264　2003

    DOI： 10.1016/S0531-5131(03)00655-1 　

    ISSN： 0531-5131

  348. 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis Peer-reviewed

    T Akaike, S Okamoto, T Sawa, J Yoshitake, F Tamura, K Ichimori, K Miyazaki, K Sasamoto, H Maeda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　100　(2)　685-690　2003/01

    DOI： 10.1073/pnas.0235623100 　

    ISSN： 0027-8424

  349. Modulation of tumor-selective vascular blood flow and extravasation by the stable prostaglandin I-2 analogue beraprost sodium Peer-reviewed

    S Tanaka, T Akaike, J Wu, J Fang, T Sawa, M Ogawa, T Beppu, H Maeda

    JOURNAL OF DRUG TARGETING　11　(1)　45-52　2003

    DOI： 10.1080/1061186031000086072 　

    ISSN： 1061-186X

  350. Generation of Lipid Peroxyl Radicals from Oxidized Edible Oils and Heme-Iron: Suppression of DNA Damage by Unrefined Oils and Vegetable Extracts

    Ayako Kanazawa, Tomohiro Sawa, Takaaki Akaike, Hiroshi Maeda

    ACS Symposium Series　807　282-300　2002/12/01

    ISSN： 0097-6156

  351. S-nitrosothiols inhibit cytokine-mediated induction of matrix metalloproteinase-9 in airway epithelial cells Peer-reviewed

    T Okamoto, G Valacchi, K Gohil, T Akaike, A van der Vliet

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY　27　(4)　463-473　2002/10

    DOI： 10.1165/rcmb-2002-0039OC 　

    ISSN： 1044-1549

  352. Pegylated zinc protoporphyrin: A water-soluble heme oxygenase inhibitor with tumor-targeting capacity Peer-reviewed

    SK Sahoo, T Sawa, J Fang, S Tanaka, Y Miyamoto, T Akaike, H Maeda

    BIOCONJUGATE CHEMISTRY　13　(5)　1031-1038　2002/09

    DOI： 10.1021/bc020010k 　

    ISSN： 1043-1802

  353. Dietary lipid peroxidation products and DNA damage in colon carcinogenesis Peer-reviewed

    A Kanazawa, T Sawa, T Akaike, H Maeda

    EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY　104　(7)　439-447　2002/07

    ISSN： 1438-7697

  354. Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide Peer-reviewed

    J Fang, T Sawa, T Akaike, H Maeda

    CANCER RESEARCH　62　(11)　3138-3143　2002/06

    ISSN： 0008-5472

  355. Identification of bradykinin receptors in clinical cancer specimens and murine tumor tissues Peer-reviewed

    J Wu, T Akaike, K Hayashida, Y Miyamoto, T Nakagawa, K Miyakawa, W Muller-Esterl, H Maeda

    INTERNATIONAL JOURNAL OF CANCER　98　(1)　29-35　2002/03

    DOI： 10.1002/ijc.10142 　

    ISSN： 0020-7136

  356. Possible assessment for antioxidant capacity in Alzheimer's disease by measuring lymphocyte heme oxygenase-1 expression with real-time RT-PCR Peer-reviewed

    K. Ishizuka, T. Kimura, J. Yoshitake, T. Akaike, M. Shono, J. Takamatsu, S. Katsuragi, T. Kitamura, T. Miyakawa

    Annals of the New York Academy of Sciences　977　173-178　2002

    Publisher: New York Academy of Sciences

    DOI： 10.1111/j.1749-6632.2002.tb04814.x 　

    ISSN： 0077-8923

  357. Contributing role of NOS2 in LPS-induced acute airway inflammation in mice

    T Okamoto, K Gohil, E Finkelstein, T Akaike, A van der Vliet

    FREE RADICAL BIOLOGY AND MEDICINE　33　S369-S369　2002

    ISSN： 0891-5849

  358. Role of nitric oxide in host defense in murine salmonellosis as a function of its antibacterial and antiapoptotic activities Peer-reviewed

    Mohammad Samiul Alam, Takaaki Akaike, Shinichiro Okamoto, Tatsuo Kubota, Jun Yoshitake, Tomohiro Sawa, Yoichi Miyamoto, Fumio Tamura, Hiroshi Maeda

    Infection and Immunity　70　(6)　3130-3142　2002

    DOI： 10.1128/IAI.70.6.3130-3142.2002 　

    ISSN： 0019-9567

  359. Matrix metalloproteinases induction by pseudomonal virulence factors and inflammatory cytokines in vitro Peer-reviewed

    S Miyajima, T Akaike, K Matsumoto, T Okamoto, J Yoshitake, K Hayashida, A Negi, H Maeda

    MICROBIAL PATHOGENESIS　31　(6)　271-281　2001/12

    DOI： 10.1006/mpat.2001.0470 　

    ISSN： 0882-4010

  360. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation Peer-reviewed

    T Okamoto, T Akaike, T Sawa, Y Miyamoto, A van der Vliet, H Maeda

    JOURNAL OF BIOLOGICAL CHEMISTRY　276　(31)　29596-29602　2001/08

    ISSN： 0021-9258

  361. Enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases Peer-reviewed

    J Wu, T Akaike, K Hayashida, T Okamoto, A Okuyama, H Maeda

    JAPANESE JOURNAL OF CANCER RESEARCH　92　(4)　439-451　2001/04

    ISSN： 0910-5050

  362. Role of free radicals in viral pathogenesis and mutation

    Takaaki Akaike

    Reviews in Medical Virology　11　(2)　87-101　2001

    DOI： 10.1002/rmv.303 　

    ISSN： 1052-9276

  363. Dexamethasone impairs pulmonary defence against Pseudomonas aeruginosa through suppressing iNOS gene expression and peroxynitrite production in mice Peer-reviewed

    S. Satoh, K. Oishi, A. Iwagaki, M. Senba, T. Akaike, M. Akiyama, N. Mukaida, K. M. Atsushima, T. Nagatake

    Clinical and Experimental Immunology　126　(2)　266-273　2001

    DOI： 10.1046/j.1365-2249.2001.01656.x 　

    ISSN： 0009-9104

  364. Quantification of protein-bound nitrotyrosine using new HPLC analysis coupled with electrochemical detection

    S Okamoto, T Akaike, H Nishino, Y Miyamoto, M Suga, H Maeda

    FREE RADICAL BIOLOGY AND MEDICINE　31　S124-S124　2001

    ISSN： 0891-5849

  365. Modulation of lung epithelial matrix metalloproteinase-9 expression by nitric oxide.

    T Okamoto, G Valacchi, T Akaike, A van der Vliet

    FREE RADICAL BIOLOGY AND MEDICINE　31　S72-S72　2001

    ISSN： 0891-5849

  366. Poly(ethylene glycol) conjugated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with potent antitumor activity

    T Sawa, S Tanaka, SK Sahoo, J Fang, H Maeda, T Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　31　S141-S141　2001

    ISSN： 0891-5849

  367. Protective effect of S-nitrosylated alpha(1)-protease inhibitor on hepatic ischemia-reperfusion injury Peer-reviewed

    N Ikebe, T Akaike, Y Miyamoto, K Hayashida, J Yoshitake, M Ogawa, H Maeda

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS　295　(3)　904-911　2000/12

    ISSN： 0022-3565

  368. Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias Peer-reviewed

    M Suga, K Iyonaga, T Okamoto, Y Gushima, H Miyakawa, T Akaike, M Ando

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　162　(5)　1949-1956　2000/11

    ISSN： 1073-449X

  369. Nitric oxide and virus infection

    T Akaike, H Maeda

    IMMUNOLOGY　101　(3)　300-308　2000/11

    ISSN： 0019-2805

    eISSN： 1365-2567

  370. Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice Peer-reviewed

    K Yogo, H Shimokawa, H Funakoshi, T Kandabashi, K Miyata, S Okamoto, K Egashira, P Huang, T Akaike, A Takeshita

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　20　(11)　E96-E100　2000/11

    DOI： 10.1161/01.atv.20.11.e96 　

    ISSN： 1079-5642

  371. Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats Peer-reviewed

    E Akizuki, T Akaike, S Okamoto, S Fujii, Y Yamaguchi, M Ogawa, H Maeda

    PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE　225　(2)　151-159　2000/11

    DOI： 10.1046/j.1525-1373.2000.22519.x 　

    ISSN： 0037-9727

  372. 【インフルエンザ 新時代のインフルエンザの臨床】 重症化のメカニズムと対策 基礎研究から インフルエンザ重症化におけるプロテアーゼとフリーラジカルの役割 宿主反応による病態修飾

    赤池 孝章, 岡本 真一郎, 前田 浩

    カレントテラピー　18　(11)　2025-2034　2000/10

    Publisher: (株)ライフメディコム

    ISSN： 0287-8445

  373. Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase

    T Sawa, T Akaike, H Maeda

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(42)　32467-32474　2000/10

    DOI： 10.1074/jbc.M910169199 　

    ISSN： 0021-9258

  374. Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production Peer-reviewed

    H Kuwahara, Y Miyamoto, T Akaike, T Kubota, T Sawa, S Okamoto, H Maeda

    INFECTION AND IMMUNITY　68　(8)　4378-4383　2000/08

    DOI： 10.1128/iai.68.8.4378-4383.2000 　

    ISSN： 0019-9567

  375. Viral mutation accelerated by nitric oxide production during infection in vivo Peer-reviewed

    T Akaike, S Fujii, A Kato, J Yoshitake, Y Miyamoto, T Sawa, S Okamoto, M Suga, M Asakawa, Y Nagai, H Maeda

    FASEB JOURNAL　14　(10)　1447-1454　2000/07

    DOI： 10.1096/fj.14.10.1447 　

    ISSN： 0892-6638

  376. S-nitrosylated human alpha(1)-protease inhibitor

    Y Miyamoto, T Akaike, H Maeda

    BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY　1477　(1-2)　90-97　2000/03

    DOI： 10.1016/S0167-4838(99)00264-2 　

    ISSN： 0167-4838

  377. Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue

    T Sawa, J Wu, T Akaike, H Maeda

    CANCER RESEARCH　60　(3)　666-671　2000/02

    ISSN： 0008-5472

  378. Mechanisms of biological S-nitrosation and its measurement

    T. Akaike

    Free Radical Research　33　(5)　461-469　2000

    Publisher: Harwood Academic Publishers GmbH

    DOI： 10.1080/10715760000301001 　

    ISSN： 1071-5762

  379. Protective effect of S-nitroso-alpha(1)-protease inhibitor on hepatic ischemia-reperfusion injury Peer-reviewed

    N Ikebe, T Akaike, Y Miyamoto, M Ogawa, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 7　16　51-51　2000

    ISSN： 0966-4068

  380. Tyrosine nitration by peroxynitrite generated from xanthine oxidase-hypoxanthine and nitric oxide Peer-reviewed

    T Sawa, T Akaike, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 7　16　174-174　2000

    ISSN： 0966-4068

  381. Viral mutation and evolution accelerated by nitric oxide-induced oxidative stress Peer-reviewed

    T Akaike, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 7　16　16-16　2000

    ISSN： 0966-4068

  382. Novel functions of human alpha(1)-protease inhibitor after S-nitrosylation: Inhibition of cysteine protease and antibacterial activity Peer-reviewed

    Y Miyamoto, T Akaike, MS Alam, K Inoue, T Hamamoto, N Ikebe, J Yoshitake, T Okamoto, H Maeda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　267　(3)　918-923　2000/01

    ISSN： 0006-291X

  383. Vascular permeability enhancement by peroxynitrite involving activation of collagenase followed by subsequent protease cascade leading to bradykinin generation in tumor Peer-reviewed

    H Maeda, J Wu, A Okuyama, T Akaike

    BIOLOGY OF NITRIC OXIDE, PT 7　16　204-204　2000

    ISSN： 0966-4068

  384. Urease functions as a defense system of Helicobacter pylori against peroxynitrite through the production of carbon dioxide Peer-reviewed

    Y Miyamoto, T Akaike, H Kuwahara, T Kubota, S Yoshimatsu, T Sawa, S Okamoto, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 7　16　30-30　2000

    ISSN： 0966-4068

  385. Generation of lipid peroxyl radicals from edible oils and their biological activities: A need for consideration for anti-radical components and purification processing

    A Kanazawa, T Sawa, T Akaike, S Morimura, K Kida, H Maeda

    BIOFACTORS　13　(1-4)　187-193　2000

    ISSN： 0951-6433

  386. Nitrosothiol formation catalyzed by ceruloplasmin - Implication for cytoprotective mechanism in vivo Peer-reviewed

    K Inoue, T Akaike, Y Miyamoto, T Okamoto, T Sawa, M Otagiri, S Suzuki, T Yoshimura, H Maeda

    JOURNAL OF BIOLOGICAL CHEMISTRY　274　(38)　27069-27075　1999/09

    ISSN： 0021-9258

  387. Kallikrein-kinin in infection and cancer

    H Maeda, J Wu, T Okamoto, K Maruo, T Akaike

    IMMUNOPHARMACOLOGY　43　(2-3)　115-128　1999/09

    DOI： 10.1016/S0162-3109(99)00104-6 　

    ISSN： 0162-3109

  388. Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presence of NADH

    H Maeda, T Sawa, T Yubisui, T Akaike

    CANCER LETTERS　143　(2)　117-121　1999/09

    DOI： 10.1016/S0304-3835(99)00139-1 　

    ISSN： 0304-3835

  389. Combined effects of both bacteria and gastric juice on pneumonia in mice Peer-reviewed

    Koh Iwasaki, Takashi Ohrui, Qiang Wang, Kiyohisa Sekizawa, Takaaki Akaike, Hiroshi Maeda, Hidetada Sasaki

    Respiration Physiology　116　(2-3)　201-209　1999/08/03

    DOI： 10.1016/S0034-5687(99)00045-6 　

    ISSN： 0034-5687

  390. Role of peroxynitrite in airway microvascular hyperpermeability during late allergic phase in guinea pigs Peer-reviewed

    H Sugiura, M Ichinose, T Oyake, Y Mashito, Y Ohuchi, N Endoh, M Miura, S Yamagata, A Koarai, T Akaike, H Maeda, K Shirato

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　160　(2)　663-671　1999/08

    ISSN： 1073-449X

  391. Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth

    K Doi, T Akaike, S Fujii, S Tanaka, N Ikebe, T Beppu, S Shibahara, M Ogawa, H Maeda

    BRITISH JOURNAL OF CANCER　80　(12)　1945-1954　1999/08

    DOI： 10.1038/sj.bjc.6690624 　

    ISSN： 0007-0920

    eISSN： 1532-1827

  392. Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats Peer-reviewed

    S Fujii, T Akaike, H Maeda

    VIROLOGY　256　(2)　203-212　1999/04

    ISSN： 0042-6822

  393. Activation of matrix metalloproteinases by bacterial proteinases and its involvement in bacterial tissue invasion

    Takaaki Akaike, Tatsuya Okamoto, Hiroshi Maeda

    Japanese Journal of Infectious Diseases　52　(1)　25　1999/02

    ISSN： 1344-6304

  394. Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds: Implications for the anti-tumor-promoter effect of vegetables

    T Sawa, M Nakao, T Akaike, K Ono, H Maeda

    JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY　47　(2)　397-402　1999/02

    DOI： 10.1021/jf980765e 　

    ISSN： 0021-8561

  395. Direct evidence of in vivo nitric oxide production and inducible nitric oxide synthase mRNA expression in the brain of living rat during experimental meningitis Peer-reviewed

    Yasuhiro Suzuki, Satoshi Fujii, Teiji Tominaga, Takashi Yoshimoto, Shigemoto Fujii, Takaaki Akaike, Hiroshi Maeda, Tetsuhiko Yoshimura

    Journal of Cerebral Blood Flow and Metabolism　19　(11)　1175-1178　1999

    Publisher: Lippincott Williams and Wilkins

    DOI： 10.1097/00004647-199911000-00001 　

    ISSN： 0271-678X

  396. Effects of Qing Fei Tang (TJ-90) on aspiration pneumonia in mice Peer-reviewed

    K. Iwasaki, Q. Wang, N. Satoh, S. Yoshida, T. Akaike, K. Sekizawa, H. Maeda, H. Sasaki

    Phytomedicine　6　(2)　95-101　1999

    Publisher: Urban und Fischer Verlag Jena

    DOI： 10.1016/S0944-7113(99)80042-7 　

    ISSN： 0944-7113

  397. Ceruloplasmin-catalyzed nitrosothiol formation

    T Akaike, Y Miyamoto, T Sawa, H Maeda

    FREE RADICAL BIOLOGY AND MEDICINE　27　S71-S71　1999

    ISSN： 0891-5849

  398. Vascular permeability and efficacy of drug delivery: Factors involved and EPR-effect for polymeric drug delivery to solid tumor

    H. Maeda, J. Wu, S. Tanaka, T. Sawa, T. Akaike

    Proceedings of the Controlled Release Society　40-41　1999/01/01

    ISSN： 1022-0178

  399. Lipid peroxyl radicals from oxidized oils and heme-iron: Implication of a high-fat diet in colon carcinogenesis

    T Sawa, T Akaike, K Kida, Y Fukushima, K Takagi, H Maeda

    CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION　7　(11)　1007-1012　1998/11

    ISSN： 1055-9965

  400. The possible effect of nitric oxide on relaxation and noradrenaline release in the isolated rabbit urethra Peer-reviewed

    Masaki Yoshida, Takaaki Akaike, Akito Inadome, Wataru Takahashi, Hiroshi Seshita, Makoto Yono, Shingo Goto, Hiroshi Maeda, Shoichi Ueda

    European Journal of Pharmacology　357　(2-3)　213-219　1998/09/18

    DOI： 10.1016/S0014-2999(98)00566-4 　

    ISSN： 0014-2999

  401. Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice Peer-reviewed

    K Sato, M Suga, T Akaike, S Fuji, H Muranaka, T Doi, H Maeda, M Ando

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　157　(3)　853-857　1998/03

    ISSN： 1073-449X

    eISSN： 1535-4970

  402. Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues Peer-reviewed

    Y Noguchi, J Wu, R Duncan, J Strohalm, K Ulbrich, T Akaike, H Maeda

    JAPANESE JOURNAL OF CANCER RESEARCH　89　(3)　307-314　1998/03

    DOI： 10.1111/j.1349-7006.1998.tb00563.x 　

    ISSN： 0910-5050

  403. Involvement of bradykinin generation in intravascular dissemination of Vibrio vulnificus and prevention of invasion by a bradykinin antagonist Peer-reviewed

    K Maruo, T Akaike, T Ono, H Maeda

    INFECTION AND IMMUNITY　66　(2)　866-869　1998/02

    ISSN： 0019-9567

  404. Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals

    H Maeda, T Okamoto, T Akaike

    BIOLOGICAL CHEMISTRY　379　(2)　193-200　1998/02

    ISSN： 1431-6730

  405. Enhanced tumor targeting and antitumor activity of xanthine oxidase by chemical conjugation with PEG

    T. Sawa, J. Wu, T. Akaike, H. Maeda

    Proceedings of the Controlled Release Society　12-13　1998/01/01

    ISSN： 1022-0178

  406. Improved nitric oxide detection using 2,3-diaminonaphthalene and its application to the evaluation of novel nitric oxide synthase inhibitors Peer-reviewed

    Naoki Nakatsubo, Hirotatsu Kojima, Kuniko Sakurai, Kazuya Kikuchi, Hiroshi Nagoshi, Yasunobu Hirata, Takaaki Akaike, Hiroshi Maeda, Yasuteru Urano, Tsunehiko Higuchi, Tetsuo Nagano

    Biological and Pharmaceutical Bulletin　21　(12)　1247-1250　1998

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpb.21.1247 　

    ISSN： 0918-6158

  407. Expression of inducible nitric oxide synthase and role of nitric oxide on the formation of granuloma in rat lung Peer-reviewed

    K Setoguchi, M Suga, M Takeya, T Akaike, R Hattori, H Maeda, K Takahashi, M Ando

    ADVANCES IN THE PREVENTION OF OCCUPATIONAL RESPIRATORY DISEASES　1153　860-865　1998

    ISSN： 0531-5131

  408. Free radicals in viral pathogenesis: Molecular mechanisms involving superoxide and NO

    T Akaike, M Suga, H Maeda

    PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE　217　(1)　64-73　1998/01

    ISSN： 0037-9727

  409. Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger

    J Wu, T Akaike, H Maeda

    CANCER RESEARCH　58　(1)　159-165　1998/01

    ISSN： 0008-5472

  410. Effect of the NO scavenger carboxy-PTIO on endothelium-dependent vasorelaxation of various blood vessels from rabbits Peer-reviewed

    Masaki Yoshida, Takaaki Akaike, Shingo Goto, Wataru Takahashi, Akito Inadome, Makoto Yono, Hiroshi Seshita, Hiroshi Maeda, Shoichi Ueda

    Life Sciences　62　(3)　203-211　1997/12/12

    DOI： 10.1016/S0024-3205(97)01088-6 　

    ISSN： 0024-3205

  411. Nitric oxide generation from hydroxyurea via copper-catalyzed peroxidation and implications for pharmacological actions of hydroxyurea

    K Sato, T Akaike, T Sawa, Y Miyamoto, M Suga, M Ando, H Maeda

    JAPANESE JOURNAL OF CANCER RESEARCH　88　(12)　1199-1204　1997/12

    ISSN： 0910-5050

  412. Nanomolar quantification and identification of various nitrosothiols by high performance liquid chromatography coupled with flow reactors of metals and Griess reagent Peer-reviewed

    T Akaike, K Inoue, T Okamoto, H Nishino, M Otagiri, S Fujii, H Maeda

    JOURNAL OF BIOCHEMISTRY　122　(2)　459-466　1997/08

    ISSN： 0021-924X

  413. Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease Peer-reviewed

    K Maruo, T Akaike, T Ono, T Okamoto, H Maeda

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY　100　(2)　253-260　1997/08

    ISSN： 0091-6749

  414. Induction of nitric oxide synthesis and xanthine oxidase and their roles in the antimicrobial mechanism against Salmonella typhimurium infection in mice Peer-reviewed

    K Umezawa, T Akaike, S Fujii, M Suga, K Setoguchi, A Ozawa, H Maeda

    INFECTION AND IMMUNITY　65　(7)　2932-2940　1997/07

    ISSN： 0019-9567

    eISSN： 1098-5522

  415. Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: A novel mechanism for procollagenase activation involving nitric oxide Peer-reviewed

    T Okamoto, T Akaike, T Nagano, S Miyajima, M Suga, M Ando, K Ichimori, H Maeda

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　342　(2)　261-274　1997/06

    ISSN： 0003-9861

  416. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis Peer-reviewed

    D. Craig Hooper, Omar Bagasra, Joseph C. Marini, Anna Zborek, S. Tsuyoshi Ohnishi, Rhonda Kean, Jean M. Champion, Ashit B. Sarker, Lisa Bobroski, John L. Farber, Takaaki Akaike, Hiroshi Maeda, Hilary Koprowski

    Proceedings of the National Academy of Sciences of the United States of America　94　(6)　2528-2533　1997/03/18

    DOI： 10.1073/pnas.94.6.2528 　

    ISSN： 0027-8424

  417. Superoxide scavenging activity of erythromycin-iron complex Peer-reviewed

    H Muranaka, M Suga, K Sato, K Nakagawa, T Akaike, T Okamoto, H Maeda, M Ando

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　232　(1)　183-187　1997/03

    ISSN： 0006-291X

  418. Activation of human matrix metalloproteinases by various bacterial proteinases Peer-reviewed

    T Okamoto, T Akaike, M Suga, S Tanase, H Horie, S Miyajima, M Ando, Y Ichinose, H Maeda

    JOURNAL OF BIOLOGICAL CHEMISTRY　272　(9)　6059-6066　1997/02

    ISSN： 0021-9258

  419. Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo

    T Urakami, C Yoshida, T Akaike, H Maeda, H Nishigori, E Niki

    JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY　43　(1)　19-33　1997/02

    DOI： 10.3177/jnsv.43.19 　

    ISSN： 0301-4800

  420. Development of a fluorescent indicator for the bioimaging of nitric oxide Peer-reviewed

    Hirotatsu Kojima, Kuniko Sakurai, Kazuya Kikuchi, Shigenori Kawahara, Yutaka Kirino, Hiroshi Nagoshi, Yasunobu Hirata, Takaaki Akaike, Hiroshi Maeda, Tetsuo Nagano

    Biological and Pharmaceutical Bulletin　20　(12)　1229-1232　1997

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpb.20.1229 　

    ISSN： 0918-6158

  421. Activation of matrix metalloproteinases by bacterial proteinases and pathogenic implication Peer-reviewed

    H Maeda, T Okamoto, T Akaike, S Miyajima, M Suga, M Ando, Y Ichinose

    MEDICAL ASPECTS OF PROTEASES AND PROTEASE INHIBITORS　15　128-138　1997

    ISSN： 0929-6743

  422. Expression of inducible nitric oxide synthase and its involvement in pulmonary granulomatous inflammation in rats

    K Setoguchi, M Takeya, T Akaike, M Suga, R Hattori, H Maeda, M Ando, K Takahashi

    AMERICAN JOURNAL OF PATHOLOGY　149　(6)　2005-2022　1996/12

    ISSN： 0002-9440

    eISSN： 1525-2191

  423. Pharmacological advantages of conjugation of Cu,Zn-superoxide dismutase with succinylated keratin fragment: Improvement of biological properties and resistance to oxidative damage Peer-reviewed

    J Noda, M Otagiri, T Akaike, H Maeda

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS　279　(1)　162-171　1996/10

    ISSN： 0022-3565

  424. Polymer conjugation to Cu,Zn-SOD and suppression of hydroxyl radical generation on exposure to H2O2: Improved stability of SOD in vitro and in vivo Peer-reviewed

    Y Kojima, T Akaike, K Sato, H Maeda, T Hirano

    JOURNAL OF BIOACTIVE AND COMPATIBLE POLYMERS　11　(3)　169-190　1996/07

    ISSN： 0883-9115

  425. Bradykinin and nitric oxide in infectious disease and cancer Peer-reviewed

    H Maeda, T Akaike, J Wu, Y Noguchi, Y Sakata

    IMMUNOPHARMACOLOGY　33　(1-3)　222-230　1996/06

    ISSN： 0162-3109

  426. Activation of bradykinin generating cascade by Vibrio cholerae protease Peer-reviewed

    Y Sakata, T Akaike, MMH Khan, Y Ichinose, H Hirayama, M Suga, M Ando, H Maeda

    IMMUNOPHARMACOLOGY　33　(1-3)　377-379　1996/06

    ISSN： 0162-3109

  427. Further evidence of bradykinin involvement in septic shock: Reduction of kinin production in vivo and improved survival in rats by use of polymer tailored SBTI with longer t(1/2) Peer-reviewed

    YH Shin, T Akaike, MMH Khan, Y Sakata, H Maeda

    IMMUNOPHARMACOLOGY　33　(1-3)　369-373　1996/06

    ISSN： 0162-3109

  428. Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth Peer-reviewed

    K Doi, T Akaike, H Horie, Y Noguchi, S Fujii, T Beppu, M Ogawa, H Maeda

    CANCER　77　(8)　1598-1604　1996/04

    ISSN： 0008-543X

    eISSN： 1097-0142

  429. Pathogenesis of influenza virus-induced pneumonia: Involvement of both nitric oxide and oxygen radicals Peer-reviewed

    T Akaike, Y Noguchi, S Ijiri, K Setoguchi, M Suga, YM Zheng, B Dietzschold, H Maeda

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　93　(6)　2448-2453　1996/03

    ISSN： 0027-8424

  430. Direct quantitation of nitric oxide released from cells using liposome-encapsulated PTIO Peer-reviewed

    T Akaike, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 5　10　171-171　1996

    ISSN： 0966-4068

  431. Therapeutic effects of the soybean trypsin inhibitor and its gelatin conjugate on the pseudomonal elastase induced shock in guinea pig Peer-reviewed

    YH Shin, T Akaike, H Maeda

    ADVANCED BIOMATERIALS IN BIOMEDICAL ENGINEERING AND DRUG DELIVERY SYSTEMS　339-340　1996

  432. Septic shock: Prevention by NO-scavenger (PTIO) and by kinin inhibitor Peer-reviewed

    H Maeda, YH Shin, T Akaike, M Yoshida

    SHOCK　1102　43-52　1996

    ISSN： 0531-5131

  433. Quantitation of nitric oxide using 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO)

    T Akaike, H Maeda

    NITRIC OXIDE, PT A - SOURCES AND DETECTION OF NO; NO SYNTHASE　268　211-221　1996

    ISSN： 0076-6879

  434. Bradykinin generation triggered by Pseudomonas proteases facilitates invasion of the systemic circulation by Pseudomonas aeruginosa Peer-reviewed

    Y Sakata, T Akaike, M Suga, S Ijiri, M Ando, H Maeda

    MICROBIOLOGY AND IMMUNOLOGY　40　(6)　415-423　1996

    ISSN： 0385-5600

  435. Pathogenesis of influenza virus-induced pneumonia: Involvement of both nitric oxide and superoxide anion Peer-reviewed

    T Akaike, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 5　10　25-25　1996

    ISSN： 0966-4068

  436. Polymer conjugation of Cu,Zn-SOD and suppression of hydroxyl radical generation during exposure to H2O2: Improved stability of SOD Peer-reviewed

    T Akaike, Y Kojima, T Hirano, H Maeda

    23RD INTERNATIONAL SYMPOSIUM ON CONTROLLED RELEASE OF BIOACTIVE MATERIALS, 1996 PROCEEDINGS　240-241　1996

    ISSN： 1022-0178

  437. Pharmacological advantages of conjugation of superoxide dismutase with succinylated keratin fragment Peer-reviewed

    J Noda, M Otagiri, T Akaike, H Maeda

    23RD INTERNATIONAL SYMPOSIUM ON CONTROLLED RELEASE OF BIOACTIVE MATERIALS, 1996 PROCEEDINGS　867-868　1996

    ISSN： 1022-0178

  438. Induction of nitric oxide biosynthesis and its role in solid tumor Peer-reviewed

    K Doi, T Akaike, Y Noguchi, H Horie, M Ogawa, H Maeda

    BIOLOGY OF NITRIC OXIDE, PT 5　10　163-163　1996

    ISSN： 0966-4068

  439. DETERMINATION OF PEROXYL RADICAL-SCAVENGING ACTIVITY IN FOOD BY USING BACTERICIDAL ACTION OF ALKYL PEROXYL RADICAL Peer-reviewed

    T AKAIKE, S IJIRI, K SATO, T KATSUKI, H MAEDA

    JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY　43　(7)　1864-1870　1995/07

    ISSN： 0021-8561

  440. インフルエンザウイルス肺炎モデルにおけるNO産生動態の電子スピン共鳴法による解析

    赤池 孝章

    生化学　67　(7)　655-655　1995/07

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  441. FOURNIER'S GANGRENE WITH TOXIC SHOCK-LIKE SYNDROME : A CASE REPORT

    GOTO SHINGO, YOSHIDA MASAKI, UTO IWAO, UEDA SHOICHI, OHISHI MUNASHI, ONO TOMOMICHI, IJIRI SUMIKO, AKAIKE TAKAAKI, MAEDA HIROSHI

    西日本泌尿器科　57　(6)　784-787　1995/06/20

    ISSN： 0029-0726

  442. ANTIVIRAL EFFECT OF ORYZACYSTATIN, A PROTEINASE-INHIBITOR IN RICE, AGAINST HERPES-SIMPLEX VIRUS TYPE-1 IN-VITRO AND IN-VIVO Peer-reviewed

    H AOKI, T AKAIKE, K ABE, M KURODA, S ARAI, RI OKAMURA, A NEGI, H MAEDA

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY　39　(4)　846-849　1995/04

    DOI： 10.1128/AAC.39.4.846 　

    ISSN： 0066-4804

  443. A new nitric oxide scavenger, imidazolineoxyl N-oxide derivative, and its effects in pathophysiology and microbiology

    H. Maeda, T. Akaike, M. Yoshida, K. Sato, Y. Noguchi

    Current Topics in Microbiology and Immunology　196　37-50　1995

    ISSN： 0070-217X

  444. MULTIPLE FUNCTIONS OF NITRIC-OXIDE IN PATHOPHYSIOLOGY AND MICROBIOLOGY - ANALYSIS BY A NEW NITRIC-OXIDE SCAVENGER

    H MAEDA, T AKAIKE, M YOSHIDA, M SUGA

    JOURNAL OF LEUKOCYTE BIOLOGY　56　(5)　588-592　1994/11

    ISSN： 0741-5400

  445. POTENTIATION OF INFECTIVITY AND PATHOGENESIS OF INFLUENZA-A VIRUS BY A HOUSE-DUST MITE PROTEASE

    T AKAIKE, H MAEDA, K MARUO, Y SAKATA, K SATO

    JOURNAL OF INFECTIOUS DISEASES　170　(4)　1023-1026　1994/10

    ISSN： 0022-1899

  446. Vasodilator effect of carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl in the coronary circulation: in vivo and in vitro studies Peer-reviewed

    Ryusuke Tsunoda, Ken Okumura, Hiroshi Ishizaka, Toshiro Matsunaga, Toshifumi Tabuchi, Hirofumi Yasue, Takaaki Akaike, Keizo Sato, Hiroshi Maeda

    European Journal of Pharmacology　262　(1-2)　55-63　1994/09/01

    DOI： 10.1016/0014-2999(94)90028-0 　

    ISSN： 0014-2999

  447. THERAPEUTIC EFFECTS OF IMIDAZOLINEOXYL N-OXIDE AGAINST ENDOTOXIN-SHOCK THROUGH ITS DIRECT NITRIC OXIDE-SCAVENGING ACTIVITY

    M YOSHIDA, T AKAIKE, Y WADA, K SATO, K IKEDA, S UEDA, H MAEDA

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　202　(2)　923-930　1994/07

    DOI： 10.1006/bbrc.1994.2018 　

    ISSN： 0006-291X

  448. ENHANCED VASCULAR-PERMEABILITY IN SOLID TUMOR IS MEDIATED BY NITRIC-OXIDE AND INHIBITED BY BOTH NEW NITRIC-OXIDE SCAVENGER AND NITRIC-OXIDE SYNTHASE INHIBITOR

    H MAEDA, Y NOGUCHI, K SATO, T AKAIKE

    JAPANESE JOURNAL OF CANCER RESEARCH　85　(4)　331-334　1994/04

    ISSN： 0910-5050

  449. Generation of Freeradicals from Neocarzinostatin Mediated by NADPH/cytochrome P-450 Reductase via Activation of Endiyne Chromophore. （共著）（共著）

    SATO K, AKAIKE T, SUGA M, ANDO M, MAEDA H

    Biochemical and Biophysical Research Communications　205　(3)　1716-1723　1994

    DOI： 10.1006/bbrc.1994.2866 　

    ISSN： 0006-291X

  450. EFFECT OF MICROBIAL AND MITE PROTEASES ON LOW AND HIGH-MOLECULAR-WEIGHT KININOGENS - GENERATION OF KININ AND INACTIVATION OF THIOL PROTEASE INHIBITORY ACTIVITY Peer-reviewed

    K MARUO, T AKAIKE, Y INADA, OHKUBO, I, T ONO, H MAEDA

    JOURNAL OF BIOLOGICAL CHEMISTRY　268　(24)　17711-17715　1993/08

    ISSN： 0021-9258

  451. PRONOUNCED ENHANCEMENT OF .NO-DEPENDENT ANTIMICROBIAL ACTION BY AN .NO-OXIDIZING AGENT, IMIDAZOLINEOXYL N-OXIDE

    K YOSHIDA, T AKAIKE, T DOI, K SATO, S IJIRI, M SUGA, M ANDO, H MAEDA

    INFECTION AND IMMUNITY　61　(8)　3552-3555　1993/08

    ISSN： 0019-9567

  452. THE PROTECTIVE EFFECT OF PYRROLOQUINOLINE QUINONE AND ITS DERIVATIVES AGAINST CARBON TETRACHLORIDE-INDUCED LIVER-INJURY OF RATS Peer-reviewed

    T TSUCHIDA, T YASUYAMA, K HIGUCHI, A WATANABE, T URAKAMI, T AKAIKE, K SATO, H MAEDA

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY　8　(4)　342-347　1993/07

    ISSN： 0815-9319

  453. SUPEROXIDE ANION GENERATION BY PACIFIC OYSTER (CRASSOSTREA-GIGAS) HEMOCYTES - IDENTIFICATION BY ELECTRON-SPIN-RESONANCE SPIN-TRAPPING AND CHEMILUMINESCENCE ANALYSIS Peer-reviewed

    K TAKAHASHI, T AKAIKE, K SATO, K MORI, H MAEDA

    COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY　105　(1)　35-41　1993/05

    ISSN： 0305-0491

  454. RESISTANCE TO NITRIC-OXIDE IN MYCOBACTERIUM-AVIUM COMPLEX AND ITS IMPLICATION IN PATHOGENESIS

    T DOI, M ANDO, T AKAIKE, M SUGA, K SATO, H MAEDA

    INFECTION AND IMMUNITY　61　(5)　1980-1989　1993/05

    ISSN： 0019-9567

  455. Role of bradykinin in microbial infection: Enhancement of septicemia by microbial proteases and kinin Peer-reviewed

    H. Maeda, T. Akaike, Y. Sakata, K. Maruo

    Agents and Actions　42　159-165　1993

    ISSN： 0065-4299

  456. ANTAGONISTIC ACTION OF IMIDAZOLINEOXYL N-OXIDES AGAINST ENDOTHELIUM-DERIVED RELAXING FACTOR .NO THROUGH A RADICAL REACTION Peer-reviewed

    T AKAIKE, M YOSHIDA, Y MIYAMOTO, K SATO, M KOHNO, K SASAMOTO, K MIYAZAKI, S UEDA, H MAEDA

    BIOCHEMISTRY　32　(3)　827-832　1993/01

    ISSN： 0006-2960

  457. HYDROXYL RADICAL PRODUCTION BY H2O2 PLUS CU,ZN-SUPEROXIDE DISMUTASE REFLECTS THE ACTIVITY OF FREE COPPER RELEASED FROM THE OXIDATIVELY DAMAGED ENZYME

    K SATO, T AKAIKE, M KOHNO, M ANDO, H MAEDA

    JOURNAL OF BIOLOGICAL CHEMISTRY　267　(35)　25371-25377　1992/12

    ISSN： 0021-9258

  458. EVIDENCE OF DIRECT GENERATION OF OXYGEN FREE-RADICALS FROM HETEROCYCLIC AMINES BY NADPH CYTOCHROME-P-450 REDUCTASE INVITRO

    K SATO, T AKAIKE, Y KOJIMA, M ANDO, M NAGAO, H MAEDA

    JAPANESE JOURNAL OF CANCER RESEARCH　83　(11)　1204-1209　1992/11

    ISSN： 0910-5050

  459. HIGH CORRELATION BETWEEN LIPID PEROXIDE RADICAL AND TUMOR-PROMOTER EFFECT - SUPPRESSION OF TUMOR PROMOTION IN THE EPSTEIN-BARR-VIRUS LYMPHOCYTE-B SYSTEM AND SCAVENGING OF ALKYL PEROXIDE RADICALS BY VARIOUS VEGETABLE EXTRACTS

    H MAEDA, T KATSUKI, T AKAIKE, R YASUTAKE

    JAPANESE JOURNAL OF CANCER RESEARCH　83　(9)　923-928　1992/09

    ISSN： 0910-5050

  460. BACTERICIDAL ACTIVITY OF ALKYL PEROXYL RADICALS GENERATED BY HEME-IRON-CATALYZED DECOMPOSITION OF ORGANIC PEROXIDES Peer-reviewed

    T AKAIKE, K SATO, S IJIRI, Y MIYAMOTO, M KOHNO, M ANDO, H MAEDA

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS　294　(1)　55-63　1992/04

    ISSN： 0003-9861

  461. Microbial proteinases as an universal trigger of kinin generation in microbial infections Peer-reviewed

    H. Maeda, K. Maruo, T. Akaike, H. Kaminishi, Y. Hagiwara

    Agents and Actions　38　(III)　362-369　1992

    ISSN： 0065-4299

  462. Intracellular killing mechanisms of alveolar macrophages against Mycobacterium avium complex Peer-reviewed

    M. Suga, T. Doi, T. Akaike, M. Ando

    Kekkaku　67　(1)　55-62　1992

    ISSN： 0022-9776

  463. Hydroxyl radical generation by red tide algae Peer-reviewed

    Tatsuya Oda, Takaaki Akaike, Keizo Sato, Atsushi Ishimatsu, Satoshi Takeshita, Tsuyoshi Muramatsu, Hiroshi Maeda

    Archives of Biochemistry and Biophysics　294　(1)　38-43　1992

    DOI： 10.1016/0003-9861(92)90133-H 　

    ISSN： 1096-0384 0003-9861

  464. FREE-RADICAL SCAVENGING POTENTIAL OF THE LUNG IN INFLUENZA VIRUS-INFECTED MICE Peer-reviewed

    Y KOJIMA, T AKAIKE, H MAEDA

    OXYGEN RADICALS　998　461-464　1992

    ISSN： 0531-5131

  465. MICROBIAL PROTEINASES AS AN UNIVERSAL TRIGGER OF KININ GENERATION IN MICROBIAL INFECTIONS Peer-reviewed

    H MAEDA, K MARUO, T AKAIKE, H KAMINISHI, Y HAGIWARA

    RECENT PROGRESS ON KININS　38　(III)　362-369　1992

    ISSN： 0379-0363

  466. OXYGEN FREE-RADICALS AS PATHOGENIC MOLECULES IN VIRAL DISEASES Peer-reviewed

    H MAEDA, T AKAIKE

    PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE　198　(2)　721-727　1991/11

    ISSN： 0037-9727

  467. Triggering of the vascular permeability reaction by activation of the Hageman factor-prekallikrein system by house dust mite proteinase Peer-reviewed

    Keishi Maruo, Takaaki Akaike, Yasuhiro Matsumura, Shoichi Kohmoto, Yuji Inada, Tomomichi Ono, Tatsuyoshi Arao, Hiroshi Maeda

    BBA - General Subjects　1074　(1)　62-68　1991/05/24

    DOI： 10.1016/0304-4165(91)90040-N 　

    ISSN： 0304-4165

  468. TRIGGERING OF THE VASCULAR-PERMEABILITY REACTION BY ACTIVATION OF THE HAGEMAN FACTOR-PREKALLIKREIN SYSTEM BY HOUSE DUST MITE PROTEINASE Peer-reviewed

    K MARUO, T AKAIKE, Y MATSUMURA, S KOHMOTO, Y INADA, T ONO, T ARAO, H MAEDA

    BIOCHIMICA ET BIOPHYSICA ACTA　1074　(1)　62-68　1991/05

    ISSN： 0006-3002

  469. PATHOGENIC ROLE OF MICROBIAL PROTEASES AT CELLULAR AND MOLECULAR-LEVELS Peer-reviewed

    H MAEDA, T AKAIKE, K MARUO

    FRONTIERS OF MUCOSAL IMMUNOLOGY, VOL 1　939　553-558　1991

  470. PQQ AS A GENERATOR AND A SCAVENGER OF OXYGEN RADICALS - DETERMINATION WITH ESR SPECTROSCOPY USING A SPIN TRAP AGENT Peer-reviewed

    T AKAIKE, K SATO, M KOHNO, H MAEDA

    ENZYMES DEPENDENT ON PYRIDOXAL PHOSPHATE AND OTHER CARBONYL COMPOUNDS AS COFACTORS　199　511-513　1991

  471. INACTIVATION OF CHEMOTACTIC ACTIVITY OF C5A BY THE SERRATIAL 56-KILODALTON PROTEASE Peer-reviewed

    T ODA, Y KOJIMA, T AKAIKE, S IJIRI, A MOLLA, H MAEDA

    INFECTION AND IMMUNITY　58　(5)　1269-1272　1990/05

    ISSN： 0019-9567

  472. Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice Peer-reviewed

    Takaaki Akaike, Masayuki Ando, Tatsuya Oda, Toshinori Doi, Sumiko Ijiri, Shukuro Araki, Hiroshi Maeda

    Journal of Clinical Investigation　85　(3)　739-745　1990

    Publisher: The American Society for Clinical Investigation

    DOI： 10.1172/JCI114499 　

    ISSN： 0021-9738

  473. INACTIVATION OF VARIOUS PROTEINASE-INHIBITORS AND THE COMPLEMENT-SYSTEM IN HUMAN-PLASMA BY THE 56-KILODALTON PROTEINASE FROM SERRATIA-MARCESCENS

    A MOLLA, T AKAIKE, H MAEDA

    INFECTION AND IMMUNITY　57　(6)　1868-1871　1989/06

    ISSN： 0019-9567

  474. MOLECULAR MECHANISM OF COMPLEX INFECTION BY BACTERIA AND VIRUS ANALYZED BY A MODEL USING SERRATIAL PROTEASE AND INFLUENZA-VIRUS IN MICE Peer-reviewed

    T AKAIKE, A MOLLA, M ANDO, S ARAKI, H MAEDA

    JOURNAL OF VIROLOGY　63　(5)　2252-2259　1989/05

    ISSN： 0022-538X

  475. OXYGEN RADICALS IN INFLUENZA-INDUCED PATHOGENESIS AND TREATMENT WITH PYRAN POLYMER-CONJUGATED SOD Peer-reviewed

    T ODA, T AKAIKE, T HAMAMOTO, F SUZUKI, T HIRANO, H MAEDA

    SCIENCE　244　(4907)　974-976　1989/05

    ISSN： 0036-8075

  476. Activation of Hageman factor and prekallikrein and generation of kinin by various microbial proteinases Peer-reviewed

    A. Molla, T. Yamamoto, T. Akaike, S. Miyoshi, H. Maeda

    Journal of Biological Chemistry　264　(18)　10589-10594　1989

    ISSN： 0021-9258

  477. STREPTOCOCCUS-ACIDOMINIMUS INFECTIONS IN A HUMAN

    T AKAIKE, M SUGA, M ANDO, Y ANDO, S ARAKI, R FUJISE

    JAPANESE JOURNAL OF MEDICINE　27　(3)　317-320　1988/08

    DOI： 10.2169/internalmedicine1962.27.317 　

    ISSN： 0021-5120

  478. Deferoxamine mesylate inhibits bacterial growth in vivo.

    Y. Ando, T. Akaike, M. Inoue, Y. Horisawa, Y. Yamada, K. Uekawa, R. Fujise, S. Araki

    [Hokkaido igaku zasshi] The Hokkaido journal of medical science　63　(2)　207-212　1988

    ISSN： 0367-6102

Show all ︎Show first 5

Books and Other Publications 203

  1. 呼吸器ウイルス感染症と呼気オミックス

    松永哲郎, 張 田力, 赤池孝章

    臨床免疫・アレルギー科　2024/09

  2. 新型コロナウイルス感染症と酸化ストレス

    松永 哲郎, 赤池孝章

    酸化ストレスの医学 改訂第３版　2024

  3. 超硫黄分子による呼吸器疾患制御と呼気オミックス

    緒方星陵, 松永哲郎, 赤池孝章

    呼吸器疾患最新の治療 2025-2026・南江堂　2024

  4. 超硫黄分子の化学と生理機能

    緒方星陵, Uladzimir Barayeu, 赤池孝章

    酸化ストレスの医学 改訂第３版・診断と治療社　2024

  5. 環境物質と生命の起源：超硫黄生物学プロローグ

    松永哲郎, 赤池孝章

    メディカルサイエンスダイジェスト・ニューサイエンス社　2023/01

  6. ［特集］環境化学物質と生体応答

    赤池孝章

    メディカルサイエンスダイジェスト・ニューサイエンス社　2023/01

  7. 呼気オミックスと個別化医療

    アカイケ タカアキ, マツナガ テツロウ, イダ トモアキ, タカタ ツヨシ, モリタ マサノブ, モトハシ ホズミ

    2021/12

  8. Supersulfides as essential biomolecules emerging from innovation of measurement technology

    Motohashi Hozumi, Akaike Takaaki

    2021/10/25

    DOI： 10.14952/seikagaku.2021.930593 　

  9. Chemistry and metabolism of supersulfides

    Akaike Takaaki, Matsunaga Tetsuro, Takata Tsuyoshi

    2021/10

    DOI： 10.14952/seikagaku.2021.930708 　

  10. Chapter 16: Supersulfide-Mediated Signaling during Differentiation and De-Differentiation

    Tsuyoshi Takata, Masanobu Morita, Tetsuro Matsunaga, Hozumi Motohashi, Takaaki Akaike

    CRC Press　2021/08/26

    DOI： 10.1201/9781003204091 　

  11. 第５章 呼気オミックスと新型コロナウイルス感染症

    松永哲郎, 本橋ほづみ, 赤池孝章

    AI・ナノ・量子による超高感度・迅速バイオセンシング・シーエムシー出版　2021/08/20

  12. 緒言 生命を支える超硫黄分子の代謝と革新的な計測技術

    本橋ほづみ, 赤池孝章

    (公社)日本生化学会　2021

  13. 活性硫黄分子種によるエネルギー代謝とタンパク質劣化防止機能

    高田 剛, 松永 哲郎, 赤池 孝章

    バイオサイエンスとインダストリー・(一財)バイオインダストリー協会　2021/01

  14. 超硫黄代謝物の化学と代謝

    高田剛, 松永哲郎, 赤池孝章

    実験医学[特集]・(株)羊土社　2021

    ISBN: 9784758125468

  15. Novel biosynthetic pathway and metabolism regulation of reactive sulfur species

    2020/10

  16. 【食と健康を結ぶメディカルサイエンス 生体防御系を亢進し、健康の維持に働く分子機構】(第2章)食による生体防御系の活性化 抗酸化 活性パースルフィドによる制御

    高田 剛, 松永 哲郎, 赤池 孝章

    実験医学[増刊]・(株)羊土社　2020/06

  17. 硫黄呼吸は幹細胞のエネルギー代謝を担っているか?

    高田 剛, 松永 哲郎, 赤池 孝章

    再生医療・メディカルレビュー社　2019/11

  18. エレクトロンバイオダイナミクスが支える生命の生存戦略【活性イオウによる生体防御とエネルギー代謝】

    西村明, 本橋ほづみ, 赤池孝章

    2019/07/20

  19. 生体成分のレドックス修飾と機能解析 タンパク質パースルフィドの生合成・生理機能とイオウプロテオーム

    赤池 孝章

    日本電気泳動学会　2019/07

  20. Biological defense and energy production system regulated by reactive sulfur species

    西村 明, 本橋 ほづみ, 赤池 孝章

    ニューサイエンス社　2019/07

  21. 活性硫黄研究の新展開

    居原秀, 本橋ほづみ, 赤池孝章

    2019/06

    DOI： 10.14952/SEIKAGAKU.2019.910388 　

  22. 生物のエネルギー代謝 : イオウ呼吸の再発見

    赤池 孝章

    学士会　2019/03

  23. 哺乳類におけるイオウ呼吸の発見

    西村明, 赤池孝章

    2018/11

  24. タンパク質・核酸の分子修飾 II.細胞質/オルガネラでの分子修飾 酸化還元状態 ポリスルフィド化

    西村明, 井田智章, 赤池孝章

    2018/10

    DOI： 10.11477/mf.2425200871 　

  25. タンパク質・核酸の分子修飾 II.細胞質/オルガネラでの分子修飾 酸化還元状態 SH(ポリスルフィド)酸化

    西村明, 井田智章, 赤池孝章

    2018/10

    DOI： 10.11477/mf.2425200872 　

  26. 硫黄呼吸の発見 : ペルスルフィド産生酵素による新しいエネルギー代謝

    西村 明, 赤池 孝章

    東京化学同人　2018/04

  27. 実験医学増刊 Vol.36 No.5 レドックス疾患学〜酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?

    赤池 孝章, 本橋 ほづみ, 内田 浩二, 末松 誠

    羊土社　2018/03/08

    ISBN: 4758103690

  28. 【レドックス疾患学 酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?】 (第3章)レドックスの検出手法、応用など 活性イオウメタボローム イオウ代謝物とレドックスバイオマーカー

    井田 智章, 西村 明, 守田 匡伸

    (株)羊土社　2018/03

  29. レドックス疾患学 : 酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?

    赤池, 孝章, 本橋, ほづみ, 内田, 浩二, 末松, 誠

    羊土社　2018/03

    ISBN: 9784758103695

  30. Discovery of a novel biosynthetic pathway and critical physiological functions of cysteine hydropersulfide, a predominant reactive persulfide species formed endogenously

    西村 明, 赤池 孝章

    硫酸協会　2017/11

  31. 私達の研究 ニトロ化環状ヌクレオチドと活性イオウ分子によるレドックスシグナル制御と生理機能

    藤井 重元, 赤池 孝章

    (株)医薬ジャーナル社　2017/10

  32. イオウ呼吸とイオウ毒性(生命進化のイオウパラドックス):ヒトの新しいエネルギー代謝と解毒代謝経路の発見

    赤池孝章, 西村明, 井田智章, 松永哲郎, 守田匡伸, 本橋ほづみ

    2017

  33. 細菌のイオウ呼吸はすべての生物種に保存されている:ほ乳類における新しいエネルギー代謝経路・イオウ呼吸の発見

    赤池孝章, 井田智章, 松永哲郎, 守田匡伸, 笠松真吾, 西村明, 藤井重元, 居原秀, JUNG Minkyung, 赤司壮一郎, 澤智裕, 本橋ほづみ

    2017

  34. 酸化ストレスシグナルと8‐ニトロ‐cGMPによる感染防御機構

    笠松真吾, 藤井重元, 赤池孝章

    2016/10/29

  35. 【病態バイオマーカーの"いま"】代謝 酸化ストレス病態とバイオマーカー

    藤井 重元, 赤池 孝章

    (公財)金原一郎記念医学医療振興財団　2016/10

  36. Oxidative stress signaling and 8-nitro-cGMP-mediated antibacterial host defense

    笠松 真吾, 藤井 重元, 赤池 孝章

    医歯薬出版　2016/10

  37. 活性イオウ分子種によるミトコンドリア機能制御

    赤池孝章, 井田智章

    2016

  38. 【活性イオウ分子種の生理機能に迫る チオールバイオロジーの新たなステージ】 RSSによる抗酸化・レドックスシグナル制御

    井田 智章, 藤井 重元, 赤池 孝章

    (株)学研メディカル秀潤社　2015/03

  39. 活性酸素のシグナル伝達機能

    赤池, 孝章

    [赤池孝章]　2014/03

  40. 活性酸素の本当の姿

    藤原 範子, 大河原知水, 木崎 節子, 李 昌一, 住本 英樹, 赤池 孝章, 藤井 重元, 岡崎 泰昌, 豊國 伸哉, 内藤 裕二, 大野 秀樹, 鈴木敬一郎

    ナップ　2014/02/16

    ISBN: 4905168295

  41. 【酸化ストレスとその防御】 活性酸素シグナルの調節機構 ROS毒性説から脱却した新たな概念

    居原 秀, 井田 智章, 赤池 孝章

    フレグランスジャーナル社　2013/02

  42. 活性酸素・ガス状分子による恒常性制御と疾患 : 酸化ストレス応答と低酸素センシングの最新知見からがん,免疫,代謝・呼吸・循環異常,神経変性との関わりまで

    赤池, 孝章, 一條, 秀憲, 森, 泰生, 山本, 雅之

    羊土社　2012/11

    ISBN: 9784758103268

  43. 実験医学増刊 Vol.30 No.17 活性酸素・ガス状分子による恒常性制御と疾患〜酸化ストレス応答と低酸素センシングの最新知見からがん,免疫,代謝・呼吸・循環異常,神経変性との関わりまで (実験医学増刊 Vol. 30-17)

    山本 雅之, 赤池 孝章, 一條 秀憲, 森 泰生

    羊土社　2012/10/20

    ISBN: 4758103267

  44. 高病原性鳥インフルエンザの診断・治療に関する国際連携研究 小児致死的ARDSおよび鳥インフルエンザウイルス感染症例の血漿蛋白質中の3‐ニトロチロシンの解析

    赤池孝章, 岡本竜哉

    2012

  45. 特集を読むまえに 基礎の基礎 (特集 活性酸素シグナル制御とレドックスホメオスタシス)

    赤池 孝章

    学研メディカル秀潤社　2012

  46. 新・活性酸素中毒学

    赤池 孝章

    公益社団法人 日本薬学会　2012

    DOI： 10.14894/faruawpsj.48.1_1 　

  47. The critical role of nitrated cyclic guanine nucleotide signaling via protein S-guanylation in the antioxidant adaptive response

    Shigemoto Fujii, Takaaki Akaike

    日本生化学会　2012

  48. 細胞工学 12年2月号 31ー2 特集:活性酸素とシグナル制御とレドックスホメオスタシス

    赤池孝章

    学研メディカル秀潤社　2012/01

    ISBN: 4780901278

  49. 高病原性鳥インフルエンザの診断・治療に関する国際連携研究 インフルエンザウイルス肺炎・ARDSにおける酸化ストレスバイオマーカー

    赤池孝章, 岡本竜哉

    2011

  50. 基礎医学から 新興感染症原因菌--Helicobacter cinaedi

    河村 好章, 赤池 孝章

    日本医事新報社　2010/10/30

  51. 【広範囲血液・尿化学検査免疫学的検査[第7版] その数値をどう読むか】その他 Nitric oxide(NO)およびNO関連物質

    岡本 竜哉, 澤 智裕, 赤池 孝章

    (株)日本臨床社　2010/07

  52. Nitric oxide（NO）およびNO関連物質．

    岡本竜哉, 澤 智裕, 赤池孝章

    2010

  53. インフルエンザ(H5N1)の死因となる劇症型ARDSの病態解析と治療法の開発に関する研究 インフルエンザウイルス肺炎・ARDSにおける酸化ストレスバイオマーカー

    赤池孝章, 岡本竜哉

    2010

  54. インフルエンザ(H5N1)の死因となる劇症型ARDSの病態解析と治療法の開発に関する研究 インフルエンザウイルス肺炎・ARDSにおける酸化ストレスバイオマーカー

    赤池孝章, 岡本竜哉

    2010

  55. Discovery of a New Signaling Molecule 8-Nitro-cGMP and Its Physiological Functions

    FUJII Shigemoto, SAWA Tomohiro, AKAIKE Takaaki

    公益社団法人 日本農芸化学会　2010/01/01

    DOI： 10.1271/kagakutoseibutsu.48.22 　

    More details Close

    これまで毒性物質ととらえられていた活性酸素が，細胞機能を変化させるシグナルとして機能していることがわかってきた．近年，巧妙に制御された細胞内活性酸素シグナルの受容と伝達の仕組みが次第に明らかになりつつある．生体内において活性酸素と一酸化窒素により生成する8-nitro-cGMPは，親電子性を有するユニークな特性をもった新規な二次メッセンジャーであり，活性酸素シグナル伝達において重要な役割を果たしている．

  56. NOと活性酸素による酸化ストレス適応応答

    赤池孝章

    2009/09/25

  57. 【病態解明に迫る活性酸素シグナルと酸化ストレス 癌、神経変性疾患、循環・代謝異常にかかわるレドックス制御機構と最新の技術開発】活性酸素・NOの生理機能 チオール基の修飾による活性酸素のセンサー機能制御

    澤 智裕, 有本 博一, 赤池 孝章

    (株)羊土社　2009/09

  58. 活性酸素シグナルと酸化ストレス―病態解明に迫る 癌、神経変性疾患、循環・代謝異常にかかわるレドックス制御機構と最 (実験医学増刊 Vol. 27-15)

    赤池 孝章

    羊土社　2009/09/01

    ISBN: 4758103011

  59. 【感染症防御・慢性疾患の初期機構 好中球の役割】活性酸素・NOによる感染防御シグナルの新展開

    岡本 竜哉, 澤 智裕, 藤井 重元, 赤池 孝章

    (株)ニュー・サイエンス社　2009/02

  60. 活性酸素・NO による感染防御シグナルの新展開

    岡本 竜哉, 澤 智裕, 藤井 重元, 赤池 孝章

    2009

  61. インフルエンザ(H5N1)の死因となる劇症型ARDSの病態解析と治療法の開発に関する研究 インフルエンザウイルス肺炎・ARDSにおける酸化ストレスバイオマーカー

    赤池孝章, 岡本竜哉

    2009

  62. 放射線・酸化ストレスにおけるNO・活性酸素シグナル制御

    赤池孝章, 澤智裕

    長崎医学会　2008/09/25

  63. NOによる細胞内感染防御の新しい展開

    赤池孝章

    2008/04/01

  64. Nitrativa stress during infection and inflammation in the lung

    岡本 竜哉, 赤池 孝章

    医歯薬出版　2008/03/15

  65. 活性酸素を消去する物質8-ニトロcGMP

    澤 智裕, 赤池 孝章

    2008

    DOI： 10.11477/mf.1543102136 　

  66. インフルエンザ(H5N1)の死因となる劇症型(ARDS)の病態解析と治療法の開発に関する研究 インフルエンザウイルス肺炎におけるニトロ化ストレスと生体防御機構

    赤池孝章, 岡本竜哉

    2008

  67. 【RIの逆襲 アイソトープを活用した簡単・安全バイオ実験】応用編 酸化ストレス研究 35Sを用いたタンパク質翻訳後修飾S-グルタチオン化の評価法

    岡本 竜哉, 澤 智裕, 赤池 孝章

    (株)学研メディカル秀潤社　2007/12

  68. 酸化ストレスと毒作用発現 NOによるニトロ化ストレスとシグナル伝達機構

    赤池 孝章, 澤 智裕

    (一社)日本毒性学会　2006/06

  69. 【敗血症性ショックの現在的理解】敗血症とショックの病態

    田村 文雄, 澤 智裕, 赤池 孝章

    (株)医薬ジャーナル社　2006/02

  70. Active oxygen, free-radical action and pathogenicity. Biospin and signal transduction. Introduction. Biochemistry of biospin and signal transduction.

    赤池孝章

    2006/01/22

  71. 【活性酸素・フリーラジカル機能と病態解明への新たなる展開:バイオスピンとシグナル伝達】ニトロ化修飾反応によるNOの新しいシグナル機構

    澤 智裕, 芥 照夫, 有本 博一, 赤池 孝章

    (株)学研メディカル秀潤社　2006/01

  72. 敗血症とショックの病態

    赤池 孝章, 澤 智裕

    2006

  73. ニトロ化修飾反応によるNOの新しいシグナル機構

    赤池 孝章, 澤 智裕

    2006

  74. 【活性酸素・フリーラジカル機能と病態解明への新たなる展開:バイオスピンとシグナル伝達】 バイオスピンのケミカルバイオロジーとシグナル伝達

    赤池 孝章

    (株)学研メディカル秀潤社　2006/01

  75. プリン異化代謝と活性酸素・N0 : 尿酸の抗酸化作用とニトログアニンのシグナル機能

    芥 照夫, 赤池 孝章

    2005/12/01

  76. 肺の炎症病態におけるNO・活性酸化窒素種の生成とマトリックスメタロプロテアーゼの活性発現調節--活性酸化窒素種によるMMPの制御 (あゆみ 酸化ストレスと疾患)

    岡本 竜哉, 赤池 孝章

    医歯薬出版　2005/09/10

  77. 発がんにおける炎症の役割と発がん予防に関する研究

    赤池孝章, 小倉勤, 高橋真美, 岡田太, 伝田阿由美, 村上明, 島影美鈴

    2005/09

  78. 8‐ニトログアノシンの生体内生成と細胞保護作用

    AKUTA TERUO, AKAIKE TAKAAKI, YOSHITAKE ATSUSHI, KANEKO KAZUYOSHI, NAKAYAMA HITOSHI, TERASAKI YASUHIRO, TAKEYA MOTOHIRO, MAEDA HIROSHI

    (公社)日本生化学会　2004/11/25

  79. 免疫系 感染症の病態を操る分子 NO 感染症におけるNOの役割

    赤池 孝章

    医歯薬出版(株)　2004/05

  80. 一酸化窒素・酸素ラジカルによる感染防御と病態形成に関する研究

    赤池孝章

    2004/02/25

  81. NOによる微生物遺伝子変異と感染制御異常

    赤池孝章, 久保田竜生, 芥照夫, 田村文雄, 吉武淳, 前田浩

    2003/10

  82. NOによる病原体遺伝子変異―感染制御・予防との関連性

    赤池孝章, 前田浩

    2003/08

  83. NOによる病原体遺伝子異変-感染防御・予防との関連性

    赤池 孝章, 前田 浩

    長崎大学　2003/08

  84. 基礎 インフルエンザと抗生剤

    田村 文雄, 赤池 孝章, 前田 浩

    メディカルレビュー社　2003/04

  85. 呼吸器疾患における酸化・ニトロ化ストレスの評価法

    赤池孝章

    (一社)呼吸研究　2003/03/15

  86. 【NOと病態】 感染症の病態を操る分子 NO 感染症におけるNOの役割

    赤池 孝章

    医歯薬出版(株)　2003/03

  87. 感染症の病態を操る分子 NO 感染症におけるNOの役割

    赤池孝章

    2003/03/01

  88. NOによる腫瘍増殖および転移促進のメカニズム

    林田 和之, 赤池 孝章, 前田 浩

    放射線生物研究会　2003/03

  89. 免疫系 感染症の病態を操る分子:NO--感染症におけるNOの役割 (第1土曜特集 NOと病態)

    赤池 孝章

    医歯薬出版　2003/03/01

  90. Generation of Lipid Peroxyl Radicals from Oxidized Edible Oils and Heme-Iron: Suppression of DNA Damage by Unrefined Oils and Vegetable Extracts

    Ayako Kanazawa, Tomohiro Sawa, Takaaki Akaike, Hiroshi Maeda

    2002/12/01

  91. 抗8-ニトログアノシン抗体の作製と生体内8-ニトログアノシンの検出

    田村 文雄, 赤池 孝章, 澤 智裕, 岡本 真一郎, 村上 恵理, 宮崎 公徳, 佐々本 一美, 前田 浩

    (公社)日本生化学会　2002/12

  92. 【臨床 フリーラジカルと呼吸器疾患】 フリーラジカルと呼吸器感染症 Free radical-dependent pathogenesis in respiratory tract infections

    赤池 孝章

    (株)先端医学社　2002/03

  93. フリーラジカルと呼吸器疾患 フリーラジカルと呼吸器感染症Free radical‐dependent pathogenesis in respiratory tract infections

    赤池孝章

    2002/03/01

  94. Endogenous Generation of Free Radicals is Involved in Carcinogenesis

    SAWA Tomohiro, AKAIKE Takaaki, MAEDA Hiroshi

    公益社団法人 日本農芸化学会　2002/01/05

    DOI： 10.1271/kagakutoseibutsu1962.40.15 　

  95. 感染とNO

    赤池孝章

    克誠堂出版(株)　2001/12/07

  96. 感染とNO (日本麻酔科学会第48回大会講演特集号) -- (学術講演)

    赤池 孝章

    克誠堂出版　2001/12

  97. 酸化ストレス フリーラジカル医学生物学の最前線 第1章 酸化ストレスの基礎 41 感染症によるNO代謝制御

    赤池孝章

    2001/09/30

  98. 新規水溶性ヘムオキシゲナーゼ阻害剤の合成とその抗腫瘍効果

    前田 浩, サンジーブ・サフー, 澤 智裕, 田中 真一郎, 方 軍, 宮本 洋一, 赤池 孝章

    日本癌学会　2001/09

  99. 【酸化ストレス フリーラジカル医学生物学の最前線】 酸化ストレスの基礎 感染症によるNO代謝制御

    赤池 孝章

    医歯薬出版(株)　2001/09

  100. 【フリーラジカルと神経系】フリーラジカルによる生体障害 フリーラジカルによる発癌

    澤 智裕, 赤池 孝章, 前田 浩

    (株)中外医学社　2001/05

  101. NOによる変異原性と腫よう原性の発現

    赤池孝章, 沢智裕, 前田浩

    2001/04/14

  102. NOによる変異原性と腫瘍原性の発現

    赤池 孝章, 澤 智裕, 前田 浩

    日本心脈管作動物質学会　2001/04/14

  103. 【炎症制御】感染・炎症におけるフリーラジカルの産生とその制御

    澤 智裕, 赤池 孝章, 前田 浩

    (株)メディカルレビュー社　2001/04

  104. Impairment of host defense via activation of host's proteases by bacterial proteases.

    赤池孝章, 岡本竜哉, 前田浩

    2001/03/10

  105. フリーラジカルによるウイルスの変異誘導

    赤池孝章

    医歯薬出版(株)　2001/03/10

  106. 【生物間の攻撃と防御の蛋白質】 微生物毒素とヒトとの戦い:現状と展開 細菌性プロテアーゼによる生体内プロテアーゼの活性化と生体制御の破綻

    赤池 孝章, 岡本 竜哉, 前田 浩

    共立出版(株)　2001/03

  107. Analysis of the pathogenicity expression mechanism of the protease in the fulminant A group streptococcus infectious disease and development of the therapy ( public welfare Ministry of Labor S ).

    赤池孝章

    2001

  108. Influenza - clinical medicine of influenza in new era - mechanism of exacerbation and its countermeasures. From basic study - roles of protease and free radical in exacerbated influenza - pathological modification by host response.

    赤池孝章, 岡本真一郎, 前田浩

    2000/11

  109. 【インフルエンザ 新時代のインフルエンザの臨床】 重症化のメカニズムと対策 基礎研究から インフルエンザ重症化におけるプロテアーゼとフリーラジカルの役割 宿主反応による病態修飾

    赤池 孝章, 岡本 真一郎, 前田 浩

    (株)ライフメディコム　2000/10

  110. 感染・炎症病態におけるプロテアーゼによる組織リモデリングの分子メカニズム

    赤池孝章

    2000/08/01

  111. NOとウイルスゲノムの進化

    赤池孝章

    日本ウイルス学会　2000/06/01

    DOI： 10.2222/jsv.50.73 　

  112. PP-1227 肝虚血再灌流障害におけるニトロソ化α_1 : プロテアーゼインヒビターの治療効果

    池辺 宗三人, 赤池 孝章, 宮本 洋一, 吉田 正貴, 濱本 高義, 小川 道雄, 前田 浩

    一般社団法人日本外科学会　2000/03/10

  113. 生態系でのNO,活性酸素測定における問題点 生体内細胞レベルにおけるNO量の実測

    赤池孝章, 沢智裕

    2000/03

  114. 【生態系でのNO,活性酸素測定における問題点】生体内細胞レベルにおけるNO量の実測

    赤池 孝章, 澤 智裕

    (株)先端医学社　2000/02

  115. 【生態系でのNO,活性酸素測定における問題点】 生体内細胞レベルにおけるNO量の実測

    赤池 孝章, 澤 智裕

    (株)先端医学社　2000/02

  116. A群レンサ球菌感染症におけるプロテアーゼの役割 厚生省S

    赤池孝章

    2000

  117. Nitric oxide and its related compounds.

    赤池孝章

    1999/12/26

  118. 広範囲血液・尿化学検査,免疫学的検査 その他 Nitric oxide(NO)及びNO関連物質

    赤池 孝章

    (株)日本臨床社　1999/12

  119. Activation mechanism of matrix metalloproteinases

    T Okamoto, T Akaike, H Maeda

    1999/12

  120. Peroxynitrite-induced pathogenesis of viral pneumonia.

    赤池孝章

    メディカルドゥ　1999/08/10

  121. Infectious Disease ウイルス性肺炎とパーオキシナイトライト

    赤池 孝章

    (株)メディカルドゥ　1999/08

  122. Gastrointestinal Diseases and NO. Nitric Oxide in Relation to Infections, Inflammation and Immunity.

    赤池孝章, 前田浩

    1999/06

  123. 【消化器疾患とNO】 NOの生理活性 感染,炎症,免疫とNO

    赤池 孝章, 前田 浩

    (株)日本メディカルセンター　1999/05

  124. NO and Organ Failure. Regulation mechanism of NO synthesis and NO antidotes.

    赤池孝章

    (株)ニュー・サイエンス社　1999/04/25

  125. Reactive oxygen and nitrogen species and nerve systems. NO-dependent tyrosine nitration in biological systems.

    赤池孝章

    1999/04/10

    DOI： 10.11477/mf.1431901040 　

  126. NO,パーオキシナイトライトとチロシンニトロ化反応 (特集 活性酸素・窒素種と神経系)

    赤池 孝章

    医学書院　1999/04

  127. 【肺の炎症・線維化の分子医学】 基礎 肺の炎症・線維化における酸化・抗酸化因子

    赤池 孝章

    (株)現代医療社　1999/02

  128. Redox Regulation in Viral Pathogenesis.

    赤池孝章

    (株)医学書院　1999/02

    DOI： 10.11477/mf.1404901842 　

  129. Molecular medical science of inflammation and fibrillation of lung Oxidant and antioxidant factors in inflammation and fibrillation of lung.

    赤池孝章

    1999/02

  130. Pathogenesis of Virus-induced Pneumonia Mediated through Peroxynitrite Formation: Lung Injury via Extensive Tissue Nitration and Accelaration of Viral Mutation.

    赤池孝章, 宮本洋一, 沢智裕, 前田浩

    1999

  131. Pathogenesis of Virus-induced Pneumonia Mediated through Peroxynitrite Formation: Lung Injury via Extensive Tissue Nitration and Accelaration of Viral Mutation.

    赤池孝章, 宮本洋一, 沢智裕, 前田浩

    1999

  132. Molecular mechanism of syndrome and disease state. Respiratory organ. Disease state, abnormal value and unusual observation. Lung injury factor.

    赤池孝章

    (株)中山書店　1998/12

  133. 【活性酸素・窒素種と神経系】 NO,パーオキシナイトライトとチロシンニトロ化反応

    赤池 孝章

    (株)医学書院　1998/10

  134. NO(Nitric Oxide). Clinical application of NOS inhibitors.

    赤池孝章

    (有)科学評論社　1998/10

  135. 活性酸素代謝系と生物の生存戦略 酸化ストレスによるウイルス遺伝子変異

    赤池 孝章

    (公社)日本生化学会　1998/08

  136. Role of NO and Oxygen Radical in Pathogenesis of Viral Infections.

    赤池孝章, 前田浩

    (株)学研メディカル秀潤社　1998/02

  137. Enhanced tumor targeting and antitumor activity of xanthine oxidase by chemical conjugation with PEG

    T. Sawa, J. Wu, T. Akaike, H. Maeda

    1998/01/01

  138. 【呼吸器系の生物学】 肺における活性酸素とスカベンジャー

    赤池 孝章

    (株)中外医学社　1998/01

  139. Gene variation of virus by oxidative stress. (the Inst. for Tropical Medicine, Nagasaki Univ. S).

    赤池孝章, 前田浩

    1998

  140. Pathophysiology of Peroxynitrite through Matrix Metalloproteinase Activation and Enhanced Viral Mutation.

    赤池孝章

    1998

  141. Molecular Pathogenesis of Viral Infections via Peroxynitrite-mediated Viral Mutation.

    赤池孝章

    1998

  142. Respiratory organ. I. The biology of the respiratory system. 5. Active oxygen and scavenger in the lung.

    赤池孝章

    1998/01

  143. NO is the Pathogenesis of viral infections

    AKAIKE Takaaki

    日本ウィルス学会　1997/12/01

    DOI： 10.2222/jsv.47.165 　

  144. ニトロソチオール及びパーオキシナイトライトの生体内検出

    赤池 孝章

    (一社)日本臨床化学会　1997/09

  145. NO合成酵素阻害剤と抗NO物質の化学と薬理

    赤池 孝章

    (株)最新医学社　1997/05

  146. NO. New Findings after Its Discovery. Chemistry and Pharmacology of NO Synthase Inhibitors and Anti-NO Substances.

    赤池孝章

    1997/05

  147. Imminent wave of new infectious diseases. Influenza virus infection.

    赤池孝章

    (株)医薬ジャーナル社　1997/04

  148. Generation of peroxynitrite and its pathophysiology in influenza virus pneumonia model. ( Ministry of Health and Welfare S ).

    赤池孝章

    1997

  149. Pathogenic Potential of Nitric Oxide and Superoxide in Influenza Virus Pneumonia in Mice: Involvement of Peroxynitrite in its Pathogenesis.

    赤池孝章

    1997

  150. Role of NO in virus infection disease state. (Uehara Commemorative Life Science Foundation S).

    赤池孝章

    1996/11/30

  151. Role of NO in inflammation.

    赤池孝章

    医歯薬出版(株)　1996/11/05

  152. Pathogenesis of influenza virus pneumonia involving free radical generation.

    赤池孝章

    1996/10

  153. NO-Chemistry and Biology. Chemsitry of NO. Nitronyl Nitroxides as NO Scavengers and a Novel Quantitative Assay for NO Using Liposome-incorporated Nitronyl Nitroxides.

    赤池孝章

    1996/10

  154. NO消去・定量化合物:PTIO (NO--化学と生物) -- (NOの化学)

    赤池 孝章

    学会出版センタ-　1996/10

  155. Pathogenesis of Pseudomonas Septicemia Involving Bacterial Exoproteases

    SAKATA Yoshifumi, OKAMOTO Tatsuya, AKAIKE Takaaki, SUGA Moritaka, ANDO Masayuki, MAEDA Hiroshi

    1996/10/01

  156. 感染防御におけるNOの意義

    赤池 孝章, 梅澤 和夫

    (株)中外医学社　1996/09

  157. Quantification of NO by Using Nitronyl Nitroxides.

    赤池孝章

    1996/09

  158. Topics on infectious diseases.Ssignificance of NO in phylaxis.

    赤池孝章, 梅沢和夫

    1996/09

  159. Up Date抗酸化物質と動脈硬化 基礎と臨床 酸化的傷害におけるNOの役割

    赤池 孝章

    (株)現代医療社　1996/08

  160. Antioxidant and arteriosclerosis - basic and clinic. Roles of NO in oxidative injury.

    赤池孝章

    1996/08

  161. Virus infection and nitrogen monoxide. (Nagasaki Univ., Inst. for Tropical Medicine S)

    赤池孝章, 前田浩

    1996/06/30

  162. Free radicals in viral pathogenesis.

    赤池孝章, 前田浩

    1996/06/29

  163. Induction of NO and superoxide in virus infection and pathogenicity expression.

    赤池孝章

    医歯薬出版(株)　1996/06/15

  164. ウイルス感染とフリーラジカル

    赤池 孝章, 前田 浩

    医歯薬出版(株)　1996/06

  165. Significance of NO in virus infection disease state.

    赤池孝章

    (株)医学書院　1996/05

    DOI： 10.11477/mf.1542902922 　

  166. スーパーオキシドと一酸化窒素の毒性発現機構

    赤池 孝章, 前田 浩

    (株)ニュー・サイエンス社　1996/04

  167. Cytotoxicity caused by Superoxide and No.

    赤池孝章, 前田浩

    1996/04

  168. Role of NO in infection diseases and inflammation.

    赤池孝章

    1996/02

  169. インフルエンザウイルス肺炎病態への一酸化窒素の関与

    赤池 孝章, 前田 浩

    (株)メディカルレビュー社　1996/01

  170. NOと感染防御/炎症反応

    赤池 孝章

    (株)医薬ジャーナル社　1996/01

  171. 血管反応,特にショック病態とNO

    赤池 孝章

    (株)メディカルレビュー社　1995/06

  172. NO放出剤とNO生成の定量的検出

    赤池 孝章, 前田 浩

    (株)羊土社　1995/05

  173. Role of nitric oxide in the pathogenesis of viral diseases.

    赤池孝章

    1995/05

  174. NO releasing agents and quantitation of NO.

    赤池孝章, 前田浩

    1995/05

  175. Up Date NOをめぐる話題 NO消去剤を用いたショックおよび炎症病態の治療

    赤池 孝章

    (株)現代医療社　1995/03

  176. インフルエンザウイルス肺炎モデルにおける一酸化窒素生成系の誘導とその病態生理学的意義

    赤池 孝章

    (一社)日本感染症学会　1995/03

  177. Update : Topics on NO.Basics and clinics.Treatment for shock and inflammatious disease state using NO erasers.

    赤池孝章

    1995/03

  178. 6. 抗NO薬 (<シンポジウム>4 NOと気道炎症)

    赤池 孝章

    一般社団法人 日本アレルギー学会　1995

    DOI： 10.15036/arerugi.44.834_2 　

  179. 敗血症 エンドトキシンショックと一酸化窒素

    赤池 孝章

    (株)医学書院　1994/12

  180. Infection, inflammation and nitrogen monoxide (NO).

    赤池孝章, 前田浩

    1994/12

  181. 病態生理モデル実験法 NO消去モデル

    赤池 孝章, 佐藤 圭創, 前田 浩

    (株)学研メディカル秀潤社　1994/09

  182. 活性酸素関連酵素およびタンパク質の測定法 Xanthine oxidase

    赤池 孝章

    (株)学研メディカル秀潤社　1994/09

  183. インフルエンザウイルス感染病態における一酸化窒素の役割

    赤池 孝章

    (公社)日本生化学会　1994/07

  184. Nitrogen monoxide (NO) and disease states.Endotoxin shock and NO.

    赤池孝章, 前田浩, 吉田正貴

    (株)北隆館　1994/06

  185. エンドトキシンショックにおける一酸化窒素(NO)の役割

    赤池 孝章

    日本細菌学会　1994/05

  186. Nitric Oxide and Cancer. A Novel Nitric Oxide Scavenger, Imidazolineoxyl N-Oxide and its Mechanism of Action.

    赤池孝章, 吉田正貴, 前田浩

    1993/12

  187. Nitric oxide scavenging activity of imidazolineoxyl N-oxides.

    赤池孝章, 前田浩

    1993/11

  188. Inhibitors of NO synthase and NO scavenger -importance and pitfall in research on NO.

    赤池孝章, 前田浩

    1993/07/17

  189. 一酸化窒素合成阻害剤と一酸化窒素消去剤

    赤池 孝章, 前田 浩

    医歯薬出版(株)　1993/07

  190. Oxygen radicals in infuluenza viral pneumonia.

    赤池孝章, 前田浩, 安藤正幸

    (一社)呼吸研究　1992/02

  191. Pathogenic mechanism of virus infection mediated by host respose: Important role of host-dependent oxygen radical generation.:Important role of host-dependent oxygen radical generation

    Maeda Hiroshi, Akaike Takaaki

    日本ウイルス学会　1992

  192. Interaction among hosts, pathogens and environments in influenza infection disease state.Its molecular pathology.

    赤池孝章, 前田浩

    (株)羊土社　1991/11

  193. 肺感染症1

    久世 文幸, 苑田 文成, 田中 栄作, 赤池 孝章, 後藤 純, 渡辺 秀裕, 大垣 憲隆, 永武 毅

    社団法人 日本呼吸器学会　1990

    DOI： 10.11389/jjrs1963.28.Supplement_139 　

  194. Elevation of cascade generating oxygen free radicals in influenza virus-infected mice.

    赤池孝章, 吉岡誠, 前田浩, 小田達也, 鈴木富士夫, 安藤正幸, 荒木淑郎

    1989/03/25

  195. マウスインフルエンザウイルス肺炎モデルにおける病原性増幅機構の検討 purine catabolismとO2-産生系について

    赤池 孝章

    (一社)日本呼吸器学会　1989/03

  196. マウスインフルエンザウイルス感染症における病因としての活性酸素の役割と活性酸素産生カスケードの亢進

    赤池 孝章, 吉岡 誠, 前田 浩

    医歯薬出版(株)　1989/03

  197. 感染防御系2

    安藤 正幸, 多部田 弘士, 赤池 孝章, 松本 充博, 杉本 峯晴, 今村 文哉

    社団法人 日本呼吸器学会　1989

    DOI： 10.11389/jjrs1963.27.Supplement_458 　

  198. Usefulness of serum adenosine deaminase activity in the early diagnosis of mycoplasma pneumonia

    M. Suga, H. Nishikawa, M. Ando, F. Tanaka, T. Akaike, T. Sakata, O. Kawano, K. Ito, H. Nakashima, S. Araki

    社団法人 日本呼吸器学会　1989

  199. 細菌性プロテアーゼによるインフルエンザウイルス感染症の病原性増強効果の解析

    赤池 孝章

    日本ウイルス学会　1988/12

  200. 肺炎および心外膜炎を合併したα-Streptococcusによる髄膜炎の1症例

    赤池 孝章

    (一社)日本内科学会　1987/03

  201. The effect of L-threo-DOPS in obstructive sleep apnea syndrome.

    赤池孝章, 中嶋博徳, 安東由喜雄, 西口聖治, 興ろぎ博次, 安藤正幸, 荒木淑郎

    日本自律神経学会　1986/12

  202. 閉塞型睡眠時無呼吸症候群に対するL-threo-DOPSの効果

    赤池 孝章

    日本自律神経学会　1986/04

  203. L-DOPSが有効であった閉塞型睡眠時無呼吸症候群の2症例

    赤池 孝章

    (一社)日本呼吸器学会　1986/03

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Presentations 140

  1. 超硫黄レドックス生命科学から見た生物進化論の新たな視点 Invited

    赤池 孝章

    第78回日本酸化ストレス学会学術集会 理事長講演　2025/05/23

  2. 酸素・超硫黄呼吸の代謝スイッチング機構の発見 Invited

    赤池孝章

    2024年末 オンラインセミナー in 熊本　2024/12/28

  3. レドックス生命科学の国際先導研究:超硫黄の巨大潮流

    赤池 孝章

    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　2024/05/19

  4. Supersulfide redox biology in life science and its translational medicine for disease control Invited

    Takaaki Akaike

    International Symposium “Signals for Human, Animal and Planetary Health: From Metabolites To Biological Interactions” (Tokyo Univ.)　2024/03/07

  5. 超硫黄分子のラマン分光イメージングを 駆使した定量分析

    赤池 孝章

    CREST「多細胞」領域，第5回領域会議プログラム・連携課題（浜松）　2023/12/21

  6. 超硫黄分子の発見と生理機能の解明 Invited

    赤池孝章

    第96回日本生化学会大会・特別講演（福岡）　2023/10/31

  7. 定量的超硫黄オミックス・イメージング技術の開発と標準化プロトコールの確立

    赤池 孝章

    学術変革領域研究(A) 「硫黄生物学」第3回領域会議・超硫黄フロンティアシンポジウム2023（熊本）　2023/09/16

  8. Supersulfide biology and translational medicine for disease control Invited

    Takaaki Akaike

    Chemical Biology/Redox Biology Seminar (Rhode Island, USA)　2023/08/30

  9. 超硫黄分子によるエネルギー産生と過酸化脂質・カルボニル代謝制御 Invited

    赤池孝章

    名古屋大学大学院生命農学研究科・特別セミナー（名古屋）　2023/06/27

  10. Measurement of inorganic polysulfides and understanding their chemical and biochemical properties

    Takaaki Akaike

    2023/05/12

  11. 活性酸素シグナル~酸素生物学~そして硫黄生物学：三つの領域のレドックス生命科学研究から俯瞰される世界 Invited

    赤池孝章

    第96回日本細菌学会総会(姫路)　2023/03/18

  12. Nitric Oxide Synthases, a New Family of NADPH-Dependent Sulfur Oxidoreductases Invited

    Takaaki Akaike

    Nitric Oxide Gordon Research Conference　2023/02/13

  13. 空間生体情報メタオミックス解析と呼気医療 Invited

    赤池孝章

    JASIS関西2023トピックス セミナー（大阪）　2023/02/02

  14. 環化超硫黄分子の生体内検出と機能解明 Invited

    赤池孝章

    CREST多細胞領域 第4回領域会議プログラム（名古屋）　2023/01/12

  15. Physiological formation and function of new supersulfide, cyclic octa-sulfur in mammals Invited

    Takaaki Akaike

    3rd STINT-JSPS Redox Biology Conference (Stockholm)　2023/01/20

  16. The physiological functions of cyclic octa-sulfur (S8) formed endogenously in diverse organisms including mammals Invited

    Takaaki Akaike

    Redox week in Sendai 2022 (Sendai)　2022/10/29

  17. Sulfur biology and redox signaling in energy metabolism, infection, and immunity Invited

    Takaaki Akaike

    The 15th Korea-Japan International Symposium on Microbiology (Korea)　2022/10/13

  18. 呼気オミックスから空間バイオミックスへの新展開 Invited

    赤池孝章

    レドックス R&D 戦略委員会第3回企画シンポジウム　2022/09/27

  19. Cyclo-octasulfur, S8, formed endogenously in mammals: its biosynthesis and physiological functions Invited

    Takaaki Akaike

    GRC “Thiol-Based Redox Regulation and Signaling: The Chemical Biology of Sulfur”　2022/06/10

  20. Reactive persulfide regulation of redox signaling and immune response Invited

    Takaaki Akaike

    6th World Congress on Hydrogen Sulfide in Biology & Medicine Keynote Lecture, Molecular Mechanisms　2022/05/28

  21. 前田 浩 先生の偉業を偲んで Invited

    赤池孝章

    第95回 日本細菌学会総会（オンライン）　2022/03/29

  22. 定量的超硫黄オミックス・イメージング技術の開発と標準化プロトコールの確立 Invited

    赤池孝章

    令和3(2021)年度 学術変革領域研究(A) 新興硫黄生物学が拓く生命原理変革(硫黄生物学) 第1回 領域会議（オンライン）　2022/03/19

  23. 呼気オミックスによる硫黄代謝解析と新型コロナ感染症 Invited

    赤池孝章

    第99回日本生理学会大会 企画シンポジウム（仙台）　2022/03/18

  24. 超硫黄化タンパク質の特異的検出法 新規超硫黄ビオチンスイッチ法

    Jung Minkyung, 笠松 真吾, 井田 智章, 松永 哲郎, 守田 匡伸, 本橋 ほづみ, 赤池 孝章

    日本生化学会大会プログラム・講演要旨集　2021/11

  25. 最近の超硫黄計測技術の展開 Invited

    赤池孝章

    令和3(2021)年度 学術変革領域研究(A) 新興硫黄生物学が拓く生命原理変革(硫黄生物学) 第1回 総括班会議（オンライン）　2021/10/16

  26. 呼気分析から解き明かす生体情報 呼気オミックスによる生体情報モニタリングと未来型医療

    赤池 孝章

    第59回日本臨床生理学会総会（オンライン）　2021/10

  27. 新型コロナの感染予防制御とポストコロナ時代の先進医療 Invited

    赤池孝章

    第94回日本細菌学会総会（オンライン）　2021/03/23

  28. Supersulfide signal regulation and metabolism Invited

    Takaaki Akaike

    2021/03/19

  29. 活性硫黄分子によるシグナル伝達と代謝制御 Invited

    赤池孝章

    第１回 レドックスR&D戦略委員会シンポジウム　2021/03/04

  30. NO・活性酸素シグナルから始まる 硫⻩⽣物学研究 Invited

    赤池孝章

    プラズマバイオコンソーシアム2020 年度研究会　2020/11/24

  31. 活性硫黄シグナルとエネルギー代謝制御

    赤池孝章

    日本生化学会大会(Web)　2020

  32. 新興感染症菌Helicobacter cinaediの骨髄内の潜伏感染と細胞内寄生性の分子機構の解明

    松永 哲郎, 西村 明, 守田 匡伸, 井田 智章, 津々木 博康, 澤 智裕, 河村 好章, 赤池 孝章

    日本細菌学雑誌　2019/03

  33. 環境医学におけるイオウ毒性学のニューパラダイム:イオウ医学生物学の黎明

    赤池孝章

    Journal of Toxicological Sciences　2019

  34. 活性パースルフィドによるエネルギー代謝とタンパク質機能のレドックス制御

    赤池孝章

    日本生化学会大会(Web)　2019

  35. Reactive sulfur metabolism, and its antioxidant, anti-inflammatory, and immunomodulatory functions

    赤池孝章

    日本生体防御学会学術総会講演抄録集　2019

  36. タンパク質パースルフィドの生合成・生理機能とイオウプロテオーム

    赤池孝章

    日本プロテオーム学会大会プログラム・抄録集　2019

  37. 新興感染症菌Helicobacter cinaediの骨髄内における潜伏感染と細胞内寄生性の解析

    松永 哲郎, 西村 明, 守田 匡伸, 藤井 重元, 井田 智章, 澤 智裕, 河村 好章, 赤池 孝章

    日本細菌学雑誌　2018/02

  38. イオウ呼吸とイオウストレス:レドックス病学の新しい概念の確立に向けて

    赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　2018

  39. ニトロソグルタチオン還元酵素(GSNOR)選択的欠損マウスの開発

    松永 哲郎, 西村 明, 笠松 真吾, Alam Morshedul, 井田 智章, 守田 匡伸, 居原 秀, 藤井 重元, 下田 翔, 西田 基宏, 本橋 ほづみ, 赤池 孝章

    生命科学系学会合同年次大会　2017/12

  40. レドックスとエネルギー代謝の時空間的制御機構解明から見える新たな疾病制御戦略 Cysteinyl-tRNA synthetase(CARS)は活性パースルフィド産生とミトコンドリア機能をコントロールしている

    赤池 孝章

    生命科学系学会合同年次大会　2017/12

  41. がん代謝にもとづく生物像の理解(代謝ネットワーク) イオウ呼吸とがん細胞エネルギー代謝

    赤池 孝章

    日本癌学会総会記事　2017/09

  42. 新規蛍光プローブを用いた活性パースルフィド分子種のイメージング解析

    松永哲郎, 梅澤啓太郎, 神谷真子, 井田智章, 藤井重元, 渡邊泰男, XIAN Ming, 浦野泰照, 赤池孝章

    日本細菌学雑誌(Web)　2017/02

  43. 腸肝在位Helicobacter感染症研究の最前線 Helicobacter cinaediの持続感染と動脈硬化症の進展・促進機構

    松永 哲郎, 藤井 重元, 澤 智裕, 河村 好章, 赤池 孝章

    日本細菌学雑誌　2017/02

  44. 抗酸化レドックスと活性イオウによる解毒代謝機構の新展開 環境親電子ストレスの新規分子メカニズム 生体内パースルフィド解毒制御系の破綻

    赤池 孝章, 井田 智章, 居原 秀, 西田 基宏

    The Journal of Toxicological Sciences　2017

  45. 低分子量ガス体の基礎と臨床 酸化ストレスと活性イオウ分子の解毒代謝 新しいエネルギー代謝・イオウ呼吸の発見

    赤池 孝章

    The Journal of Toxicological Sciences　2017

  46. 細菌のイオウ呼吸はすべての生物種に保存されている:ほ乳類における新しいエネルギー代謝経路・イオウ呼吸の発見

    赤池孝章, 井田智章, 松永哲郎, 守田匡伸, 笠松真吾, 西村明, 藤井重元, 居原秀, JUNG Minkyung, 赤司壮一郎, 澤智裕, 本橋ほづみ

    日本細菌学雑誌(Web)　2017

  47. 細菌感染におけるレドックスシグナル制御機構

    赤池孝章

    微生物シンポジウム講演要旨集　2016/09/02

  48. 細菌における新規シグナル伝達物質8‐ニトロ‐cGMPの生成と制御

    松永哲郎, 井田智章, 小野勝彦, 津々木博康, 藤井重元, 澤智裕, 赤池孝章

    日本生化学会大会(Web)　2016/09

  49. レドックスバイオロジーの新たなステージ 活性パースルフィドによるレドックス制御の分子基盤

    赤池 孝章

    Journal of Oral Biosciences Supplement　2016/09

  50. "酸素リモデリング"の破綻と疾患 Cysteinyl t-RNAシンテターゼは活性型過硫化物の主要供給源でありミトコンドリア生態調節を行う(Cysteinyl-tRNA synthetase is a major source of reactive persulfide and controls mitochondrial biology)

    赤池 孝章

    日本生化学会大会プログラム・講演要旨集　2016/09

  51. 活性イオウ分子種によるミトコンドリア機能制御

    赤池孝章, 井田智章

    日本酸化ストレス学会学術集会プログラム・抄録集　2016/08/30

  52. 生体内タンパク質ポリスルフィドの検出とその生成機構

    赤池孝章, 笠松真吾

    日本酸化ストレス学会学術集会プログラム・抄録集　2016/08/30

  53. 気道炎症と呼気NO

    赤池孝章

    日本呼吸器学会誌　2016/03

  54. 活性イオウシグナル伝達の新展開 活性イオウ分子種の生体内生成と生理機能

    赤池 孝章

    日本薬学会年会要旨集　2016/03

  55. 活性イオウ分子種 新しい活性酸素制御因子の生合成と制御機構

    赤池 孝章

    昭和学士会雑誌　2016/02

  56. 細菌における新規シグナル伝達物質8‐ニトロ‐cGMPの生成とその機能

    松永哲郎, 藤井重元, 井田智章, ジョン ミンキョン, 赤司壮一郎, 津々木博康, 居原秀, 澤智裕, 赤池孝章

    日本生化学会大会(Web)　2014/10

  57. 硫化水素によるレドックスシグナル制御:新しいセカンドメッセンジャー8‐SH‐cGMPの発見

    赤池孝章

    日本NO学会学術集会プログラム抄録集　2012

  58. 硫化水素により調節されるROSと求電子性細胞内シグナル伝達(ROS and electrophilic cellular signaling regulated by hydrogen sulfide)

    赤池 孝章, 澤 智裕, 西田 基宏

    日本生化学会大会プログラム・講演要旨集　2011/09

  59. 日本とケニアにおけるヘリコバクターシネディ感染症の分子疫学研究

    赤池孝章, 岡本竜哉

    長崎大学熱帯医学研究拠点共同研究報告集　2011/09

  60. 内因性硫化水素イオンによる親電子シグナル制御

    赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　2011/06/27

  61. 活性酸素シグナル伝達と加齢

    赤池孝章

    日本抗加齢医学会総会プログラム・抄録集　2011/04/26

  62. 抗酸化環境応答と加齢 活性酸素シグナル伝達と加齢

    赤池 孝章

    日本抗加齢医学会総会プログラム・抄録集　2011/04

  63. ニトロ化環状ヌクレオチドとガス状メディエーターの交叉シグナリング

    赤池孝章

    日本薬学会年会要旨集　2011/03/05

  64. 活性酸素シグナル研究の最前線 ニトロ化環状ヌクレオチドとガス状メディエーターの交叉シグナリング

    赤池 孝章

    日本薬学会年会要旨集　2011/03

  65. NO・活性酸素シグナルによる酸化ストレス応答

    赤池孝章

    日本衛生学雑誌　2010/04/15

  66. 酸化ストレス研究の最前線と疾病予防 NO・活性酸素シグナルによる酸化ストレス応答

    赤池 孝章

    日本衛生学雑誌　2010/04

  67. 金属・小分子ネットワークによる遺伝情報発現制御 NOと活性酸素による酸化ストレス適応応答

    赤池 孝章

    日本生化学会大会プログラム・講演要旨集　2009/09

  68. 活性酸素とNOによる親電子シグナル伝達

    赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　2009/06/11

  69. New paradigm of host defense against intracellular pathogens by nitric oxide

    Takaaki Akaike, Tatsuya Okamoto, Hasan Md Zaki, Shigemoto Fujii, Tomohiro Sawa

    Japanese Journal of Leprosy　2009

  70. タンパク質S-ニトロシル化による細胞内シグナリング調節 NO・活性酸素によるタンパク質S-Guanylationとシグナル伝達

    赤池 孝章

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　2008/11

  71. 放射線・酸化ストレスにおけるNO・活性酸素シグナル制御

    赤池孝章, 澤智裕

    原子爆弾後障害研究会特集号　2008/09/25

  72. Regulation of NO and reactive oxygen signaling for radiation-induced oxidative stress

    Akaike Takaaki

    Nagasaki Igakkai zasshi = Nagasaki medical journal　2008/09/25

  73. これからのハンセン病基礎研究の展開 NOによる細胞内感染防御の新しい展開

    赤池 孝章

    日本ハンセン病学会雑誌　2008/04

  74. Nitrative stress and signal transduction induced by NO

    Akaike Takaaki, Sawa Tomohiro

    Annual Meeting of the Japanese Society of Toxicology　2006/06/10

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    一酸化窒素（NO）は、血管・神経系の主要な情報伝達物質であるが、感染炎症において過剰に産生された場合、生体に毒性を発揮して様々なストレス応答を引き起こす。我々は、NOにより誘導されるユニークなストレス応答として、核酸塩基グアニンのニトロ化反応を介する細胞の生存シグナル伝達機構について解析を進めてきた。その結果、感染・炎症に伴って生成するNOがニトロ化ストレスにより、heme oxygenase-1（HO-1）を誘導して、様々なストレスに対して細胞保護作用を発揮していることが分かってきた。&lt;BR&gt;例えば、マウスの細菌（サルモネラ）感染モデルにおいて、NO産生に依存してHO-1の発現が誘導され、細胞保護・感染防御効果をもたらしていることが明らかとなった。また、NOによるHO-1の誘導と細胞保護作用は、培養マクロファージの感染系においても確認された。一方、NOを産生している細胞内で著明なグアニンニトロ化がもたらされ、各種8-ニトログアニン誘導体とともに、全く新規のcGMP誘導体である8-ニトロcGMPが産生されることを、免疫化学ならびに電気化学検出器を用いたHPLC分析により証明した。さらに興味あることに、8-ニトロcGMPが、強力にHO-1の誘導をもたらし、抗アポトーシス・細胞死抑制活性を発揮することにより、NOの二次的なシグナル分子として機能することが示された。&lt;BR&gt;これらの知見より、NOが、8-ニトロcGMP生成を介して、ニトロ化シグナル経路の活性化をもたらし、さらに、このユニークなNOシグナル系の活性化によりHO-1が発現・誘導され、NOの強力な感染防御効果がもたらされるものと考えられた。今後、感染防御のみならず、その他の多彩なNO機能の発現におけるNO−ニトロ化シグナル機構の解明が期待される。

  75. 酸化ストレスと毒作用発現 NOによるニトロ化ストレスとシグナル伝達機構

    赤池 孝章, 澤 智裕

    The Journal of Toxicological Sciences　2006/06

  76. 尿酸の生理的役割と低尿酸血症 プリン異化代謝と活性酸素・NO 尿酸の抗酸化作用とニトログアニンのシグナル機能

    赤池 孝章

    日本痛風・核酸代謝学会総会プログラム抄録集　2005/02

  77. プリン異化代謝と活性酸素・NO:尿酸の抗酸化作用とニトログアニンのシグナル機能

    赤池孝章

    日本痛風・核酸代謝学会総会プログラム・抄録集　2005

  78. 8‐ニトログアノシンの生体内生成と細胞保護作用

    AKUTA TERUO, AKAIKE TAKAAKI, YOSHITAKE ATSUSHI, KANEKO KAZUYOSHI, NAKAYAMA HITOSHI, TERASAKI YASUHIRO, TAKEYA MOTOHIRO, MAEDA HIROSHI

    生化学　2004/11/25

  79. 酸化ストレス・炎症発がんの分子メカニズム

    赤池孝章

    日本補完代替医療学会学術集会プログラム・抄録集　2004/10/05

  80. 炎症とがん 炎症発がんの分子基盤 8-ニトログアノシンの生体内生成と発がん

    赤池 孝章

    日本癌学会総会記事　2004/09

  81. 発がんにおける炎症の役割と発がん予防に関する研究

    赤池孝章

    厚生労働省がん研究助成金による研究報告集　2004/09

  82. 発がんにおける炎症の役割と発がん予防に関する研究

    赤池孝章

    厚生労働省がん研究助成金による研究報告集　2004/09

  83. 炎症とがん 炎症発がんの分子基盤:8‐ニトログアノシンの生体内生成と発がん

    赤池孝章

    日本癌学会総会記事　2004/08/25

  84. NOによる新しいシグナル伝達―8‐ニトログアノシン生成のインパクト―

    赤池孝章

    日本生体防御学会学術総会講演抄録集　2004/07/08

  85. ヒトアルブミン変異体を用いた新規S‐ニトロソタンパクの作製とその生物活性の解析

    異島優, 赤池孝章, 金場俊二, 末永綾香, 芥照夫, 宮本洋一, 小田切優樹

    日本薬学会年会要旨集　2004/03

  86. 宿主応答におけるラジカル解析

    赤池孝章

    日本細菌学雑誌　2004/02/25

  87. Methods in Microbiology 最先端研究手法の試み 宿主応答におけるラジカル解析

    赤池 孝章

    日本細菌学雑誌　2004/02

  88. インフルエンザウイルス肺炎モデルにおけるNO依存性蛋白・核酸ニトロ化反応と組織障害

    岡本 真一郎, 赤池 孝章, 前田 浩, 菅 守隆

    日本呼吸器学会雑誌　2003/03

  89. 感染病態におけるNO・酸化ストレスと発がん

    赤池孝章

    日本細菌学雑誌　2003/02/28

  90. 感染と発がん 感染病態におけるNO・酸化ストレスと発がん

    赤池 孝章

    日本細菌学雑誌　2003/02

  91. NOによる感染防御と病態形成のメカニズム

    赤池孝章

    阿蘇シンポジウム記録　2002/07/10

  92. 【感染症研究の新戦略】 NOによる感染防御と病態形成のメカニズム

    赤池 孝章

    阿蘇シンポジウム記録　2002/07

  93. NOの多面的機能発現の分子メカニズム

    赤池 孝章

    日本性機能学会雑誌　2002/06

  94. NO誘発性酸化ストレス

    赤池孝章

    日本薬学会年会要旨集　2002/03/05

  95. NOシグナル/酸化ストレスと病態・治療 NO誘発性酸化ストレス

    赤池 孝章

    日本薬学会年会要旨集　2002/03

  96. NO in Host Defense and Microbial Pathogenesis

    AKAIKE Takaaki

    Nippon Saikingaku Zasshi　2001/08/30

    More details Close

    一酸化窒素 (nitric oxide, NO) は, 循環系・神経系の情報伝達にとどまらず, 感染・炎症・免疫反応のメディエーターとして機能し, さらには免疫反応の調節, アポトーシスの制御, 発癌など幅広い生命現象にかかわっていることが明らかにされつつある。この様な多彩な活性は, NOそのものによる直接的作用のみならず, パーオキシナイトライトなどのNO由来の反応性窒素酸化物により間接的に発現されることもわかってきた。興味あることに, NOは感染症においてほぼ普遍的に産生され, 生体内で抗菌活性を発揮するだけでなく病原体と宿主の相互作用を修飾する重要な役割を演じている。感染防御と病態形成におけるNOの多彩な生物活性の解明は, 21世紀における感染病因論の新たな展開の糸口となるかもしれない。

  97. レドックス反応による新しい血管リモデリング機構

    赤池孝章

    生化学　2001/08/25

  98. 一酸化窒素(NO)による感染防御と病態形成に関する研究

    赤池孝章

    日本細菌学雑誌　2001/08/25

  99. 血管機能のレドックス制御機構 レドックス反応による新しい血管リモデリング機構

    赤池 孝章

    生化学　2001/08

  100. NOによる変異原性と腫瘍原性の発現

    赤池 孝章, 澤 智裕, 前田 浩

    血管　2001/04

  101. A群レンサ球菌のブラジキニン分解酵素

    赤池孝章, 宮本洋一, 川端重忠, 浜田茂幸, 前田浩

    日本細菌学雑誌　2001/02/28

  102. NOによる腫瘍増殖促進のメカニズム

    赤池 孝章, 澤 智裕, 林田 和之, 岡本 真一郎, 呉 軍, 前田 浩

    日本癌学会総会記事　2000/09

  103. NOによる腫よう増殖促進のメカニズム

    赤池孝章, 沢智裕, 林田和之, 岡本真一郎, WU J, 前田浩

    Japanese Journal of Cancer Research　2000/09/01

  104. NOによるmatrix metalloproteinase(MMP)の活性化メカニズム

    赤池孝章, 岡本竜哉, 沢智裕, 前田浩

    生化学　2000/08/25

  105. 感染症と活性酸素・NO

    赤池孝章

    炎症　2000/07/10

  106. ネズミチフス症の感染防御反応における誘導型NO合成酵素の役割

    赤池孝章, ALAM M S, 宮本洋一, 前田浩

    日本細菌学雑誌　2000/04/25

  107. 【生態系でのNO,活性酸素測定における問題点】生体内細胞レベルにおけるNO量の実測

    赤池 孝章, 澤 智裕

    炎症と免疫　2000/02

  108. 炎症反応によるNO過剰生成と変異原性の発現

    赤池孝章, 赤木淳, 岡本真一郎, 沢智裕, 宮本洋一, 前田浩

    日本癌学会総会記事　1999/08/30

  109. NOの生化学 医学と生物学におけるNOの役割 感染と炎症におけるNO生成とウイルスの分子進化

    赤池 孝章, 前田 浩

    生化学　1999/08

  110. 気道感染のメカニズムと対策 インフルエンザウイルス感染病態における酸素ラジカルとNOの役割

    赤池 孝章

    日本呼吸器学会雑誌　1999/03

  111. パーオキシナイトライトのウイルス変異促進作用

    赤池 孝章, 藤井 重元, 宮本 洋一, 加藤 篤, 永井 美之, 浅川 誠, 前田 浩

    生化学　1998/12

  112. 【NOと臓器障害】 感染とNO

    赤池 孝章

    日本集中治療医学会雑誌　1998/01

  113. Induction mechanism of NO biosynthesis and its molecular pathogenesis in virus infections.

    赤池孝章

    日本分子生物学会年会プログラム・講演要旨集　1997/12

  114. 酸化ストレスと細胞外マトリックス:グルタチオン及びNOによるマトリックスメタロプロテアーゼのレドックス制御

    赤池 孝章

    日本細胞生物学会大会講演要旨集　1997/10

  115. 酸化ストレスと細胞外マトリックス グルタチオンおよびNOによるマトリックスメタロプロテアーゼのレドックス制御

    赤池孝章, 前田浩

    日本細胞生物学会大会講演要旨集　1997

  116. リポソームPTIOのNO消去活性の解析

    赤池 孝章, 藤井 重元, 吉田 正貴, 岡本 竜哉, 前田 浩

    日本分子生物学会年会プログラム・講演要旨集　1996/08/01

  117. Analysis of NO erasure activity of liposome PTIO.

    赤池孝章, 藤井重元, 吉田正貴, 岡本竜哉, 前田浩

    日本分子生物学会年会プログラム・講演要旨集　1996/07

  118. 活性酸素/一酸化窒素による好中球プロコラゲナーゼの活性化機構

    赤池 孝章

    生化学　1994/12

  119. 敗血症/エンドトキシンショック発症機構における一酸化窒素(NO)の役割

    赤池 孝章

    感染症学雑誌　1994/09

  120. ラジカル-ラジカル反応による・NO活性の中和

    赤池 孝章

    生化学　1993/08

  121. Nitric Oxideの殺菌作用の検討

    赤池 孝章

    日本細菌学雑誌　1993/05

  122. Nitric oxideの殺菌作用の検討

    赤池 孝章

    日本細菌学雑誌　1993/01

  123. Endothelium-derived relaxing factor(EDRF)〔NO〕の新しい阻害物質,phenyl-imidazoline-oxide-oxyl誘導体

    赤池 孝章

    生化学　1992/08

  124. NADPH/Cytochrome P-450reductaseによるacridinium saltsの化学発光機構の解析

    赤池 孝章

    生化学　1992/07

  125. 有機peroxyl radicalの有する殺菌作用を指標とした抗酸化活性測定法

    赤池 孝章

    日本細菌学雑誌　1992/01

  126. ハウスダストプロテアーゼの生物活性の検討 特にキニン産生カスケードの活性化とインフルエンザウイルスの感染性増幅機構

    赤池 孝章

    生化学　1991/08

  127. ハウスダストプロテアーゼの生物活性の検討 特にキニン産生カスケードの活性とインフルエンザウイルスの感染性増幅機構

    赤池 孝章

    生化学　1991/07

  128. マウスインフルエンザ肺炎モデルにおけるxanthine oxidaseの誘導と活性酸素産生機構の解析

    赤池 孝章

    日本胸部疾患学会雑誌　1990/03

  129. マウスインフルエンザウイルス感染症における活性酵素の役割

    赤池 孝章

    生化学　1989/09

  130. セラチア菌プロテアーゼによる補体とプロテアーゼインヒビターの不活化と分解

    赤池 孝章

    日本細菌学雑誌　1989/01

  131. 細菌性プロテアーゼによるインフルエンザウイルスの病原性増強効果 Hageman factor dependent plasmin generation cascadeによるウイルスの活性化機構

    赤池 孝章

    生化学　1988/08

  132. インフルエンザ感染症における細菌性プロテアーゼの影響

    赤池 孝章

    日本細菌学雑誌　1988/07

  133. 細菌性プロテアーゼによるインフルエンザウイルス感染症の病原性増強効果の解析

    赤池 孝章

    日本細菌学雑誌　1988/01

  134. 超硫黄分子の発見と感染防御・免疫・代謝制御に関する研究 Invited

    赤池孝章

    第3回 太田原豊一賞 受賞講演（熊本）　2022/03/10

  135. 硫黄呼吸の生命進化論 Invited

    赤池孝章

    第20回 日本ミトコンドリア学会（東京）　2021/12/09

  136. Redox biology and bioenergetics innovated by supersulfide paradigm Invited

    2021/11/03

  137. Development of innovative imaging system for sulfur respiration in humans Invited

    2021/09/28

  138. 呼気オミックスと未来型医療 Invited

    赤池孝章

    第46回日本医用マススペクトル学会 シンポジウム1 「臨床バイオマーカー」（オンライン）　2021/09/17

  139. 超硫黄分子による生体防御学の新たな潮流 Invited

    赤池孝章

    第32回 日本生体防御学会学術総会 シンポジウム（オンライン）　2021/09/08

  140. 超硫黄分子による感染免疫制御とエネルギー代謝 Invited

    赤池孝章

    第41回 阿蘇シンポジウム（熊本）　2021/08/21

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Industrial Property Rights 48

  1. 新規抗酸化眼内灌流液

    中澤 徹, 赤池 孝章, 國方 彦志

    特許第6943390号

    Property Type: Patent

  2. 新規抗酸化眼内灌流液

    中澤 徹, 赤池 孝章, 國方 彦志

    特許第6943390号

    Property Type: Patent

  3. 抗8−チオアルコキシグアノシン−3’,5’−サイクリック1リン酸抗体

    赤池 孝章, 澤 智裕

    特許第5261708号

    Property Type: Patent

  4. ニトログアノシン−3’,5’−サイクリック1リン酸化合物およびプロテインキナーゼG活性化剤

    赤池 孝章, 芥 照夫

    特許第4956752号

    Property Type: Patent

  5. 脂肪酸を含有するS−ニトロソタンパク質とその製法

    異島 優, 赤池 孝章, 小田切 優樹

    特許第4935242号

    Property Type: Patent

  6. 抗8−ニトロサイクリックグアノシン3’,5’−一リン酸抗体

    赤池孝章, 有本博一, 芥 照夫, 佐々本一美

    特許第4857431号

    Property Type: Patent

  7. 抗菌作用が増強されたアルブミン

    小田切 優樹, 赤池 孝章

    特許第4649954号

    Property Type: Patent

  8. 一酸化窒素消去剤、検出剤及び定量剤

    前田 浩, 赤池 孝章, 佐々本 一美, 片山 佳樹

    特許第3484584号

    Property Type: Patent

  9. S−ニトロソ化合物検出方法

    赤池 孝章, 西野 博仁

    特許第3013239号

    Property Type: Patent

  10. イミダゾリン誘導体及び血圧維持薬

    宮本 洋一, 赤池 孝章, 前田 浩

    特許第2793096号

    Property Type: Patent

  11. 新規イミダゾリンオキシル誘導体

    奥村 謙, 角田 隆輔, 前田 浩, 赤池 孝章, 佐藤 圭創, 佐々本 一美, 片山 佳樹

    特許第2526368号

    Property Type: Patent

  12. ニトログアノシン−3’,5’−サイクリック1リン酸化合物およびプロテインキナーゼG活性化剤

    赤池 孝章, 芥 照夫

    Property Type: Patent

  13. 8−ニトログアニンを認識する抗体

    赤池 孝章, 澤 智裕, 宮崎 公徳, 渡辺 恵理

    Property Type: Patent

  14. 活性硫黄の定量方法

    國澤 研大, 遠山 敦彦, 赤池 孝章, 飯伏 翼

    Property Type: Patent

  15. 学習モデルの生成方法、プログラム、演算装置

    赤池 孝章, 高木 智史

    Property Type: Patent

  16. 感染症のバイオマーカ

    赤池 孝章, 高木 智史

    Property Type: Patent

  17. ポリスルフィドの安定化

    赤池 孝章

    Property Type: Patent

  18. ヘリコバクター・シネディー由来ポリペプチド及びその利用方法

    赤池 孝章, 佐々木 裕, 正木 孝幸

    Property Type: Patent

  19. SH基修飾剤

    赤池 孝章, 有本 博一, 澤 智裕

    Property Type: Patent

  20. 抗8−チオアルコキシグアノシン−3’,5’−サイクリック1リン酸抗体

    赤池 孝章, 澤 智裕

    Property Type: Patent

  21. 脂肪酸を含有するS−ニトロソタンパク質とその製法

    異島 優, 赤池 孝章, 小田切 優樹

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  22. 抗8−ニトロサイクリックグアノシン3’,5’−一リン酸抗体

    赤池孝章, 有本博一, 芥 照夫, 佐々本一美

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  23. 体液中の一酸化炭素濃度測定方法

    赤池 孝章, 植田 秀雄

    Property Type: Patent

  24. 抗菌作用が増強されたアルブミン

    小田切 優樹, 赤池 孝章

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  25. 抗腫瘍剤

    澤 智裕, 赤池 孝章, 前田 浩

    Property Type: Patent

  26. 新規なシステインプロテアーゼ阻害剤

    前田 浩, 赤池 孝章, 宮本 洋一, 藤井 重元, 池邊 宗三人, 吉武 淳, モハマド・サミウル・アラム, 岡本 竜哉, 井上 勝央, 濱本 高義

    Property Type: Patent

  27. 抗腫瘍剤

    赤池 孝章, 前田 浩, 小川 道雄

    Property Type: Patent

  28. 新規な一酸化窒素供与剤

    赤池 孝章, 宮本 洋一, 前田 浩, 濱本 高義, 友清 和彦, 中垣 智弘, 宮本 誠二

    Property Type: Patent

  29. 抗腫瘍剤

    澤 智裕, 赤池孝章, 前田 浩

    Property Type: Patent

  30. S−ニトロソ化合物検出方法

    赤池 孝章, 西野 博仁

    Property Type: Patent

  31. S−ニトロソ化合物検出装置

    赤池 孝章, 西野 博仁

    Property Type: Patent

  32. 医薬組成物

    赤池 孝章, 近藤 智紀

    Property Type: Patent

  33. 修飾されたスーパーオキシドジスムターゼ及びその製造方法

    小田切 優樹, 前田 浩, 赤池 孝章

    Property Type: Patent

  34. 医薬組成物

    赤池 孝章, 近藤 智紀

    Property Type: Patent

  35. 血管保護剤及び循環器疾患用医薬組成物

    赤池 孝章, 近藤 智紀

    Property Type: Patent

  36. 抗炎症剤

    赤池 孝章, 近藤 智紀

    Property Type: Patent

  37. 呼吸器保護剤及び呼吸器疾患用医薬組成物

    赤池 孝章, 近藤 智紀

    Property Type: Patent

  38. 血圧降下剤

    宮本 洋一, 赤池 孝章, 吉田 正貴, 前田 浩

    Property Type: Patent

  39. カリクレイン阻害作用を有するトリプシンインヒビター誘導体

    前田 浩, 赤池 孝章, 大出 博功, 米田 文郎, 木下 智佳子

    Property Type: Patent

  40. 一酸化窒素消去剤、検出剤及び定量剤

    前田 浩, 赤池 孝章, 佐々本 一美, 片山 佳樹

    Property Type: Patent

  41. ウイルス感染症治療剤

    前田 浩, 赤池 孝章

    Property Type: Patent

  42. 新規イミダゾリンオキシル誘導体

    奥村 謙, 角田 隆輔, 前田 浩, 赤池 孝章, 佐藤 圭創, 佐々本 一美, 片山 佳樹

    Property Type: Patent

  43. 血圧制御剤

    前田 浩, 赤池 孝章, 佐藤 圭創, 野口 陽一郎

    Property Type: Patent

  44. イミダゾリン誘導体及び血圧維持薬

    宮本 洋一, 赤池 孝章, 前田 浩

    Property Type: Patent

  45. 抗酸化活性測定方法

    宮本 洋一, 前田 浩, 井尻 須美子, 赤池 孝章, 佐藤 圭創, 小嶋 祐一郎

    Property Type: Patent

  46. 活性酸素消去剤

    前田 浩, 赤池 孝章, 西郡 秀夫, 浦上 貞治, 吉田 智恵子

    Property Type: Patent

  47. 活性酸素消去剤

    前田 浩, 赤池 孝章, 西郡 秀夫, 浦上 貞治, 吉田 智恵子

    Property Type: Patent

  48. 空気中の微粒子捕集装置および空気中の微粒子捕集方法

    高奈秀匡, 中嶋智樹, 太田信, 赤池孝章, 安西眸, 松永哲郎

    Property Type: Patent

Show all Show first 5

Research Projects 103

  1. Global Exploration for Redox Supermolecules Evolving in Life Functions

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Fund for the Promotion of Joint International Research (International Leading Research )

    Institution: Tohoku University

    2023/11/17 - 2030/03/31

  2. 超硫黄分子によるエネルギー代謝と酸化ストレスシグナル機能の解明

    赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(S)

    Institution: 東北大学

    2024/04/01 - 2029/03/31

  3. 関節の恒常性維持と破綻における超硫黄分子の機能解明に基づく関節疾患治療の基盤構築

    宮本 洋一, 赤池 孝章, 齋藤 琢, 矢野 文子

    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: 昭和大学

    2024/04/01 - 2027/03/31

  4. Regulation of T cell immune responses by supersulfide

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  5. 呼気凝集液を用いた硫黄代謝物解析による非侵襲な新規食道癌診断法の確立

    小澤 洋平, 亀井 尚, 赤池 孝章, 飯久保 正弘, 岡本 宏史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

  6. 超硫黄分子の代謝制御メカニズムの解明

    守田 匡伸, 松永 哲郎, 井田 智章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

  7. Management of international relation and facility for promotion of research on sulfur biology

    Offer Organization: Japan Society for the Promotion of Science

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

    Category: Grant-in-Aid for Transformative Research Areas (A)

    Institution: Tohoku University

    2021/09/10 - 2026/03/31

  8. 定量的超硫黄オミックス・イメージング技術の開発と標準化プロトコールの確立

    赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 学術変革領域研究(A)

    Category: 学術変革領域研究(A)

    Institution: 東北大学

    2021/09/10 - 2026/03/31

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    本研究では、定量的超硫黄オミックスおよびイメージング技術の開発と世界標準化プロトコールとデータベースを構築する。この分析技術を基に、新たな疾病、老化制御・長寿医療の研究基盤を確立する。例えば、超硫黄オミックスやイメージングにより生体の硫黄代謝動態をモニタリングすることで、日常的な健康管理 のみならず、動脈硬化などの生活習慣病、慢性炎症性肺疾患、心筋梗塞・心不全などの難治性心疾患などにおける病状把握や病態解明や予防・治療法の開発に繋げる。さらに、本超硫黄オミックス解析設備と技術を当該研究領域のバーチャルハブとして運用することで、総括班のミッションである領域内での横断的連携の強化のみならず、総括班にて先導する超硫黄のグローバルコンソーシアム構想と国際標準化・データベース化を支援し着実に遂行する。このことにより超硫黄生物学を世界的レベルで展開する。本年度では、単離ミトコンドリアを用いたシングルミトコンドリアイメージングシステムを構築し、本システムおよび定量的な硫黄オミックス解析を組み合わせて、真核生物における硫黄依存型エネルギー代謝、すなわち、硫黄呼吸が、酸素呼吸とのハイブリット型システムであることを明らかにした。加えて、超硫黄分子を特異的に捕捉する分子カプセルを用いて、哺乳類・ヒトの細胞内に硫黄原子が環状化したS8分子が生成されることを発見した。さらに、超硫黄分子のSSP4蛍光イメージングと硫黄オミックスを駆使して、ホルムアルデヒド(HCHO)による細胞内の超硫黄分子の安定化現象を見出し、その知見をもとに、新たに、細胞内超硫黄イメージング法を考案した。現在、超硫黄イメージングに加えて、本法を応用した超硫黄ラマンイメージングの開発に取り組んでいる。

  9. 硫黄生物学から紐解く膵癌難治化機構の解明と治療応用

    正宗 淳, 赤池 孝章, 濱田 晋, 田口 恵子

    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

    2022/04/01 - 2025/03/31

    More details Close

    本年度は研究初年度として、Cars2ヘテロノックアウト付加KPCマウスの作製を実施した。Cars2ヘテロノックアウトKPCマウス（膵特異的変異Kras, p53発現）、Cars2ヘテロノックアウトKCマウス（膵特異的変異Kras発現）が得られ、野生型KPCマウスと同様に生後90日まで生存することを確認した。Cars2ヘテロノックアウトKCマウス膵組織においては前癌病変であるpancreatic intraepithelial neoplasmの形成数が減少する傾向がみられた。Cars2ヘテロノックアウトKPCマウス1頭で膵発癌がみられたが、組織型は野生型KPCマウスと類似した腺癌を呈していた。Cars2ヘテロノックアウトマウスより膵星細胞を分離し、SV40導入により不死化し細胞株を樹立した。樹立細胞株は10％ウシ胎児血清添加DMEMにて継代可能であったが、野生型膵星細胞株に比べて細胞増殖能・遊走能は低下していた。Cars2ヘテロノックアウト膵星細胞の酸化ストレス耐性を評価するためにマレイン酸ジエチル処理後の細胞生存率を野生型膵星細胞株と比較したが、Nrf2欠損膵星細胞株とは異なり明らかな脆弱性は認めなかった。我々はこれまでにヒトおよびマウス膵星細胞の培養上清刺激が膵癌細胞の増殖を促進することを報告してきたが（Takikawa, Pancreas 2017; Tanaka, AJP-GI 2021）、Cars2ヘテロノックアウト膵星細胞株の培養上清刺激ではむしろ増殖が抑制されることが判明した。処理後のKPCマウス膵癌細胞株では細胞周期の抑制因子であるp21発現が増加し、促進因子のcyclin D1は減少していた。

  10. Study on the role of sulfur respiration in homeostasis and disruption of the skeletal system under hypoxic conditions

    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: Showa University

    2022/04/01 - 2025/03/31

  11. 呼気オミックスを用いた乳がん口腔支援システムの開発

    丹田 奈緒子, 石田 孝宣, 赤池 孝章, 鷲尾 純平, 多田 寛, 高橋 信博, 小関 健由

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2022/04/01 - 2025/03/31

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    乳癌は世界で最も罹患率の高い悪性腫瘍で骨転移を伴うことが多く長期的な病状の制御と薬物療法が必要とされている。骨転移に伴う骨関連事象の抑制のため骨吸収抑制薬が使用されるが、その副作用である顎骨壊死に対し日本乳癌学会では薬剤使用開始前の口腔内リスク評価と薬剤使用中の定期的な口腔管理を推奨している。長期的な薬物療法中の乳癌患者の口腔管理には骨転移のリスクを含めた病状の理解が必要となる。２型アルデヒド脱水素酵素（aldehyde dehydrogenase 2: ALDH2）のALDH２遺伝子多型はアセトアルデヒドの体内蓄積を引き起こす。本研究の目的は、アルデヒド等代謝物の蓄積が骨転移の予測因子となりうるかについて呼気オミックスとALDH２遺伝子多型から解析し、薬物療法時ならびに骨吸収抑制薬使用時の口腔環境因子について探索することにより、長期薬物療法中乳癌患者の顎骨壊死等有害事象の予防を目指した口腔支援システムを開発することである。 初年度は「人を対象とする生命科学・医学系研究に関する倫理指針」に従い、東北大学大学院歯学研究科研究倫理委員会へ臨床研究倫理申請を行った。「乳癌患者の骨転移・骨関連事象に関する呼気・口腔環境の解析」という課題名のもと、研究実施許可を得た。その後当院総合外科（乳腺・内分泌外科）患者を対象に、現在まで30名の適格症例の研究登録同意を得た。飲酒・喫煙・口腔衛生についての質問とともに口腔内診査を行い、呼気凝縮液の回収、その際の安静時唾液採取、遺伝子検査等を進めている。

  12. Elucidation of new adipocyte functions controlled by sulfur respiration

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Tohoku University

    2022/04/01 - 2025/03/31

  13. 硫黄生物学から紐解く膵癌難治化機構の解明と治療応用

    正宗 淳, 赤池 孝章, 濱田 晋, 田口 恵子

    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

    2022/04/01 - 2025/03/31

    More details Close

    本年度は研究初年度として、Cars2ヘテロノックアウト付加KPCマウスの作製を実施した。Cars2ヘテロノックアウトKPCマウス（膵特異的変異Kras, p53発現）、Cars2ヘテロノックアウトKCマウス（膵特異的変異Kras発現）が得られ、野生型KPCマウスと同様に生後90日まで生存することを確認した。Cars2ヘテロノックアウトKCマウス膵組織においては前癌病変であるpancreatic intraepithelial neoplasmの形成数が減少する傾向がみられた。Cars2ヘテロノックアウトKPCマウス1頭で膵発癌がみられたが、組織型は野生型KPCマウスと類似した腺癌を呈していた。Cars2ヘテロノックアウトマウスより膵星細胞を分離し、SV40導入により不死化し細胞株を樹立した。樹立細胞株は10％ウシ胎児血清添加DMEMにて継代可能であったが、野生型膵星細胞株に比べて細胞増殖能・遊走能は低下していた。Cars2ヘテロノックアウト膵星細胞の酸化ストレス耐性を評価するためにマレイン酸ジエチル処理後の細胞生存率を野生型膵星細胞株と比較したが、Nrf2欠損膵星細胞株とは異なり明らかな脆弱性は認めなかった。我々はこれまでにヒトおよびマウス膵星細胞の培養上清刺激が膵癌細胞の増殖を促進することを報告してきたが（Takikawa, Pancreas 2017; Tanaka, AJP-GI 2021）、Cars2ヘテロノックアウト膵星細胞株の培養上清刺激ではむしろ増殖が抑制されることが判明した。処理後のKPCマウス膵癌細胞株では細胞周期の抑制因子であるp21発現が増加し、促進因子のcyclin D1は減少していた。

  14. 超硫黄フラックス解析基盤の創出による筋頑健性構築

    西田 基宏, 赤池 孝章, 中林 孝和, 西村 明幸

    Offer Organization: 戦略的創造研究推進事業 CREST

    System: [多細胞] 多細胞間での時空間的相互作用の理解を目指した定量的解析基盤の創出

    2020 - 2025

  15. 新しい生体超分子S8環八超硫黄の発見と生理機能解明

    赤池 孝章, 吉沢 道人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 挑戦的研究(萌芽)

    Category: 挑戦的研究(萌芽)

    Institution: 東北大学

    2022/06/30 - 2024/03/31

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    驚くべきことに、火山地帯など極限環境に見られる環状化硫黄S8(環八超硫黄)が、ヒト・動物の生体内で積極的に合成され極めて豊富に検出された。これは、無機硫黄分子であるS8環八超硫黄が、生命進化論と生命現象に深く関わることを示す生物学・生命科学における極めて大きな発見である。本研究では、超硫黄分子カプセルを用いて新たに開発した超硫黄解析により、生体内S8の代謝経路その生理機能の全容を解明する。さらに、超硫黄分子カプセルの組織、細胞、オルガネラ(特に、ミトコンドリア)への選択的ターゲットとDDSにより、高等生物において今回初めて発見されたS8超硫黄の真の生理機能を解明する。当該年度では、超硫黄分子カプセルを用いることにより、各種培養細胞系および動物組織(マウス)におけるS8の細胞・生体内検出に成功した。すなわち、マウス線維芽細胞MEFを超硫黄ドナーであるグルタチオントリスルフィドGSSSGで処理すると細胞内のS8レベルが顕著に上昇し、さらに、これは超硫黄の酸化代謝酵素であるSQR (sulfide:quione reductase)により代謝維持されていることを見出した。さらに、驚くべきことに、活性酸素産生酵素であるNOX(NADPH oxidase)やNO合成酵素(NOS)が、実際は、NADPHの電子・プロトンを優先的に超硫黄(GSSSG)に渡して超硫黄の伸長反応(catenation, カテネーション)を触媒してS8産生酵素(S8 synthase)として機能していることを明らかにした。

  16. The study on the role of reactive sulfur species in the pathogenesis of periodontitis

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Showa University

    2021/04/01 - 2024/03/31

  17. Sulfur-mediated energy metabolism, sulfur respiration: Its discovery and physiological functions

    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

    2018/06/11 - 2023/03/31

  18. Remodeling of reactive sulfur metabolism by reactive oxygen species-producing enzyme, Nox: Discovery of reactive sulfur remodelase

    Akaike Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Tohoku University

    2020/07/30 - 2022/03/31

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    NADPH oxidase (Nox) is known as a major reactive oxygen species-producing enzyme in various organisms. We found that in HEK cells over-expressed with human Nox4, remarkable amount of various reduced forms of reactive persulfide species (RSS) like glutathione persulfide (GSSH) and dihydrogen persulfide (HSSH) are generated in the cells, and most intriguing thing is that sulfur is extended to become glutathione trisulfide (GSSSH), indicating the this is a unique sulfur oxido-reductase reaction. Our data therefore revealed for the first time that Nox eventually can function as NADPH-dependent sulfur oxidoreductase or RSS-producing or more strictly reactivating enzymes, through this very unique reduction and oxidation of the sulfur molecules.

  19. Regulation of bone remodeling by reactive sulfur species, the novel signal molecules

    Kamijo Ryutaro

    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: Showa University

    2019/04/01 - 2022/03/31

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    Reactive sulfur species (RSS), which are produced in our cells, are known to play a variety of physiological and pathological functions in addition to regulating redox signaling. We aimed to elucidate the functions of RSS in bone remodeling. We found that RSS promoted the differentiation of macrophages into osteoclasts after RANKL stimulation and that RSS activated the calcium-calcineurin system as a mechanism of this process. We also found that RSS is required for osteoblast differentiation and calcification after stimulation by bone morphogenetic protein-2. These results suggest that RSS is an important factor in maintaining osteoclast and osteoblast differentiation and function, which is responsible for bone remodeling.

  20. Life science basis of short-lived reactive species originated from foods

    UCHIDA Koji

    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: The University of Tokyo

    2017/05/31 - 2022/03/31

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    In this study, we focused on "short-lived molecular species" originating from plant-based food ingredients and aimed at discovering new molecular species and developing their functionality. We obtained a number of new findings, such as conversion of proteins into innate immune ligands that exhibit cross-reactivity with natural antibodies by unstable antioxidant metabolic intermediates, generation of new reactive sulfur species derived from sulfur-containing compounds in vivo, and a new protein function control mechanism by reactive nitrogen species.

  21. Pathogenesis of NRF2-addicted cancers

    Motohashi Hozumi

    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

    2018/04/01 - 2021/03/31

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    NRF2 is a master transcriptional regulator of cytoprotective genes. While NRF2 activation is principally beneficial for our health, NRF2 activation in cancer cells drives cancer malignancy and causes poor prognosis of cancer patients. We explored new therapeutic targets for NRF2-activated cancers. We found that unique enhancer formation underlies the unique transcriptional activation by NRF2 in KEAP1-mutant NSCLC cells. Among the NRF2-dependent enhancers unique to NRF2-activated cancers, NOTCH3 enhancer was found to make a key contribution to the tumor-initiating activity. Histopathological analysis supported clinical relevance of NRF2-NOTCH3 axis in lung adenocarcinoma. Because NRF2 strongly increases detoxification and extrusion capacities of chemotherapeutic drugs, NOTCH3, a transmembrane protein that can be accessed from outside of cells, is expected to be a favorable therapeutic target for KEAP1-mutant NSCLCs.

  22. Sulfur-dependent energy metabolism: sulfur respiration and its physiological role

    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

    2018/04/01 - 2019/03/31

  23. Redox signal regulation via protein polysulfidation

    KASAMATSU SHINGO, Morita Masanobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Tohoku University

    2017/04/01 - 2019/03/31

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    In this study, we investigated biological roles of protein polysulfidation of alcohol dehydrogenase 5 (ADH5) in a regulatory mechanism for redox signaling. It was revealed that human ADH5 protein was highly polysulfidated and the Cys174 residue, is known to be coordinated to the active site, played the important role to maintain its protein polysulfidation. Furthermore, we found that the protein polysufidation level of ADH5 correlated with the enzymatic activity. These results suggest that polysulfidation at the active site of ADH5 protein may involve in the regulation of nitric oxide- and formaldehyde-related redox signaling.

  24. An in vitro study of reactive sulfur species for treatment of cartilage diseases

    Hoshino Marie, Miyamoto Yoichi, Kaneko Kotaro, Nagayama Kazuhiro, Akiake Takaaki

    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: Showa University

    2017/04/01 - 2019/03/31

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    Sodium hydrogen sulfide (NaHS), a persulfide generator, accelerated elongation of mouse embryonic tibias in ex-vivo cultures. Histochemical analyses revealed that NaHS expanded width of the proliferating zone in growth plates. While NaHS facilitated proliferation of mouse primary chondrocytes, it did not affect the expression of mRNAs for type II and type X collagens and aggrecan in chondrocytes. In addition, propargylglycine, an inhibitor for cystathionine gamma-lyase, a persulfide-producing enzyme, suppressed both elongation of the tibias and proliferation of chondrocytes. These observations indicate that persulfides promote elongation of bones as a consequence of enhanced proliferation of growth plate chondrocytes.

  25. A novel model for causing senescence via mitochondrial dysfunction by environmental factors

    Nishida Motohiro, Nishimura Akiyuki, Tanaka Tomohiro, Nishiyama Kazuhiro

    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)

    2016/07/19 - 2019/03/31

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    Mitochondria are dynamic organella that can change its structure and morphology by repeating fission and fussion cycle, and its quality control is essential for maintenance of body health. In this study, we aimed to reveal the influence of environmental factors on mitochondrial quality and early senescence in view of redox signaling, and identify a novel anti-aging drug. We found that dynamin-related protein 1 (Drp1), a mitochondrial fission-promoting protein, forms polysulfide (Cys-SSH) in protein and depolysulfidation of Drp1 by environmental electrophiles triggered Drp1 activation, which led to mitochondrial fission-mediated myocardial early senescence, resulting in causing cardiac vulnerability against hemodynamic load in mice.

  26. Promotion of oxygen biology on the basis of international networks

    Mori Yasuo, MIKI hiroaki, MIURA kyoko, SUMIMOTO hideki, ITOH ken, UCHIDA kouji

    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: Kyoto University

    2015/11/06 - 2019/03/31

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    Our innovative area "Oxygen Biology" was able to make significant accomplishments in two different aspects. The first is to establish international networks, which form bases to enhance the recognition of our research accomplishments. More specifically, we edited a special issue "Oxygen Physiology: sensors and ion channels" (January issue of 2015), in which leaders of the field including members of our innovative area "Oxygen Biology" contributed reviews, for Pflugers Archiv. - European Journal of Physiology, the internationally recognized journal in the field of physiology. The second is the support to individual international collaborations, which were carried out among members of the innovative area together and the laboratories in universities and research institutes in Europe, north America, and Asia. Obtained data were summarized and published as papers in international journals.

  27. Oxygen biology: a new criterion for integrated understanding of life

    Mori Yasuo, INOUE masahiro, MIURA kyoko, SUMIMOTO hideki, ITOH ken, UCHIDA kouji, SUEMATSU makoto, SOGA tomoyoshi, TANIGUCHI naoyuki

    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: Kyoto University

    2014/07/10 - 2019/03/31

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    In order to demonstrate oxygen environment as molecular entities in living organisms, technical cores which give technique supports to area members were formed. In the area meetings, scientific achievements of area members were reported annually, and the direction of area managements, the strategy to foster young researchers, and the evaluation standard to call for area members were discussed. Many domestic and international symposia and workshops were organized along with annual meetings of different societies were held by our area. Aiming at enhancing networks among young scientists, meetings were arranged twice in collaboration with the innovative area "Dying Codes". Moreover, a special issue entitled "Oxygen Biology", to which area members contributed chapters, was arranged by our area and published in the Japanese scientific magazine "Cell".

  28. Polysulfur metabolome and regulation of anti-oxidative stress responses

    Akaike Takaaki

    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

    2014/07/10 - 2019/03/31

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    Polysulfides is reactive persulfide species which have extra sulfur atoms in cysteine thiol and cellular proteins contain polysulfides abundantly (protein polysulfuration). In this study, we investigated the translation-coupled mechanism of protein polysulfidation mediated by cysteinyl-tRNA synthetase (CARS) and its biological functions. CARSs from various biological species including bacteria and mammals are found to have cysteine persulfide-producing activity and to be critically involved in protein polysulfuration. Protein polysulfuration is suggested to play important roles in the regulation of cellular function such as mitochondrial morphogenesis.

  29. Study of the mechanism of biosynthesis of polysulfurated proteins coupled with translation

    AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    Polysulfur is reactive persulfide species which have extra sulfur atoms in cysteine thiol and cellular proteins contain polysulfur abundantly (protein polysulfuration). In this study, we investigated the translation-coupled mechanism of protein polysulfuration mediated by cysteinyl-tRNA synthetase (CARS) and its biological functions. CARSs from various biological species including bacteria and mammals are found to have cysteine persulfide-producing activity and to be critically involved in protein polysulfuration. Protein polysulfuration is suggested to play important roles in the regulation of cellular function such as mitochondrial morphogenesis.

  30. Molecular mechanisms for metabolisms of bacterial reactive sulfur species: implication in antibacterial resistance

    Sawa Tomohiro

    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: Kumamoto University

    2015/04/01 - 2018/03/31

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    Antixoxidative machineries that eliminate reactive oxygen species are of great benefit to bacteria to grow aerobically and to escape from oxygen-dependent bacterial killing by macrophages. Cysteine persulfide and glutathione persulfide are present abundantly in mammalian cells and act as potent antioxidants. Here we investigated the occurrence of persulfide in Gram-negative bacteria. Roles of persulfide species on bacterial resistance against oxidative stress was studied. Cysteine persulfide and glutathione persulfide/trisulfide were detected in all bacteria studied. Treatment of Salmonella Typhimurium with persulfide donors significantly increased intracellular persulfide levels. More importantly, persulfide boosted bacteria became highly resistant against oxidative stress-mediated bacterial killing induced by hydrogen peroxide challenging and by macrophages. These data suggest the importance of reactive persulfides in bacterial resistance against oxidative stress.

  31. On the regulatory mechanism of hard tissue metabolism by 8-nitro-cGMP

    Kamijo Ryutaro, TANAKA Sakae, SUZUKI Dai, YOSHIMURA Kentaro, FUNATO Sakie, IZUMIDA Eri

    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: Showa University

    2015/04/01 - 2018/03/31

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    We investigated the production and functions of 8-nitro-cGMP, a novel second messenger of nitric oxide and reactive oxygen species, in the cartilage and bone tissues. It had been accepted that cGMP is a mediator of bone growth. In this study, we found that not only cGMP but also 8-nitro-cGMP was produced in chondrocytes in the growth plate cartilage. In addition, 8-nitro-cGMP promoted the proliferation of chondrocytes in the growth plates, which caused enhancement in bone growth. Secondly, we found that production of 8-nitro-cGMP in osteoclast precursor cells after exposure to inflammatory cytokines. Since 8-nitro-cGMP was found to promote osteoclast differentiation, it is suggested that inflammatory bone resorption is explained, at least in part, by increased production of 8-nitro-cGMP under inflammatory conditions.

  32. Comprehensive study on environmental electrophiles-mediated signal transduction pathways regulated by reactive sulfur species

    Kumagai Yoshito

    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: University of Tsukuba

    2013/05/31 - 2018/03/31

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    Environmental electrophiles covalently bind to thiol groups in proteins to form protein adducts. In the present study, we found that exposure of cultured cells to environmental electrophiles such as naphthoquinones, methylmercury, cadmium and crotonaldehyde at lower concentrations activated redox signaling pathways through covalent modification of sensor proteins. However, exposure to these electrophiles at higher concentrations disrupted the redox signaling pathways and caused substantial cytotoxicity through non-selective covalent modification of cellular proteins. It was also found that while reaction of environmental electrophiles with reactive sulfur species (RSS) resulted in formation of their sulfur adducts, knockdown of cystathionine γ-lase, an enzyme to produce RSS, enhanced the modulation of redox signaling and toxicity in vitro and in vivo, whereas treatment with Na2S4 diminished these phenomena during exposure to environmental electrophiles.

  33. Analysis of intarocular antioxidant and development of intraocular irrigating solution

    Nakazawa Toru, Kunikata HIROSHI, Ida TOMOAKI, Akaike TAKAAKI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    We found that there were reactive persulfides and polysulfides in blood, aqueous humor and vitreous in diabetic eyes as well as controls. Furthermore, the concentration of some persulfides was different between diabetic eyes and controls, and there were some correlations between the persulfides in aqueous humor and vitreous.

  34. Novel signaling pathway of bacterial stress responses and host defense via autophagy

    AKAIKE Takaaki, MATSUNAGA Tetsuro, IDA Tomoaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    To clarify the molecular mechanism of pathogenesis of bacterial infection, we investigated the functions of 8-nitro-cGMP which is a signaling molecule both in bacteria and host cells. Protein S-guanylation induced by 8-nitro-cGMP was involved in stress responses in bacteria, and also play an important role in antibacterial host defense via autophagy. Hydrogen sulfide and reactive sulfur species produced by bacteria were suggested to regulate signaling function of 8-nitro-cGMP and to be involved in bacterial growth in infected cells.

  35. Ameliorating effects of nitric oxide and/or hydrogen gas inhalation on ARDS

    KOBAYASHI Hirosuke, KUBOTA Masaru, FUJII Shigemoto, AKAIKE Takaaki, KOKUBO Kenichi

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kitasato University

    2013/04/01 - 2016/03/31

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    The objective of the present study was to clarify the effects of inhalation of either nitric oxide (NO) or hydrogen gas, or simultaneous inhalation of both gases for a mouse model of lethal septic shock due to severe lung injury. NO gas inhalation provide beneficial effect such as inhibitions of neutrophil infiltration and vascular permeability increase, but adverse effect such as interleukin-6 (proinflammatory cytokine) increase, and resulted in the no change in the survival. On the other hand, hydrogen gas inhalation cannot inhibit neutrophil infiltration but inhibit vascular permeability increase and did not change interleukin-6 level, and resulted in the improved survival. Simultaneous inhalation of both gases will be a good strategy to reduce adverse effects of NO without eliminating the beneficial effects of NO.

  36. Mechanism of intracellular formation of cysteine polysulfide and reactive oxygen species signaling

    AKAIKE Takaaki

    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

    2013/04/01 - 2016/03/31

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    We investigated physiological roles of reactive sulfur species having extra sulfur atoms in cysteine thiol moiety, such as cysteine polysulfides. Quantitation of these species indicated that high levels of glutathione persulfide (over 100 microM) and other cysteine persulfides were produced in cells and its roles in regulation of reactive oxygen species signaling and protein functions were revealed. We also found a new cysteine persulfide-producing system in cells, which is originally known as a master enzyme for protein translation, and elucidated its pivotal roles in protein polysulfidation and regulation of mitochondrial function.

  37. Regulatory mechanisms of redox signal transduction mediated by endogenous electrophiles

    SAWA Tomohiro, AKAIKE Takaaki, YOSHITAKE Jun, KUMAGAI Yoshito

    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)

    2012/04/01 - 2015/03/31

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    This study identified the endogenous formation of cysteine persulfide species that brings additional sulfur atom to cysteine thiol. It is noteworthy that cysteine persulfide species are capable of metabolizing reactive oxygen species and their second messenger molecules such as 8-nitro-cGMP. Further study is warranted to clarify regulatory mechanisms of cycteine persulfide species formation as well as their biological functions.

  38. Signaling Functions of Reactive Oxygen Species

    AKAIKE Takaaki, SUMIMOTO Hideki, UCHIDA Koji, MATSUMOTO Akio, URANO Yasuteru, ARIMOTO Hirokazu, ITOH Ken, SHIMOKAWA Hiroaki, TSUTSUI Hiroyuki, UEHARA Takashi, KAMATA Hideaki, NISHIDA Motohiro

    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)

    2008/11/13 - 2014/03/31

  39. Signaling functions of reactive oxygen species

    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)

    2008/11/13 - 2013/03/31

  40. Molecular regulation of ROS signal receptor proteins: S-guanylation proteomics

    AKAIKE Takaaki, SAWA Tomohiro, IWAI Sumio, IHARA Hideshi

    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)

    2008/11/13 - 2013/03/31

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    8-Nitro-cGMP functions as a second messenger for ROS signaling via protein S-guanylation, a unique posttranslational protein thiol modification. In this study, new methodology was developed for identification of S-guanylation proteome. Several ROS sensor proteins were identified and examined for their impacts of S-guanylation on cellular functions. We further identified that metabolic regulation n of 8-nitro-cGMP via sulfhydration to form 8-SH-cGMP mediated by reactive sulfur species generated by cys tathione beta-synthase and cystathione gamma-lyase systems.

  41. エンドトキシンショックにおける新規環状ヌクレオチド : ニトロcGMPのシグナル制御

    赤池 孝章, AHMED KhandakerAhtesham

    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

    2011 - 2013

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    敗血症における重篤な臨床症状として、遷延性の血圧低下とそれにともなう多臓器不全がある。しかしながら、このような症状の進展の詳細な分子機構はいまだ十分には分かっていない。8-Nitroguanosine3', 5'-cyclic monophosphate (8-nitro-cGMP)は炎症反応にともなって生成し、親電子性を有するユニークな環状ヌクレオチドで、タンパク質のシステイン残基にcGMPを付加するタンパク質S-グアニル化という翻訳後修飾をもたらす。cGMP依存性プロテインキナーゼ(プロテインキナーゼG ; PKG)は、平滑筋の弛緩を制御するリン酸化酵素である。本研究では、PKGに対するS-グアニル化反応と、それによる酵素活性の制御機構、さらには血管弛緩反応を解析した。精製酵素標品を用いてキナーゼ活性を検討したところ、8-nitro-cGMPはPKGを強力に、かつ不可逆的に活性化した。また、organ bathによる検討から、8-nitro-cGMP処理はマウス大動脈を、不可逆的にフェニレフリンに対する血管収縮反応を減弱させた。質量分析による結果から、8-nitro-cGMPはPKGの42番目ならびにcGMP結合ドメインに存在する195番目のシステイン残基をS-グアニル化していた。PKGのS-グアニル化は、リボ多糖を投与したマウスの心臓において顕著に増加していた。以上の結果より、敗血症における8-nitro-cGMPの生成は、PKGの活性化ドメインである195番目システインのS-グアニル化を介して、PKGを遷延性かつ不可逆的に活性化し、敗血症においてみられる血圧低下に関わる可能性が示唆された。

  42. Regulation mechanism by hydrogen sulfide anion of electrophilesignaling

    AKAIKE Takaaki, FUJII Shigemoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Kumamoto University

    2011 - 2012

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    In the cellular response to oxidative stress, electrophiles suchas 8-nitro-cGMP function as important signal mediators. In this study, we examined thereaction mechanism of hydrogen sulfide-related compounds with electrophiles to revealits role in the signal regulation. As a result, we found that hydrogen sulfide-relatedcompounds react with 8-nitro-cGMP to produce 8-SH-cGMP, and are involved in the regulationof electrophile signaling.

  43. Detection and measurement of transthyretin with oxidative modification as a biomarker for disease prevention

    YOSHIKAWA Toshikazu, NAITO Yuji, OSAWA Toshihiko, AKAIKE Takaaki

    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: Kyoto Prefectural University of Medicine

    2009 - 2011

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    Clinical significance of serum transthyretin with oxidative modification was investigated in order to use it as a molecular biomarker for the disease prevention study.

  44. Involvement of oxidative stress in the pathogenesis of ARDS associated with viral pneumonia

    OKAMOTO Tatsuya, FUJII Shigemoto, AKAIKE Takaaki, ITOH Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2009 - 2011

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    Nitric oxide(NO) and reactive oxygen species(ROS) have been suggested to be involved in the pathogenesis of ARDS. NO/ROS have also been reported to induce nitration of tyrosine and guanine leading to the formation of 3-nitrotyrosine(3-NT) and 8-nitro-cGMP, respectively. In this study, we found significant increase of 3-NT and 8-nitro-cGMP levels in the lungs of influenza virus(IFV)-infected mice. Strong induction of an antioxidant enzyme heme oxygenase-1 was also detected in the lung of infected mice. Upregulation of HO-1 in parallel with the formation of 8-nitro-cGMP suggested that formation of 8-nitro-cGMP or 3-NT may be involved in the oxidative stress responses in the IFV-infected mice. Therefore, we postulated that formation of 3-NT might also influence on the disease activity of ARDS in humans. We performed a case-control study for plasma 3-NT levels of ARDS patients with/without IFV infection and of control subjects. The ARDS patients with IFV infection had significantly higher 3-NT levels than the control subjects. Additionally, ARDS patients with high 3-NT levels had better survival rate compared to patients with low 3-NT levels. These data thus suggest that NO/ROS-mediated formation of 3-NT or 8-nitro-cGMP may be involved in a unique signal transduction contributing to the host defense or tissue repair against IFV-induced fulminant pneumonia/ARDS.

  45. Molecular mechanism of signal transduction by reactive oxygen species

    AKAIKE Takaaki, FUJII Shigemoto

    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: Kumamoto University

    2009 - 2011

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    8-Nitro-cGMP is involved in reactive oxygen species-mediated signaling via protein S-guanylation. Here we identified several particular S-guanylated proteins(e. g., H-Ras etc.) occurring in cells and their involvement in various cellular signaling functions. We also revealed that endogenously produced hydrogen sulfide regulates protein S-guanylation in cells.

  46. 新興感染症菌ヘリコバクターシネディの感染病態と動脈硬化・心疾患との関連性の解析

    赤池 孝章, 岡本 竜哉

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 挑戦的萌芽研究

    Category: 挑戦的萌芽研究

    Institution: 熊本大学

    2009 - 2010

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    Helicobacter cinaediは1984年に初めてヒトへの感染が確認された新興感染症菌である。これまでの報告の多くは、免疫能低下症例における日和見感染症であるが、我々は免疫異常のない術後患者における敗血症・蜂窩織炎の事例を報告した。本菌は培養効率が悪いため、我々は本菌の主要抗原組換え蛋白質を用いた本菌感染の血清診断法を確立した。近年、非消化器疾患、特に動脈硬化症や不整脈の病態に、H.pyloriなどの慢性感染の関与が示唆されている。H.cinaediはH.pyloriに比べ血管侵襲性が強く、様々な非消化器疾患に関連している可能性が示唆される。そこで本菌と動脈硬化症や不整脈との関連について臨床疫学的な解析を行った。まず、熊本大学附属病院にて2005年から2009年にかけて精査・加療した症例で、心房性不整脈を有する群(不整脈群:132症例)と、有しない群(非不整脈群:137症例)を対象に、抗H.cinedi抗体レベルをELISA法にて測定した。その結果、非不整脈群に比べ不整脈群において有意に高い抗体レベルを認めた。一方、これまで上室性不整脈との関連が示唆されてきたH.pyloriやChlamydophila pneumoniaeに対する抗体レベルは両群間で差を認めなかった。また多変量解析にて、H.cinaedi抗体が陽性であることは、心房性不整脈に対する有意な独立した危険因子であることがわかった。さらに、本菌に対する特異抗体を作成し、解離性大動脈瘤症例から得られた剖検組織(9例)を免疫組織染色した結果、全例にて粥状硬化巣のマクロファージに一致した陽性像を認めた。以上の知見は、H.cinaedi感染が動脈硬化症や不整脈といった心臓血管疾患の病因に関連していることを強く示唆しており、当該疾患の病態解明ならびに新たな診断・治療法の確立に大きく寄与できるものと期待される。

  47. Academic project of oncogenic factors in malignant tumors and the related diseases in northeast China

    HASUI Kazuhisa, IZUMO Syuji, KANEKURA Takuro, MATSUYAMA Takami, EIZURU Yoshito, KAWANO Yoshifumi, YONEZAWA Sugury, KANZAKI Tamotu, JIA Xinshan, WANG Jia, TAKEYA Motohiro, AKAIKE Takaaki, SATO Eiichi, OKUMURA Teruhisa

    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: Kagoshima University

    2007 - 2010

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    This study examined many cases of nasopharyngeal lymphomas frequently seen in northeast China, elucidating neoplastic expansion of Epstein-Barr virus (EBV) latent infection, complication of minute EBV-not-associated squamous cell carcinoma in EBV-associated NK/T-cell lymphomas, peculiar necrosis of autophagic cell death, lymphoma cells' antioxidant response suggesting point mutations induced by environmental factors before its occurrence, and peculiar symbiotic dendritic cells and developed immunohistochemical methods of malignant tumor diagnosis by detecting a nature of tissue stem cells, analysis for autophagy and its cell death, and analysis for oxidation in DNA.

  48. 感染防御におけるNOの新規シグナル伝達機構の解明

    赤池 孝章, ZAKI Mohammad Hasan

    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: 熊本大学

    2008 - 2008

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    一酸化窒素(NO)および活性酸素が、生体内で主要な感染防御因子として機能していることが知られているが、そのシグナル伝達メカニズムについては不明な点が多い。我々はごく最近、まったく新規な環状ヌクレオチドである8-nitroguanosine 3',5'-cyclic monophosphate(8-nitro-cGMP)が、NOによる感染防御メカニズムの重要なシグナル伝達物質であることを発見した(Nature Chem.Biol.,2,729-735,2007)。本研究では、サルモネラ感染における8-nitro-cGMPの感染防御シグナルを解析した。その結果、サルモネラ感染に伴い細胞内に顕著な8-nitro-cGMP生成が認められること、さらに8-nitro-cGMPがKeap1蛋白質のチオール基と反応してcGMp構造を付加(蛋白質S-グアニル化)して活性化し、下流の遺伝子であるヘムオキシゲナーゼ-1の発現が誘導されることがわかった。その結果、感染によるアポトーシスが抑制されるとともに、サルモネラのクリアランスが向上した(論文投稿中)。さらに蛋白質S-グアニル化の標的オルガネラとしてミトコンドリアを解析し、複数の蛋白質がS-グアニル化を受けていることが明らかとなった(投稿準備中)。以上の結果より、8-nitro-cGMPは、感染防御における重要なシグナル分子であり、そのシグナル伝達には蛋白質S-グアニル化によるレセプター分子の活性化が重要であることが示唆された。

  49. Involvement of nitrative stress due to influenza virus infection on the pathogenesis and progression of interstitial pneumonias

    OKAMOTO Tatsuya, AKAIKE Takaaki, ITOH Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2007 - 2008

  50. Mechanism of glutathione-mediated regulation of nitrative signal in cells

    FUJII Shigemoto, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2007 - 2008

  51. Biological formation of 8-nitroguanosine 3'5'-cyclic monophosphate and its implication in NO signaling

    SAWA Tomohiro, OKAMOTO Tatsuya, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2007 - 2008

  52. Application of functional recombinant HSAs as a DDS carrier

    OTAGIRI Masaki, AKAIKE Takaaki, MARUYAMA Toru

    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: Kumamoto University

    2006 - 2008

  53. Functional analysis of nitric oxide metabolites in hard tissues

    MIYAMOTO Yoichi, KAMIJO Ryutaro, SUZAWA Ibtsuo, TAKAMI Masamichi, YAMADA Atsushi, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Showa University

    2006 - 2007

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    Nitric oxide (NO) acts as an infra- and intercellular signaling molecule. In addition to the cGMP-dependent signaling, it has been suggested that signals are transmitted by chemical modifications of biological molecules by NO and NO metabolites. In this study, we investigated the roles of NO and its metabolites in the differentiation and function of the cells which constitute hard tissues. First, we established their cell culture models. Namely, odontoblast differentiation, inflammation-induced osteoclast differentiation, and chondrocyte culture as a model of inflammatory joint diseases. We obtained the following findings using these models Expression of inducible type of NO synthase (iNOS) was induced in the pulp after abrasion of teeth without exposure of pulp. Then we studied the effects of NO on the pulp cell growth and differentiation. NO suppressed the proliferation of pulp cells and promoted the odontoblastic differentiation and mineralization, suggesting NO is involved in the formation of reparative dentin after tooth abrasion. TNF-α-induced bone resorption in ex-vivo was strongly suppressed in the iNOS-knockout calvaria In addition, osteoclast differentiation in the presence of TNF-α was retarded in the iNOS-knockout cultures NO-dependent formation of nitrated nucleotides was observed in the course of osteockast differentiation in the wild type cells. Finally, we studied the metabolism of extracellular matrix of chondmcytes after IL-1 exposure and found that IL-1 induced and activated the phagocyte-type NADPH-oxidase in the chondrocytes through the activation of TRAF-6 and NF-κB. We had already reported that IL-1 induced the expression of iNOS and formation of peroxynitrite, a reaction product of NO and superoxide in chondrocytes. The present results indicate that one of the sources of superoxide is the phagocyte type NADPH-oxidase. Interestingly, extra- and intracellular pH was decreased in the NADPH-oxidase-dependent manner, which in turn activated hyaluronidase and accelerated the loss of extracellular matrix.

  54. EPR効果に基づく活性酸素生成型高分子薬の固形癌ターゲティング療法

    前田 浩, 方 軍, 中村 秀明, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 崇城大学

    2005 - 2007

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    臨床がん治療薬へ実用化を目指して、PEG-ZnPPの薬理作用、ADME試験、in vivo毒性実験、及びinVivo細胞毒性実験、特に光照射によるPDTの可能性を検討した。PEG-ZnPPはヒト正常細胞においてIC_<50>>100μM、多種のヒトがん細胞においてIC_<50>=14.3±6.4μMを示し、PEG-ZnPP治療の腫瘍特異性及び安全域が広いことが明らかになった。さらに、ヒトCML細胞では、IC_<50>=5〜10μMと高い感受性を示した。Glevec耐性のCML株においても同様な感受性が見られた。体内動態解析により、PEG-ZnPPの大幅な血中半減期の延長、EPR効果による時間依存的な腫瘍への集積、緩やかな糞便からの排泄、各組織中での時聞依存的な分解が明らかになった。In vivo 毒性実験において、90mg/kg(ZnPP相当)では、急性および慢性毒性がほとんど認められなかった。 PEG-ZnPPを実用化する時のコストを考える上、PEG-2000を用いてPEG(2000)-ZnPP合成した。PEG(2000)-ZnPPは体内動態、代謝及び毒性試験においてPEG(5000)-ZnPPと同様な値を示した。さらに、PEG(2000)-ZnPPは顕著な抗癌活性を示し、Xenon光源の照射により薬効が大幅に増強されることが分かった。このことから、PEG-ZnPPが薪規抗癌剤としての実用性が高いものであることが益々明らかになった。 次に、ブタ型recombinantD-アミノ酸酸化酵素(rDAO)の大量生産系を確立した。PEG-rDAOは従来のPEG-DAOより活性・安定性が高いことが分かった。腫瘍組織はカタラーゼ活性が正常組織と比べて低く、この治療に対する感受性が極めて高いことが明らかとなった。さらに、PEG-rDAOのin vivo抗腫瘍活姓は多種のマウス腫瘍モデルにおいて、優れた抗腫瘍効果が得られた。ところが、この治療において、DAOの補酵素であるFAD及び基質であるD-アミノ酸(D-プロリン)の投与の量とタイミングが非常に大事であるが認識され、今後の研究はFADとより強く結合するDAOの作製について検討したい。

  55. The pathophysiology of malignant glioma and treatment strategies

    KURATSU Jun-ichi, AKAIKE Takaaki, NAKAMURA Hideo, MAKINO Keishi

    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: Kumamoto University

    2005 - 2007

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    We have been investigating for three subjects in analysis of malignant glioma cell biology; 1. Identification and functional analysis of cytokines high expressing in malignant glioma cells. 2. Molecular identification of genes and proteins contributing to malignancy in glioma cells. 3. Characterization of glioma cancer stem cells. We have found that several cytokines such as MCP-1 and IL-6 were overexpressed in malignant glioma cells and they contributed to proliferation or invasion of malignant glioma cells. We have analyzed, the genes related to the malignancy of glioma cells using the methods of DNA microarray, DNA tip and proteomix. However it is necessary for furthermore investigation to confirm whether these genes are involved in the signal of the malignancy of glioma cells. We have confirmed that the glioma cancer stem cells established from the patients with glioma had the potential to grow up in the brain of the mouse and have been investigating for the quality of resistance for the tumor therapy such as chemotherapy or radiotherapy. Based on the new discovery we have found in these study, we have been tackling to make up the new molecular targeting therapy such as to block the autocline cytokines loop, to suppress the activating signal in the malignancy of glioma cells. Furthermore we have been trying to establish a new technology to deliver the drug through the blood-brain barrier using the nano-technology. We need furthermore investigation for the application to clinical therapeutical methods in the therapies for glioma patients.

  56. Oxidative stress regulation through NO-induced nucleic acid nitration in pulmonary diseases

    TAKAHASHI Kiyoshi, TAKEYA Motohiro, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2005 - 2007

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    8-nitroguanosine, a modified base, draws people's attention as a marker for nucleic acid damage during carcinogenesis or other gene modification. Since we have succeeded in producing a specific antibody against 8-nitroguanosine, we studied the generation and localization of 8-nitroguanosine in various pulmonary diseases using the antibody. In pulmonary fibrosis, strong immunostaining for 8-nitroguanosine was observed in metaplastic epithelial cells as well as macrophages and alveolar epithelia. Colocalization of 8-nitroguanosine with iNOS, eNOS, hemoxygenase-1, 8-nitotyrosine, and p53 was detected in confocal laser scanning microscopy. In lung cancer, 8-nitroguanosine is observed both in cytoplasm and nuclei of cancer cells. These results suggest that 8-nitroguanosin is involved in injury of air-space epithelia and also in pulmonary carcinogenesis. In lung injury mouse models induced by hyperoxia-exposure or bleomycin showed that 8-nitorguanosine is generated in air-space epitheial cells as well as in macrophages accumulated in injured tissue indicating that 8-nitroguanosine is involved in such disease processes. We have previously shown that 8-nitro-cyclic GMP, a nitroguanosine derivative, activates cell survival by inducing hemoxigenase-1 and other cytoprotective molecules. It is considered that 8-nitoroguanosine is not a silent damaged base but a highly active molecule possessing signaling transmittal function.

  57. Molecular mechanisms of nitric oxide-dependent modification and regulation of genome functions

    AKAIKE Takaaki, ARIMOTO Hirokazu, SAWA Tomohiro

    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: Kumamoto University

    2005 - 2007

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    Excess production of free radical species including superoxide and nitric oxide (NO) has been implicated in pathophysiology of infectious and inflammatory diseases, by causing chemical modifications of biological molecules. In the present study, we investigated the roles of genome modifications and regulation by NO, with particular focus on the formation and biological effects of 8-nitroguanosine, a unique product of NO-mediated nucleic acid modification. Followings are summary of the present study. 1. 8-Nitroguanosine was found to be mutagenic to mammalian cultured cells. CHO cells treated with 8-nitroguanosine exhibited remarkably higher mutation frequency of the marker gene gpt, with G to T transversion as a dominant form of mutation, compared with control cells. Furthermore, 8-nitroguanosine treatment induced enhanced formation of abasic sites in genome DNA of CHO cells. 2. Formation of 8-nitroguanosine was significantly stimulated in the regenerative epithelium of the lung tissues of idiopathic pulmonary fibrosis. Importantly, lung squamous cell carcinoma cells were also strongly stained with 8-nitroguanosine immunohistochemistry. It was found that 8-nitroguanine was excreted in human urine, that was associated with cigarette smoking. 3. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) was identified, for the first time, in mammalian cells as a novel nitrated derivative of cGMP. 8-Nitro-cGMP was found to be highlyl reactive with cysteine sulfhydryls to form cGMP adduct (S-guanylation), that can be involved in cellular signaling, especially in oxidative stress response, as a unique post-translational modification. These data suggest that guanine nitration may be a novel signaling mechanism mediated by NO. that can regulate genome stability as well as stress responses. Better understanding of the mechanisms how 8-nitro-cGMP regulates cellular signaling will give insights into the molecular pathogenesis of infectious and inflammatory diseases.

  58. Mechanism of Apoptosis Induction by Bacterial Proteases and Its Implication for Bacterial Pathogenesis.

    TAMURA Fumio, AKAIKE Takaaki, AKUTA Teruo, SASAKI Yutaka

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto university

    2005 - 2006

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    Recently it was shown that streptococcal pyrogenic exotoxin B (SpeB), a thiol protease derived from group A Streptococcus (GAS) could cause an increase in apoptotic cell death. The present study is aimed to clarify the mechanism of apoptosis induced by a variety of bacterial proteases. When human monocyte- like U937 cells were treated with SpeB, Serratiamarcescens 56kDa protease, or Pseudomonas aeruginosa elastase, all these bacterial proteases induced apoptosis in U937 cells. Serratial protease was internalized by the cells in culture as a complex form with α2-macroglobulin (a2-M) via α2-M receptor, which resulted in apoptosis. Furthermore, expressions of Bcl-2, c-lAP1 and hsp70, which were anti-apoptotic proteins, were investigated by Western blot analysis after treatment of U937 cells with serratial protease. Serratial protease degraded c-IAP1 protein more selectively than others intracellular proteins. We previously reported that some bacterial proteases could activate human MMPs, which may play important roles in tissue degeneration, and in the present study, SpeB also was confirmed activation of MMPs. We investigated whether SpeB-activatedMMPcouldprocessTNF-a andFasligandfromcellmembranetocause apoptotic cell death. SpeB activated with proMM P-9, and soluble TN F-a and Fas ligand were released from culture cells by this activated MMP-9. SpeB-dependent induction of extensive apoptosis and its related proapoptotic molecules, e.g., soluble TNF-a, Fas ligand, and MMPs, was evident in a murine model of severe GAS infections. These results suggested that bacterial proteases induce apoptotic cell death either via α2-M receptor, or via activation of MMPs.

  59. Experimental and Clinical Studies on the Significance of Endothelium-Derived Hyperpolarizing Factor (EDHF)

    SHIMOKAWA Hiroaki, TAKESHIGE Kouichirou, UTSUMI Hideo, AKAIKE Takaaki, IBAYASHI Setsurou, HIROOKA Yoshitaka

    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)

    2004 - 2006

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    1.Role of Endothelial NO synthases system in the production of EDHF/H_2_O2 (1)We have demonstrated that endothelial Cu, Zn-SOD plays an important role in the synthesis of EDHF/H_2O_2 not only in animals but also in humans. (2)We have demonstrated that long-term inhibition of Rho-kinase, which down-regulates eNOS, ameliorates endothelial function in various animal models of cardiovascular diseases. (3)We have demonstrated that EDHF/H_2O_2 is involved in the effects of ACE inhibitors. (4)We have developed mice lacking all NO synthases. Those mice showed impaired survival with hypertension and myocardial infarction. (5)In those triply NOSs-KO mice, EDHF responses were abolished, demonstrating the importance of endothelial NOSs system in the synthesis of EDHF/H_2O_2. 2.Mechanisms of Physiological and Pathological H_2O_2 Synthesis (1)We were able to demonstrate that endothelial cells release H_2O_2 and NO at p.M order and that the two factors interact synergistically to maintain coronary flow in dogs in vivo. (2)We have demonstrated that other endothelial oxidases system (e.g.NADPH) are not involved in the EDHF/H_2O_2 responses. 3.In vivo imaging of H_2O_2 We were able to demonstrate endothelial production of H_2O_2 using DCF fluorescence imaging in vivo. 4.Role of EDHF/H_2O_2 in animals We have demonstrated that EDHF/H_2O_2 plays an important protective role in myocardial ischemia/reperfusion and metabolic coronary vasodilatation as well. 5.Role of EDHF/H_2O_2 in humans (1)We have demonstrated that in cultured vascular smooth muscle cells from human coronary arteries, estrogen down-regulates while nicotine up-regulates Rho-kinase. (2)We have demonstrated that selective Rho-kinase inhibitors acutely reduces pulmonary vascular resistance without systemic hemodynamic effects in patients with pulmonary hypertension.

  60. Molecular regulatory mechanisms of NO analyzed by using nitronyl nitroxide

    AKAIKE Takaaki, SAWA Tomohiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: Kumamoto University

    2003 - 2006

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    Nitric oxide (NO) has been suggested to be involved in the pathogenesis of various diseases, including infections, inflammatory diseases, and cancer. We have demonstrated the occurrence of nitratively modified nucleic acids (e.g., 8-nitroguanosine and 8-nitroguanine) in precancerous and cancer tissues, including idiopathic pulmonary fibrosis and human lung cancer, and in urine of smokers. In this study, we identified the formation of novel nitrated cyclic nucleotide, 8-nitroguano sine-3', 5'-cyclic monophosphate (8-nitro-c GMP), in macrophages stimulated with inflammatory cytokine. 8-Nitro-cGMP possesses cGMP-dependent protein kinase-activating potential and unique signal functions independent of cGMP activity. Of great importance is a novel post-translational modification (8-thioalkoxy-cGMP adduct formation) of proteins induced by 8-nitro-cGMP, coined S-guanylation. For example, a redox-sensor signal protein Keap 1 appears to be regulated by 8-nitro-cGMP, via S-guanylation of highly nucleophilic Cys sulfhydrils of Keap 1, leading to the induction of stress adaptive response signals. This study revealed 8-nitro-cGMP to be asecond messenger of NO and shed light on new areas of pathophysiology and chemical biology of signal transduction by NO and cGMP.

  61. Analysis on biological formation of a novel modified nucleic acid, 8-nitorguanosine, and its unique signal function

    AKUTA Teruo, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    2004 - 2005

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    We examined biological and signal function of a novel nucleic acids modification by NO, especially, 8-nitroguanosine (8-NO_2Guo) and 8-NO_2Guo-related compounds, e.g. 8-nitro-cyclic GMP (8-NO_2-cGMP). Our data on these compounds are summarized as follows. 1) 8-NO_2Guo formation was mainly localized in cytosol, near the endoplasmic reticulum, in HepG2 cells treated with NO, as identified by confocal microscopy and immunoelectron microscopy analysis using anti 8-NO_2Guo monoclonal antibody. We demonstrated that 8-NO_2Guo protected from apoptosis HepG2 cell through upregulation of heme oxygenase-1 and endothelial NOS (eNOS), and inhibition of bcl-XL degradation. 2) 8-NO_2Guo has mutagenic potential in DNA and RNA. Authentic 8-NO_2Guo added exogenously to cultured CV-1 cells infected with a recombinant Sendai virus containing a green fluorescent protein gene increased the viral mutation frequency. This mutation spectrum was dominantly observed with a C to U transition. 8-NO_2Guo added to AS52 cells also increased the genomic mutation frequency, with a predominant mutation, G to T transition. We supposed two different mechanisms for this mutagenesis : direct modification of nucleic acid and indirect augmentation of oxidative stress via superoxide generation by 8-NO_2Guo. 3) We established the synthesis method of 8-NO_2-cGMP and prepared large amount of this compound. Treatment of human uterine smooth muscle cells with 8-NO_2-cGMP increased in cGMP-dependent protein kinase-associated phosphorylation of vasodilator-stimulated phosphoprotein on Ser^<239>. Strong vasorelaxing potential for rat carotid artery was observed with 8-NO_2-cGMP. These results suggested that 8-NO_2-cGMP is a new cellular redox signaling molecule. 4) We developed the anti-8-NO_2-cGMP monoclonal and polyclonal antibodies. The immunostaining with anti-8-NO_2-cGMP monoclonal antibody showed high immuoreactivity in cytosol of mouse macrophage derived RAW264 cells stimulated with IFN-γ and lipopolysaccharide. Taken together, 8-NO_2Guo and 8-NO_2-cGMP have unique biochemical and pharmacological properties such as cellular redox signaling and mutagenic potential.

  62. On the regulation of survival and death of synoviocytes and chondrocytes by nitric oxide

    MIYAMOTO Yoichi, KATAGIRI Takenobu, MASAMICHI Takami, SHINKI Toshimasa, MORIMURA Naoko, KAMIJO Ryutaro

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Showa University

    2004 - 2005

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    It is known that nitric oxide production is up-regulated both in synovial tissues and articular cartilages in the joints of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. NO is regarded as one of the important molecules to regulate cell death and survival, whereas the regulatory mechanism has not been fully elucidated. On the other hand, interleukin-1 (IL-1) acts as a key mediator of the degeneration of articular cartilage in RA and OA, where chondrocyte death is observed. In this study, the viability of mouse chondrocyte-like ATDC5 cells was reduced by the treatment with IL-1β for 48 h or longer. IL-1β augmented the expression of the catalytic subunit of NADPH-oxidase gp91^<phox> as well as inducible NO synthase in ATDC5 cells. Generation of nitrated guanosine and tyrosine suggested the formation of reactive nitrogen species including peroxynitrite (ONOO^-), a reaction product of NO and superoxide in ATDC5 cells and rat primary chondrocytes treated with IL-1β. Death of ATDC5 cells after IL-1β treatment was prevented by an NADPH-oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), and a ONOO^- scavenger uric acid. The viability of ATDC5 cells was reduced by a ONOO^- generator 3-(4-morpholinyl)sydnonimine hydrochloride but not by either a NO donor 1-hydroxy-2-oxo-3-(N-methyl-2-aminopropyl)-3-methyl-1-triazene or S-nitrosoglutathione. Disruption of mitochondrial membrane potential and ATP deprivation were observed in IL-1β-treated ATDC5 cells, both of which were restored by L-NAME, AEBSF, or uric acid. On the other hand, any morphological or biochemical sign indicating apoptosis was not observed in these cells. These results suggest that the death of chondrocyte-like ATDC5 cells was mediated at least in part by mitochondrial dysfunction and energy depletion through ONOO^- formation after IL-1β treatment. We have also succeeded in the establishment of a fibroblastic cell line from the synoviocytes obtained from an RA patient.

  63. Study for Establishment of a Program Officer System of the Gant-in-Aid for Scientific Research

    HASUO Masahiro, AKAIKE Takaaki, YUASA Hideya, ARIMOTO Kazuhiro, SUZUKAWA Kazumi, SHINSHI Tadahiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Special Purposes

    Category: Grant-in-Aid for Special Purposes

    Institution: Kyoto University

    2004 - 2005

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    The results of this survey study for establish of a new program officer (PO) system of the Grant-in-Aid for Scientific Research (Kakenhi) are as follows; 1 Survey study on foreign competitive research funding systems and their PO systems We on-site visited NIH and NSF (USA), RC (UK), A*STAR (Singapore), NSC (Taiwan), KRF (Republic of Korea), HFSP (Japan-North America-Europe), ESF (EU) and DFG (Germany) to learn and investigate their competitive research funds or grants and their PO systems. 2 Survey study on domestic competitive research funding systems and their PO systems We learned and investigated competitive research fund or grant systems and PO systems of the Kakenhi (MEXT and JSPS), the Special Coordination Funds for Promoting Science and Technology (JST), the Industrial Technology Research and Development Projects (NEDO) and Research project for Utilizing Advanced Technologies in Agriculture, Forestry and Fisheries, Technical Development Program for Making Agribusiness in the Form of Utilizing the Concentrated Know-How from Private Sector (MAFF). We made a list about them for comparison. 3 Inquiry surveys on the PO system in Kakenhi of MEXT We carried out questionnaire surveys on roles and operations of POs in the Kakenhi system of MEXT, their possible carrier plan, and so on, to members of the referee boards, researchers supported by the Kakenhi of MEXT and PO's affiliations. The results were analyzed to extract their awareness, understanding, opinions and demands for the Kakenhi. 4 Enlightenment activities and inquiry surveys on the Kakenhi and PO systems With a proposal of this project we carried out symposiums and panel discussions on the Kakenhi and PO systems in annual meetings of the Chemical Society of Japan, the Japan Society of Mechanical Engineers and the Japanese Biochemical Society. We also carried out questionnaire surveys on the Kakenhi and PO systems to participants on site. The results are analyzed to extract their awareness, understanding, opinions and demands for the Kakenhi. The results were also utilized to validate the effect of our enlightenment activities.

  64. The mechanism of cell- invasion by Vibrio cholerae Non-O1 and several factors which grow worse sepsis

    EHARA Masahiko, MORITA Kouichi, AKAIKE Takaaki, TODA Takayoshi

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Nagasaki University

    2003 - 2004

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    Vibrio cholerae Non-O1 is one of etiologic pathogens causing watery diarrhea as Vibrio cholerae O1 and O139. However there are many reports on extra-intestinal infection of Vibrio cholerae Non-O1 among immunocompromised hosts with liver cirrhosis, malignant tumor as a basic disorder. Many cases are reported among those of liver cirrhosis whose infections with Vibrio cholerae Non-O1 end in sepsis. A half of them is fatal after suffering multiple organ failure. The result of our study to clarify the mechanism of sepsis by Vibrio cholerae Non-O1 is as follows : Each one x 10^8 of Vibrio cholerae Non-O1 (Y strain) was given oally to ddy mouse of 6 weeks of age. Ten hours after administration of bacteria, bacteria were recovered in peripheral blood samples. After 27 hours, bacteria were recovered from all mice in their peripheral blood samples. Between 15-30 hours post administration, all mice were dead. Fatality and incidence was increased depending on the increase of bacterial cell concentration. Through the analyses of samples from abdominal space, potal vein, liver, it was suggested that Vibrio cholerae Non-O1 enter directly into blood vessels through mucous membrane and that they enter into blood stream via portal vein and liver. The concentration of inflammatory cytokines such as L6 and TNFα was also increased depending on the progress of inflammation and sepsis. Histopathologically, degenerative necrosis of liver cells and infarction of spleen were fiequently observed. Our experiment to examine whether Zinoov (a proteinase inhibitor) will suppress sepsis or not, suggests some inhibitory effect. We found cpxP, an inhibitor of signal transduction system, in Non-O1 Vibrio cholerae. Expression of this protein also palys some role in decreasing pathogenicity by suppressing the secretion pathway. Finally, I have to apologize to have changed the reseach theme on the way to "analysis of multi-drug resistance genes of Vibrio cholerae O1"

  65. Research on a novel mechanism for oxidative stress mediated by NO-induced nucleic acid nitration.

    AKAIKE Takaaki

    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: Kumamoto University

    2003 - 2004

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    Nitric oxide(NO) plays important roles in the pathogenesis and defense mechanism involved in various diseases, including microbial infections, inflammation, cardiovascular and neurodegenerative diseases, and cancer. We currently explored NO-induced nucleic acid modifications with a focus on guanine nitration(e.g., 8-nitroguanine formation) and its signaling potential contributing to host defense against microbial pathogens(Akaike T.et al.Proc.Natl.Acad.Sci.USA,100:685-690,2003). Formation of 8-nitroguanine and its related compounds in vivo and in cultured cells was assessed immunochemically with an antibody for 8-nitroguanosine. Wild-type mice and littermate mice deficient in inducible NO synthase(iNOS) were infected with various pathogens including influenza virus and Salm onella. Strong 8-nitroguanosine immunostaining was observed primarily in the cytosol of epithelial cells and inflammatory cells such as exudate macrophages in the infectious foci of wild-type mice but not iNOS-deficient mice. This staining generally co-localized with iNOS immunostaining in the tissues and cells. NO was generated in excess in wild-type mice but was eliminated in iNOS-deficient mice after infections ; this result also correlated well with formation of 8-nitroguanosine. Similar immunostaining for 8-nitroguanosine was evident with various cells in culture depending on endogenous and exogenous NO production. It is intriguing that 8-nitroguanosine shows unique redox activity affecting NADPH-dependent reductases including NADPH-cytochrome P450 reductase and all isoforms of NOS to produce superoxide. More importantly, 8-nitroguanosine stimulated the cultured cells to significantly increase the expression of a cytoprotective enzyme heme oxygenase-1, so that the cells became resistant to apoptosis and cell death induced by infection-associated cytotoxicity and nutrient starvation. The present results prompt us a new paradigm for redox signaling via guanine nitration caused by oxidative and nitrative stress(i.e., nitrative signaling), which may thus contribute in a critical way to the cytoprotection and host defense occurring during many disease processes.

  66. 感染病態形成におけるフリーラジカル病因論に関する研究

    赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 熊本大学

    2003 - 2003

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    本年度は、感染病態におけるNOによる核酸ニトロ化反応に焦点をあて解析を行った。すなわち、NOによる修飾塩基である8-ニトログアノシンの単クローン抗体を作成し、インフルエンザウイルス感染モデルや各種培養細胞における8-ニトログアノシン生成を検討した。さらに、8-ニトログアノシンによるウイルス遺伝子変異誘発、および、新規の細胞内シグナル伝達機構について解析を行った。その結果以下の知見を得た。 (1)8-ニトログアノシンの大量有機合成法を確立し、抗8-ニトログアノシン抗体(多クローンおよび単クローン)を作成した。本抗体を用いて、マウスインフルエンザウイルス肺炎モデルにおける、8-ニトログアノシンの生体内生成を免疫組織化学的に解析した。その結果、インフルエンザウイルス感染マウスの肺組織において、誘導型NO合成酵素(iNOS)の発現に伴って、主に、気管支・細気管支上皮細胞の細胞質内に、8-ニトログアノシンが産生されることが分かった。よって、ウイルス感染病態におけるNO生成に依存した新規修飾塩基8-ニトログアノシンの生体内生成を初めて証明できた。さらに、抗8-ニトログアノシン抗体を用いたELISAを確立し、各種培養細胞における8-ニトログアノシン生成を定量的に解析したところ、生理的な濃度のNOにより、細胞内に8-ニトログアノシンが効率よく生成することが明かとなった。 (2)組換えGFP-センダイウイルス(SeV)感染CV-1細胞を8-ニトログアノシンにより処理して、ウイルスのRNAゲノムの変異頻度に与える影響を検討したところ、NOと同様に、8-ニトログアノシンが遣伝子変異促進作用を発揮した。さらに、CV-1細胞培養系において、8-ニトログアノシンにより誘発されるウイルスGFP遺伝子の変異スペクトラムは、マウス感染モデルにおいてGFP-SeV感染肺組織より分離されるウイルスのGFPゲノム変異のパターンと比較的類似していた。従って、NOが8-ニトログアノシン生成を介してウイルス変異を加速することが示唆された。 (3)NO生成を介して産生される8-ニトログアノシンは、ユニークな化学的反応性(レドックス活性)を有していることも分かってきた。すなわち、8-ニトログアノシンは、生体内に豊富に存在するNADPH依存性還元酵素、例えば、P450 reductaseやiNOSを含めたすべてのNOSアイソフォーム(血管型eNOS,神経型nNOS)により活性化され、活性酸素産生をもたらすことが明らかになった。さらに興味あることに、NO産生に依存して細胞内に生成する8-ニトログアノシンは、細胞のヘムオキシゲナーゼ-1の発現誘導を介して強い細胞保護作用を示した。よって、宿主細胞の生存シグナルにNO・8-ニトログアノシンによる新たなシグナル伝達経路が存在することが示唆された。 以上より、感染病巣において過剰に産生されるNOが、病原細菌に抗菌作用を発揮するだけでなく、8-ニトログアノシン生成を介して、ウイルスの分子進化に関与したり、宿主の生存シグナルを制御することにより、感染防御と病態発現に深く関わることが分かってきた。

  67. 従来の概念にはない脂肪細胞の機能解明-スカベンジ機能・貧食能と生体防御-

    中山 仁, 赤池 孝章, 國安 明彦

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽研究

    Category: 萌芽研究

    Institution: 熊本大学

    2002 - 2003

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    スカベンジャー受容体(SR)は、主にマクロファージ系において変性リポタンパクのクリアランスを担うが、この処理機構が破綻をきたすとマクロファージの泡沫化を引き起こし、動脈硬化の要因となると考えられている。脂肪細胞は従来、エネルギー産生が主要な役割と考えられてきたが、この細胞でも酸化LDLはSRの一つ、CD36を介してクリアランスされることを我々は見いだしたので、これを契機に多角的視点から詳細な解析を行い、「生体ホメオスタシス維持におけるSRを介した脂肪細胞の新しい役割」について、より一般化した概念を打ち立てようというのが本研究の目的である。 2年間に亘る本研究で、(1)高血糖患者に頻見されるAGE(糖化反応後期生成物)化タンパクの脂肪細胞でのクリアランスの有無、および、(2)動脈硬化や糖尿病患者に見られる酸化LDLあるいは高グルコース条件にさらされた脂肪細胞が、細胞機能上どのような変化をもたらすのかを調べた。その結果、(1)種々の化学形をもったAGE-BSAのほとんどが脂肪細胞に取り込み・分解されること、このクリアランス機能に関与するSRはCD36で説明できること、(2)酸化LDLあるいは高グルコースで刺激された脂肪細胞では、いくつかのアディポサイトカインや、CD36あるいはGLUT-4などの酸化LDLあるいはグルコース取り込み口の発現に有意の変化が観察され、それらはいずれも病態をさらに増悪させる方向への変化であることがわかった。 これらの事実は、生理学的、病態生理学的視点からも、糖尿病や動脈硬化における脂肪細胞の役割に新たな概念を提供するものである。

  68. 新しいグルタチオン誘導体の発見とそれによる蛋白質機能制御に関する研究

    赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽研究

    Category: 萌芽研究

    Institution: 熊本大学

    2002 - 2003

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    近年、血管機能が、一酸化窒素(NO)や過酸化水素などの反応性分子種によりレドックス依存的に制御されていることがわかってきた。血管組織のリモデリングは、細胞外マトリックスの分解に関わる蛋白分解酵素であるmatrix metalloproteinase(MMP)によりもたらされる。MMPは、不活性前駆体として産生され、その活性化はプロペプチドドメインに存在するconsensus motif(PRCGVPD)のCys残基の酸化によりもたらされることが知られているが、その生理学的意義は不明であった。 今回我々は、NOとスーパーオキシドの反応産物であるパーオキシナイトライト(ONOO^-)による全く新しいMMP活性化機構を見出した。この活性化は、生体内の主要なレドックス制御ペプチドであるグルタチオン(GSH)により巧妙に調節される。すなわち、ONOO^-は、GSHのニトロ化反応を介して、GSHとMMPのPRCGVPDとの付加反応(S-glutathiolation)をもたらし、MMPを強力に活性化することが明らかとなった。尚、この際形成されるジスルフィド結合は、これまで生体内生成が知られていなかったジスルフィドSオキシド結合であり、生理的還元反応では解離しない。 さらに、本年度の研究においては、NOによる細胞内ニトロ化反応による全く新規のシグナル伝達機構が存在することがわかってきた。具体的には、NOやONOO^-が、細胞内のヌクレオチドプールのグアニンを効率よくニトロ化して、8-ニトログアノシンを生成すること、この8-ニトログアノシンが、強力なレドックス活性を介して細胞内のレドックスレベルを制御することである。このことは、細胞内ニトロ化反応が、血管機能や血管リモデリングを制御していることを示唆している。

  69. Inhibitory effect of human α_2-plasmin inhibitor and it's intensified compound by S-nitrosylation on the activity of arginine-specific cysteine proteinase from Porphyromonas gingivalis.

    KAMINISHI Hidenori, AKAIKE Takaaki, TAKEUCHI Hisako, OGURA Rieko, HAMAMOTO Takayoshi

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Fukuoka Dental College

    2001 - 2003

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    We investigated the effect of human α_2-plasmin inhibitor (α_2PI) and S-nitrosylated α_2-plasmin inhibitor (S-NO-α_2PI) on the activity of arginine-specific cysteine proteinase (gingipain, RGP) from Porphyromonas gingivalis, an aetiological bacterium of adult periodontitis, with the use of fluorogenic substrates. We discovered that human α_2PI as well as S-NO-α_2PI play a inhibitory effect to the RGP in a dose-dependent manner. The α_2PI, one of the members of serpin family, is well known as a specific inhibitor of plasmin, a typical serine proteinase. However, few studies have been reported concerning the inhibitory potency of humoral factors, such as α_1-protease inhibitor or α_2-macroglobulin, against cysteine proteinases especially RGP. In this study, we found a novel function of α_2PI as a potent inhibitor of RGP. The inhibitory potencies of the S-nitrosylated derivative against both human plasmin and RGP were slightly higher than those of the intact α_2PI. These results strongly suggest that S-NO-α_2PI is a useful tool for preventing the virulence of P. gingivalis.

  70. 感染病態形成におけるフリーラジカル病因論に関する研究

    赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 熊本大学

    2002 - 2002

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    本年度の研究においては、特に、NOによる生体内での核酸ニトロ化反応に焦点をあて、ウイルス感染病態の解析を行った。具体的には、核酸塩基グアニンのパーオキシナイトライトなどの活性酸化窒素種によるニトロ化産物である8-ニトログアノシンの抗体を作製し、インフルエンザウイルス感染モデルにおける8-ニトログアノシン生成を検討した(Akaike et al.,PNAS,100:685-690,2003)。さらに、8-ニトログアノシンの生体内生成を介する毒性発現のメカニズムをその酸素ラジカル産生能に注目して解析を行った。研究成果は以下の通りである。 (1)8-ニトログアノシンの大量有概合成法を確立し、抗体作成および8-ニトログアノシンの感染病態における生体内生成とその生物効果の解析に供した。常法により、8-ニトログアノシン特異的ウサギポリクローナルおよびマウスモノクローナル抗体を作成した。 (2)本抗体を用いて、マウスインフルエンザウイルス肺炎モデルにおける8-ニトログアノシンの生体内生成を免疫組織化学的に解析した。その結果、インフルエンザウイルス感染マウスの肺組織において、誘導型NO合成酵素(iNOS)の発現に伴って、気管支・細気管支上皮細胞と一部の滲出マクロファージに濃染像が認められた。一方、正常マウスおよびiNOS欠損マウス肺では、染色像は確認出来なかった。また、抗8-ニトログアノシンのモノクローナル抗体を用いた免疫細胞化学染色により、サイトカイン刺激によりiNOSを発現したRAW 264細胞(マウスマクロファージ様細胞株)や、iNOS遺伝子を強制発現させたCOS-1細胞においても、著明な8-ニトログアノシン生成が確認された。これらの知見より、ウイルス感染病態における8-ニトログアノシンの生体内生成が明らかになった。 (3)NO生成を介して産生される8-ニトログアノシンは、強力な化学的反応性(レドックス活性)を有していることも分かってきた。すなわち、8-ニトログアノシンは、生体内に豊富に存在するNADPH依存性還元酵素、例えば、P450 reductaseやiNOSを含めたすべてのNOSアイソフォーム(血管型eNOS,神経型nNOS)により-電子還元されることにより活性化され、8-ニトログアノシンラジカルに変換し、さらに、溶存酸素を-電子還元し著明なスーパーオキサイド産生をもたらすことが明らかになった。このことは、8-ニトログアノシンが感染病態における酸化ストレスのメディエーターであることを示唆している。

  71. ポリマー結合型エンドスタチンによる癌のターゲティング療法

    赤池 孝章, 前田 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 熊本大学

    2002 - 2002

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    腫瘍転移におけるNOの関わりについて誘導型NO合成酵素(iNOS)欠損マウスと野生型マウスを用いて解析した。また、内因性血管新生抑制物質であるエンドスタチンとNOS阻害剤の併用し、それらの抗腫瘍効果についても検討した。8〜10週令iNOS欠損マウスと野生型マウスに、マウス大腸癌colon adenocarcinoma 38(C-38)腫瘍組織30mgを背部左右2カ所に移植個形腫瘍を作成した。マウス肺癌Lewis lung carcinoma (LLC)細胞を、4×106 cells/site、同様にマウス背部に移植し転移モデルを作成した。この腫瘍経を経時的に測定して腫瘍体積を求めた。転移は肺表面にある転移結節数および肺湿重量にて比較検討した。エンドスタチンは、当教室にてマウス横隔膜よりクローニングした遺伝子を大腸菌に発現させ精製した。腫瘍移植後7日目からエンドスタチン(50mg/kg、1日2回,s.c.)及び、NOS阻害剤であるS-methylisothiourea sulfate (180mg/kg/1日1回,i.p)を投与し腫瘍増殖を比較検討した。C-38腫瘍モデルでは、野生型マウスに比較してiNOS欠損マウスの腫瘍増殖が著明に抑制されており、野生型マウスにエンドスタチンとNOS阻害剤を併用することで、単独よりもさらなる腫瘍増殖抑制効果が認められた。LLCの肺転移モデルでは、野生型マウスはiNOS欠損マウスと比較して転移が促進されており、NOが腫瘍増殖促進効果のみならず、転移促進効果も発揮している可能性が示唆された。 以上の知見より、NO産生抑制に血管新生制御療法を併用した新しい抗腫瘍療法の可能性が示された.現在、ポリマー結合型エンドスタチンの作製に成功しており、今後さらに癌組織への指向性を高めた血管新生抑制療法の確立を目指している。

  72. フリーラジカルによるヘリコバクターピロリ遺伝子の変異促進作用に関する研究

    前田 浩, 赤池 孝章, 宮本 洋一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽研究

    Category: 萌芽研究

    Institution: 熊本大学

    2001 - 2002

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    近年、消化管、肝・胆道系などの固型がんの半数以上の例で、慢性感染・炎症が、がん発症の主要な要因になることが指摘されている。多くのがんにおいて、誘導型酸化窒素(NO)合成酵素(iNOS)の発現が上昇しており、活性酵素、NOやプロスタノイドなどの炎症性分子が、細胞の分化・増殖の異常や遺伝子損傷をもたらし、がん発生のメカニズムにおいて重要な役割を演じることが示唆されている。一方我々はこれまで、各種ウイルス・細菌感染モデルを用いて、NOが生体の感染防御反応における主要な炎症性メディエーターとして機能していることを報告してきた。NOは、パーオキシナイトライトなどの活性醇化窒素種の生成を介して病原体遺伝子を損傷し、生体内で強力な変異原性を発揮することが予測されている。そこで今回、感染・炎症に伴って生ずるNO・フリーラジカルによる新たな損傷塩基の検索した。そもそもパーオキシナイトライトは、核酸塩基のうち特にグアノシンの8位を効率良くニトロ化し、8-ニトログアノシンを生成することが知られていたが、これまで、この損傷塩基が生体内で生じることを証明した報告はなかった。具体的には、まず8-ニトログアノシンの大量有機合成法を確立し、これを抗原エピトープとして特異的抗8-ニトログアノシン抗体を作製した。さらに、この抗体を用いて、各種感染・炎症モデルにおける8-ニトログアノシン生成を、免疫組織化学的に解析したところ、8-ニトログアノシンが、生体内のNO生成に依存して生成することが証明された。さらに、8-ニトログアノシンが、電子吸引基であるニトロ基を有するニトロアレンという構造を有していることに着目し解析を進めたところ、本化合物が強力なレッドクス活性を示し、生体内の還元システムにより活性化され大量の活性酸素(スーパーオキサイド)産生することが分かってきた。すなわち、8-ニトログアノシンは、NOに由来する単なる損傷塩基ではなく、高い化学的反応性をもつ生理活性分子であるといえる。実際、予備的検討ではあるが、パーオキシナイトライトがヘリコバクターピロリ遺伝子の変異を促進し、クラリスロマイシンに対する耐性頻度を高めることを確認している。

  73. Research on the role of NO in microbial pathogenesis

    MAEDA Hiroshi, AKAIKE Takaaki

    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: Kumamoto University

    2000 - 2002

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    The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide and hydroxyl radical have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical [nitric oxide (NO)] in me host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-α and interleukin-1β. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS, i.e., neuronal NOS and endothelial NOS. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Our work on murine salmonellosis in iNOS-deficient mice indicated that NO has significant host defense functions in Salmonella infections not only because of its direct antimicrobial effect but also via cytoprotective actions for infected host cells, possibly through its antiapoptotic effect. Reactive nitrogen oxide species such as peroxynitrite are produced in biological systems through the reaction of NO with superoxide. Among these reactive nitrogen species, peroxynitrite and its biological actions are of considerable interest in that peroxynitrite causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. Peroxynitrite thus formed in infectious foci may be a dominant nitrogen oxide species during the host's defense reactions. Thus, understanding of the role of NO and oxygen radical generation in infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.

  74. Study on the mechanism of nitrosothiol formation in biological systems

    MIYAMOTO Yoichi, KAMIJO Ryutaro, KATAGIRI Takenobu, ITOH Kanami, MAEDA Hiroshi, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    2000 - 2002

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    Nitric oxide (NO) exhibits multiple biological actions through formation of various intermediates derived from NO. Among them, we found that nitrosothiols (RSNOs), adducts of SH moiety of biological compounds and NO, could be formed efficiently via one-electron oxidation of NO catalyzed by ceruloplasmin, a major copper-containing protein in plasma. In addition, we identified S-oxiso-nitrosoglutathione [GS(O)NO] as a reaction product of glutathione and peroxynitrite (ONOO^-), an adduct of NO and superoxide. Furthermore, GS(O)NO activated matrix metalloproteinases (MMPs) through formation of dithiothreitol-resistant S-glutathionyl MMPs, indicating that ONOO^- exerts its tissue destructive effects via formation of S-oxo-nitrosothiols as well as direct nitration or oxidation of biological molecules. In the latter part of this project, we investigated the biological significance of nitrosative and nitrative stresses in inflammatory disorders including rheumatoid arthritis (RA), where NO production is accelerated. We could detect the expression of ceruloplasmin in chondrocytes, suggests the possible formation of nitrosothiols in the inflammatory foci of RA. On the other hand, it is reported that α_1-protease inhibitor (α_1PI) level in joint is increased in RA patients. As we reported earlier, α1PI is readily S-niotrosylated by NO and S-nitrosylated α1PI shows tissue protective effects in vitro and in vivo. In this study we studied nitrosylation of methionine-oxidized α1PI [α_1PI-Met(O)] and the biological activities of this reaction products, because RA joints are thought to be under highly oxidative conditions. The efficacy of S-nitrosylation of α_1PI-Met(O) was around 80% of that of α1PI. Interestingly, antibacterial activity of S- nitrosylated α1PI-Met(O) in vitro was 100 times more potent than that of S-nitrosylated α_1PI. The further study will be performed to clarify the pathophysiological roles of S-nitrosylated α_1PI-Met(O).

  75. Research on microbial mutation and evolution involving oxidative stress

    AKAIKE Takaaki, MAEDA Hiroshi

    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: Kumamoto University

    2000 - 2002

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    Oxygen radicals and nitric oxide (NO) are generated in excess in a diverse array of microbial infections. Emerging concepts in free radical biology are now shedding light on the pathogenesis of various diseases. Free-radical induced pathogenicity in virus infections is of great importance, because evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases. Although oxygen radicals and NO have an antimicrobial effect on bacteria and protozoa, they have opposing effects in virus infections such as influenza virus pneumonia and several other neurotropic virus infections. A high output of NO from inducible NO synthase, occurring in a variety of virus infections, produces highly reactive nitrogen oxide species, such as peroxynitrite, via interaction with oxygen radicals and reactive oxygen intermediates. The production of these various reactive species confers the diverse biological functions of NO. The reactive nitrogen species cause oxidative tissue injury and mutagenesis through oxidation and nitration of various biomolecules such as guanosine. The unique biological properties of free radicals are further illustrated by recent evidence showing accelerated viral mutation by NO-induced oxidative stress. NO appears to affect a host's immune response, with immunopathological consequences. For example, NO is reported to suppress type 1 helper T cell-dependent immune responses during infections, leading to type 2 helper T cell-biased immunological host responses. NO-induced immunosuppression may thus contribute to pathogenesis of virus infections and help expansion of quacispeies population of viral pathogens. In the present study, we indeed successfully elucidated the critical roles of NO in the pathogenesis of viral diseases and in viral mutation as related to nucleic acid modifications by NO, i.e., nitration of guanosine to form 8-nitroguanosine.

  76. Development of analysis for all biologically relevant derivatives of NO

    AKAIKE Takaaki, MAEDA Hiroshi, NISHINO Hirohito

    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: Kumamoto University

    2000 - 2002

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    Reactive nitrogen oxides derived from NO produce nitration adducts of various biological molecules. We have developed a series of methods for identification and quantification of nitrated adducts of amino acids and nucleic acid bases, such as 3-nitro-L-tyrosine, nitro-L-tryptophan, and 8-nitroguanine. The assay couples an HPLC system with electrochemical (EC) analysis. Each nitrated compound in Pronase-digested samples, being separated by reverse-phase HPLC, was first reduced electrochemically at -900 mV, followed by detection with an analytical cell at +300 mV. Detection limit for 3-nitrotyrosine reached 10^<-15>mol. Increased protein-bound 3-nitrotyrosine was demonstrated in bronchoalveolar lavage from mice infected with influenza virus; whereas protein-bound 3-nitrotyrosine was not identified with mice deficient in inducible NO synthase. Similarly, appreciable amount of 3-nitrotyrosine was detected in sputum from patients with bronchial asthma and chronic bronchitis. The level of nitrotryptophan was, however, below detection limit in both murine and human samples. Also, our immunohistochemical analysis with a specific anti-3-nitroguanine antibody clearly showed formation of 3-nitroguanosine in the bronchial epithelial cells of the virus-infected mouse lungs. This is the first demonstration of a nitrated nucleotide base formed endogenously in biological systems. The present methods may help us to better understand the biological relevance and the mechanism of biological nitration.

  77. 新規水溶性ヘムオキシゲナーゼ阻害剤の合成とその抗腫瘍活性

    赤池 孝章, 前田 浩, 宮本 洋一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 熊本大学

    2001 - 2001

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    これまで、固形腫瘍において産生されるNOにより抗酸化酵素であるヘムオキシゲナーゼー1(HO-1)が、高度に誘導され、腫瘍の増殖を支えていることが分かってきた。さらに我々は、HO-1の競合阻害剤であるZnプロトポルフィリンIX(ZnPP IX)が、腫瘍細胞のアポトーシスを誘導し腫瘍増殖を抑制することを明らかにしてきた。しかしながら、ZnPP IXは水に難溶でその使用において大きな制限があった。そこで今回、ZnPP IXに水溶性高分子化合物であるポリエチレングリコール(PEG)結合させ、新規水溶性PEG-ZnPPを作成しその抗癌作用を検討した。HO-1高発現腫瘍であるマウスS-180固型腫瘍モデルにおいて、PEG-ZnPPの血中半減期が延長し腫瘍内への選択的集積することにより腫瘍組織のHOが強く抑制された。また、PEG-ZnPPの静脈内投与により、腫瘍細胞のアポトーシス誘導を介した顕著な腫瘍増殖抑制効果が確認された。尚、この際、肝障害や骨髄抑制など明かな副作用は認められなかった。以上の結果により、PEG-ZnPPがHO-1を選択的に抑制し、酸化ストレスの増強、アポトーシスの誘導を介して抗腫瘍作用を発揮することが明かとなった。今後さらに、本薬剤の抗腫瘍活性の選択性・生体親和性や細胞毒性の発現メカニズムを解析することにより、HO-1という新たな分子を標的としたがん化学療法の可能性について検討していく予定である。

  78. 慢性感染に伴うフリーラジカル産生と発がん

    前田 浩, 宮本 洋一, 澤 智裕, 赤池 孝章, 小川 道雄

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 熊本大学

    2000 - 2000

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    固型癌のうち、胃癌、肝癌、子宮癌などの原因が細菌やウイルスによることが次第に明らかになってきた。さらに、胆管や胆のう癌、食道癌も何らかの感染症に起因する容疑が濃くなってきた。これらの感染症と発癌に共通の事象として、それが長期にわたる慢性炎症を伴うこと、また活性酸素(スーパーオキサイドやH_2O_2、あるいはHOCl)や一酸化窒素(NO)などのフリーラジカル関連分子種が宿主の炎症反応に伴い、感染局所で過剰に生成していることである。さらに重要なことは、これらのラジカル分子種はDNAを容易に障害することである。そこで本研究では、微生物感染・炎症にともない生成するフリーラジカルと核酸成分との反応を特に遺伝子変異との関係から解析した。また、センダイウイルス肺炎モデルを作製し、in vivoでの遺伝子変異におけるフリーラジカルの役割を検討した。その結果、過酸化脂質がミオグロビン等のヘム鉄存在下に生じる過酸化脂質ラジカルが、2本鎖DNAに対して変異原性のある脱塩基部位の形成をもたらした。また、上記ウイルス感染においては、スーパーオキサイドラジカル(O_2^-)と一酸化窒素(NO)の過剰生成がおこることを明らかにしたが、この両者はすみやかに反応してより反応性の強いパーオキシナイトライト(ONOO^-)となる。ONOO^-とDNAやRNAとの反応では、グアニン残基のニトロ化が効率良くおこり、さらに生じたニトログアノシンがチトクロム還元酵素の作用によりO_2^-を生じることが分かった。このONOO^-がin vivo,in vitroいずれにおいてもウイルス遺伝子に対して強力な遺伝子変異をもたらすことを、NO合成酵素(NOS)ノックアウトマウスやNOS強制発現細胞を用いて明らかにし、上記の知見が正しいことを確認した。

  79. ポリマー結合酸化酵素による癌のターゲティング化学療法

    澤 智裕, 前田 浩, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 熊本大学

    2000 - 2000

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    活性酸素の細胞毒性に基づいた化学療法の構築を目的として、ポリマー結合酸化酵素を合成し、その体内分布(特に腫瘍組織への集積性)および抗腫瘍活性について検討した。酸化酵素であるD-アミノ酸オキシダーゼ(DAO)およびキサンチンオキシダーゼ(XO)は、それらのリジン残基に対して、スクシミドで活性化したポリエチレングリコール(PEG)を用いてPEG鎖を導入した(以下、それぞれPEG-DAO、PEG-XOと略す)。培養細胞をPEG-DAOあるいはPEG-XOとそれらの基質、D-アラニンあるいはヒポキサンチンとともに作用させると顕著な細胞毒性が見られた。また、この細胞毒性はカタラーゼ添加により見られなくなることから、活性酸素がその本体であることが示唆された。PEG化酵素をマウス尾静脈より投与すると、肝臓、腎臓などの正常組織にはほとんど分布せず、固型腫瘍にのみ効率良く集積した。このような体内分布は未修飾の酵素では見られなかった。さらにこれらPEG結合酸化酵素と基質の併用投与は、副作用を示すことなく顕著な抗腫瘍活性を示した。以上の結果より、PEG化酸化酵素は固型腫瘍に選択的に集まり、そこで活性酸素を産生することにより優れた抗腫瘍活性を示すことが分かった。

  80. 固型腫瘍の発育・進展における一酸化窒素・酸素ラジカルの役割についての研究

    赤池 孝章, 澤 智裕, 宮本 洋一, 前田 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 熊本大学

    2000 - 2000

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    多くの固型腫瘍では誘導型一酸化窒素(NO)合成酵素(iNOS)の発現による過剰なNOの産生が起こっており、そのNOが癌の増殖、血管新生、転移などに関与すると考えられている。そこで、本研究では、腫瘍の増殖さらには転移に関わる酵素類(ヘムオキシゲナーゼ,HO-1,とマトリックスメタロプロテアーゼ,MMPなど)とそのNOによる制御という観点から固型腫瘍におけるNOの役割について解析した。その結果、各種固型腫瘍モデルではiNOSの発現が亢進し、過剰のNO産生が起こっており、そのNOは腫瘍血流を増大し、腫瘍血管透過性を亢進させ、さらに、NOがパーオキシナイトライトの生成を介してMMPを活性化することにより腫瘍増殖や転移を促進させることが明らかになった。一方、腫瘍細胞より産生される誘導型ヘムオキシゲナーゼは、それら窒素酸化物による酸化ストレスから腫瘍細胞そのものを防御しているものと思われた。以上の知見より、iNOS、HO-1、MMPなどを標的とした新たな癌の予防・治療の開発が可能であることが示唆された。

  81. Study in clinical application of nitric oxide (NO) scavenger for treatment of urinary incontinence

    YOSHIDA Masaki, AKAIKE Takaaki

    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: KUMAMOTO UNIVERSITY

    1998 - 2000

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    We have evaluated pharmacological characteristics of NO scavenger ; carboxy 2-phenyl-4, 4, 5, 5, -tetramethylimidazoline-1-oxyl 3-oxide, (carboxy-PTIO) in systemic organs in animals, in advance of clinical application of this drug for treatment of urinary incontinence. In rabbit urethral smooth muscles, both radical NO and NO bioaducts contributed to the nitrergic nerve-mediated relaxation. There are feedback mechanisms between nitrergic and adrenergic nerves, which regulate releases of NO and noradrenaline each other. NO released from nitrergic nerves had inhibitory regulation for release of noradrenaline from adrenergic nerves. Release of NO from nitrergic nerves was increased and decreased through the alpha-2 and alpha-1 adrenergic receptors existing in nitregic nerve endings, respectively. Experiment using cultured rabbit urethral smooth muscle cells showed that smooth muscle cells itself released NO, which may contribute to the urethral smooth muscle function. In vivo and vitro animal experiments, carboxy-PTIO did not show the adverse effects to cardiovasclular and respiratory systems, digestive system, and renal function. In rabbit urethral function, carboxy-PTIO increased urethral closing pressure without significant effects of bladder capacity and voiding pressure. Carboxy-PTIO administrated intravenously was excreted in urine (80%) and feces (20%) within 24 hours. There was not any tissue accumulation and toxicity after single or recurrent carboxy-PTIO administration in rats. Furthermore, anaphylaxis induced by this drug was not observed in rats. In rats with spinal cord injury, intravenous administration of carboxy-PTIO caused increase in urethral closing pressure, but did not have significant effects on bladder capacity, voiding pressure and urinary frequency. In conclusion, carboxy-PTIO is a promising drug for treatment of urinary incontinence. However, further evaluation is needed to specify the effectiveness and safety for human.

  82. A Study on the Role of Protease Produced by Vibrio cholerae non-01 in the Pathogenic Mechanism of Sepsis.

    ICHINOSE Yoshio, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Institute of Tropical Medicine, Nagasaki University

    1998 - 2000

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    There are many reports on the cases of Vibrio cholerae infection which may extend to extra-intestinal organs. It can result in sepsis and multiple organ failure especially in immunocompromised hosts. It is then considered that a metalloprotease produced by Vibrio cholerae may be involved in its invasive mechanisms of vibrios into tissues or vessels. Because it is a permeability factor to activate kinin cascade and an activating factor of a matrix metalloprotease produced by leukocytes migrating in the inflammatory lesion. We were then trying to develop an animal model of sepsis due to Vibrio cholerae 019 to elucidate the invasive mechanisms of Vibrio cholerae. The results obtained through the study on the role of metalloprotease in pathogenic mechanisms of Vibrio cholerae and histopathological findings in sepsis model are as follows ; (1)Improvement of purification method of choleraprotease. (2)Establishment of assay system of choleraprotease using immunoblotting with ECL kit. (3)Analysis of nicking site of cholera toxin by choleraprotease. (4)Development of mouse sepsis model using Vibrio cholerae 019. (5)Involvement of choleraprotease in the pathogenic mechanism of sepsis. (6)Involvement of iNOS in the pathogenic mechanism of sepsis.

  83. Free radical generation in chronic infection and its implication in carcinogenesis

    MAEDA Hiroshi, MIYAMOTO Youichi, SAWA Tomohiro, AKAIKE Takaaki, OGAWA Michio

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    1999 - 1999

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    Excessive production of free radicals such as superoxide (O_2^<・->) and nitric oxide (NO) as well as their reaction product, peroxynitrite (ONOO^-) are known to occur during infection and inflammation. These reactive species cause oxidation and nitration of vital molecules including DNA, and hence may involve in mutagenesis and carcinogenesis. In the present study, we investigated the reaction between ONOO- and nucleic acid, particularly the products of damaged nucleic acids. We further studied the impact of ONOO^- on genomic mutation by using Sendai virus (SeV) constracted green fluorescent protein (GFP) as a marker of mutation. High performance liquid chromatography analysis showed that ONOO^- clearly nitrates guanine residues in nucleoside, RNA and DNA.Efficacy of guanine nitration in RNA was as high as that in nucleoside, and 10 times higher than that in DNA.Interestingly, nitroguanosine thus formed was found to produce O_2^<・-> to a significant extent, comparably higher than that by mitomycin C, catalyzed by cytochrome reductase system. These findings suggest that nitration of guanosine by ONOO^- further enhance cellular oxidative stress due to its potential to produce O_2^<・->. Exposure of GFP/SeV to physiologically releavant concentration of ONOO^- (0.8 μM) markedly facilitated the mutation rate of GFP/SeV compared to control GFP/SeV without ONOO^- exposure. Furthermore, in vivo mutation rate of GFP/SeV was also found to depend on NO production during infection as revealed by using NO synthase knock-out mice model. All these findings suggest that reactive nitrogen species may play an important role in infection-associated carcinogensis due to, at least in part, its genotoxic potentials.

  84. フリーラジカルによるマトリックス・メタロプロテアーゼの活性化

    赤池 孝章, 前田 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(A)

    Category: 特定領域研究(A)

    Institution: 熊本大学

    1999 - 1999

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    昨年までの研究により、一酸化窒素(NO)と活性酸素(スーパーオキサイド、O^-_2)の反応生成物であるパーオキシナイトライト(ONOO^-)が、炎症の場において重要な生理活性を有するmatrix metalloproteinase前駆体(proMMP)を活性化し、さらにこの現象が、還元型グルタチオン(GSH)により調節されることを見出した。そこで本年度は、その活性化メカニズムの解析を行った。[^<35>S]GSHを種々の濃度のONOO^-と一定時間反応した後、精製した3種類のヒトproMMP(proMMP-8,-9,-1)と反応させ、その結合をfluorographyにより解析した。その結果、[^<35>S]GSHをproMMPとincubationするだけで両者は結合したが、活性化は見られなかった。これはdithithreitol(DTT)にて容易にはずれることから、単なるSS結合と思われた。一方、ONOO^-が存在する場合、proMMPの活性化がみられ、さらにその結合はDTTにては解離しないことから、SS結合以外の何らかの非可逆的な共有結合がおこっていることが示された。さらに、HPLCおよびtime-of-flight mass spectrometerにより本反応のproduct analysisを行ったところ、比較的安定な反応産物としてニトログルタチオン(GS-NO_2)が同定され、さらに、別途に化学合成したauthenticなGS-NO_2はproMMPを強く活性化した。このことは、ONOO^-とGSHの反応により生じるGS-NO_2が、proMMPのautoinhibitory domain内のPRCGVPD配列中のシステイン残基を攻撃し、通常のジスルフィドとは異なる結合(-S(=O)-S-など)を形成することにより不可逆的で強力なMMPの活性化をもたらすことを示唆している。以上の知見より、グルタチオンのユニークなMMP活性化機構が明らかとなった。

  85. 慢性ウイルス肝炎における肝癌の成因:フリーラジカルと一酸化窒素代謝物による感染性発癌機構

    前田 浩, 菅 守隆, 高橋 潔, 赤池 孝章, 藤山 重俊

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽的研究

    Category: 萌芽的研究

    Institution: 熊本大学

    1998 - 1999

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    感染・炎症において過剰に生成するスーパーオキサイドやNO由来のパーオキシナイトライト(ONOO^-)は、タンパク質や遺伝子(塩基)のニトロ化をもたらし、生体内で酸化ストレスや変異原性を発現していることが示唆されている。そこで本年度は、ONOO^-と核酸の反応を詳細に検討し、さらにウイルス遺伝子変異に対する反応性NO酸化物(特にONOO^-)の影響を検討した。その結果、ONOO^-は核酸塩基のグアニンを効率良くニトロ化し、ニトログアニン(ニトログアノシン)を生成することが分った。また、RNAのグアニンニトロ化はDNAのそれに比べ、効率良く起こり、ヌクレオシドと同程度のニトログアノシンを生成した。さらに興味深いことに、生成したニトログアノシンがシトクローム還元酵素の存在下に顕著なスーパーオキサイドを産生することを明らかにした。この結果は、炎症局所で産生したONOO^-が核酸のニトロ化をもたらし、さらに生成したニトログアノシンが活性酸素であるスーパーオキサイドを産生することで炎症の増悪をもたらす可能性を示唆している。 つづいて反応性NO酸化物のウイルス遺伝子変異について、変異のマーカーとしてgreen fluorescent protein(GFP)を組み込んだセンダイウイルス(GFP/SeV)を用いて検討した。その結果、in vitroの系においてGFP/SeVを生理的濃度のONOO^-(0.8μM)で処理すると、ウイルスの感染性が損なわれない条件下で、ウイルスゲノムに組み込まれたGFP遺伝子が変異した株が、0.5%-1.0%の頻度で出現した。また、ONOO^-がウイルスに対して99.98%の致死率を示す反応条件下では、100%の変異率が得られた。 以上の知見は、感染・炎症において過剰に生成するNOやONOO^-がウイルスゲノムの変異を促進する因子として働く可能性を示唆している。

  86. フリーラジカルによるウイルス遺伝子変異メカニズムの解明

    赤池 孝章, 加藤 篤, 前田 浩, 宮本 洋一, 豊田 哲也, 永井 美之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽的研究

    Category: 萌芽的研究

    Institution: 熊本大学

    1998 - 1999

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    ウイルス感染病態において誘導型NO合成酵素(inducible NO synthase,iNOS)から過剰に産生されるNOは、共存する分子状酸素(O_2)や酸素ラジカル(活性酸素)などと反応し、パーオキシナイトライト(ONOO^-)などの反応性窒素酸化物の生成を介して、宿主に酸化ストレスをもたらす。一方で、感染炎症における酸化ストレスは、生体内で増殖するウイルスそのものにも加えられることが予想される。RNAウイルスは、一回の複製でヌクレチド残基あたり10^<-5>〜10^<-3>という頻度で変異し、極めて高度な遺伝的多様性を有しており、様々な環境中のストレスにより淘汰されながら分子進化を繰り返している。この様なウイルスの多様性は、これまで主にRNA複製の不正確さにより説明されてきたが、その分子メカニズムは今だに不明である。そこで今回、NOよりもたらされる酸化ストレスのウイルスの分子進化への関わりについて検討した。このため、変異のマーカー遺伝子としてgreen fluorescent protein(GFP)を組み込んだセンダイウイルス(GFP-SeV)を用いてNOやパーオキシナイトライトによるウイルス遺伝子変異促進作用について解析した。その結果、in vitroの系において、パーオキシナイトライトはウイルスに対して非常に強い変異原性を示した。さらにiNOS欠損マウスおよび野生マウスのGFP-SeV感染系において、野生マウスではiNOS欠損マウスの7倍程度高いウイルス遺伝子変異率が認められた。これらの知見は、ウイルス感染・炎症反応にともない過剰に産生されるNOやパーオキシナイトライトが、ウイルスの変異速度を高め、その分子進化に関与していることを示唆している。

  87. Helicobacter pylori and gastric cancer

    ASAKA Masahiro, KEIDA Yoshihide, OGOSHI Kazuei, KIKUCHI Syogo, SUGIYAMA Toshiro, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: HOKKAIDO UNIVERSITY

    1997 - 1999

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    The current study was designed to evaluate the relationship between Helicobacter.pylori infection, atrophic gastritis, and intestinal metaplasia in Japan. This was a multi-center study performed in 21 centers in various areas in Japan. A total of 2,622 individual who underwent endoscopic examinations were enrolled. H.pylori status was determined by a validated ELISA for anti-H.pylori IgG.Atrophic gastritis was diagnosed by three methods : histology, endoscopy with Congo Red dye scattering, and using the Kimura-Takemoto endoscopic classification. The prevalence of atrophic gastritis in the population studies increased with age (e.g.from 9.4% in those <20 to >70% in those age 60 or older), it was strongly associated with H.pylori infection. The overall prevalence of atrophic gastritis among those with H.pylori infection was 82.9% (1272/1534) compared to 9.8%(90/921) of those without (OR=44.8 ; 95%. CI=34.7-57.8). The pattern with intestinal metaplasia was similar increasing from 2.5% in those <20 to >45% in those 60 or older and being found predominantly among those with H.pylori infection (i.e., 43.1% (542/1258) in H.pylori positive persons vs. 6.2% (51/823) among H.pylori negative individuals)(OR=11.5 ; 95% CI=8.5-15.5). Although H.pylori infection, atrophic gastritis, and intestinal metaplasia all increased with age, atrophic gastritis and intestinal metaplasia were strongly associated with H.pylori and not with aging per se.

  88. Molecular Mechanisms of Redox-Regulation in Viral Pathogenesis

    AKAIKE Takaaki, SAWA Tomohiro, MAEDA Hiroshi

    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: Kumamoto University

    1997 - 1999

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    The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide (OィイD3-(/)2ィエD3) and hydroxyl radical (・OH) have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical, i.e., NO in the host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-γ and interleukin-1β. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS, i.e., neuronal NOS and endothelial NOS. Our present results indicate that overproduction of NO and oxygen radicals should be a common phenomenon in various infections. Reactive nitrogen oxide species such as peroxynitrite are produced in biological systems through the reaction of NO with OィイD3-(/)2ィエD3. Peroxynitrite and its biological actions are of considerable interest in that peroxynitrite causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. In fact, it is revealed in our current study that peroxynitrite is critically involved in the viral pathogenesis through its nonselective injury to the host'cells and tissues. Thus, understanding of the role of NO and oxygen radical generation in virus infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level. Moreover, among various NO-induced pathological effects, the mutagenic potential of NO in microbial pathogens is also intriguing. For viral mutation, it is of potential interest to investigate a possible association of oxidative stress and virulence of viruses. In this context, our recent study verifies for the first time that oxidative stress induced by high-output NO accelerates RNA virus mutations. Briefly, by using a recombinant RNA virus, Sendai virus (a negative-sense and single-strand RNA virus), containing a marker gene for genetic mutation and iNOS knockout mice, we obtained solid and direct evidence showing that overproduction of NO in the hosts (wild-type mice) in vivo apparently increases and accelerates viral mutation rates compared with the situation in iNOS-deficient mice. This process of accelerated mutation expands the heterogeneity of variants of the pathogen, leading to rapid evolution under selective pressure. NO and OィイD3-(/)2ィエD3- and hence peroxynitrite generation occurs universally in infected hosts. This finding therefore has great implications for the RNA virus evolution in general, including the rapid generation of drug-resistant and immunologically tolerant and cell tropism-altered mutants of HIV in vivo.

  89. Matrix metalloproteinase activation in bacterial pathogenesis

    MAEDA Hiroshi, MIYAMOTO Yoichi, SAWA Tomohiro, AKAIKE Takaaki

    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: Kumamoto University

    1997 - 1999

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    Matrix metalloproteases (MMPs) are secreted by numerous mammalian cells as inactive proenzymes (proMMPs). After activation they are involved in tissue remodeling and facilitate cancer metastasis. In view of microbial infection and inflammation, two distinct proMMPs, proMMP-8 with 85 kDa and proMMP-9 with 92-kDa, known to be secreted by human polymorphonuclear leukocytes, are of special interest. Macrophages as well as fibroblasts can also produce proMMP-1 with 52 kDa and proMMP-9 known as progelatinases which cleave denatured collagen preferentially. We have previously reported that microbial proteases can activate various endogenous protease cascade systems of the infected hosts. Among them, we studied the kinin (or bradykinin) generating cascade most extensively and demonstrated processing of Hageman factor to its active form or prekallikrein to kallikrein or direct generation of kinin from kininogen, and activation of the clotting cascade involving factors XII, X, II, etc. In the present study, we further found that human MMPs can be processed from proMMP to their active forms by two new and unique mechanisms: Firstly, by bacterial proteases such as Pseudomonas elastase and Vibrio cholerae protease, which cleave off the N-terminal autoinhibitory domain (so-called cysteine switch) from proMMPs. The second mechanism depends on free radical generation by activated polymorphonuclear leukocytes. In this case, peroxynitrite (ONOOィイD1-ィエD1) or nitrogen dioxide radical (NOィイD22ィエD2), the reaction products of either superoxide (OィイD3-(/)2ィエD3) or molecular oxygen (OィイD22ィエD2) and nitric oxide (NO), are the key reactants. Both OィイD3-(/)2ィエD3 and NO are generated by activated macrophages and leukocytes as a result of immunologic responses involving various proinflammatory cytokines. NOィイD22ィエD2 or ONOOィイD1-ィエD1 seems to interact with a single cysteine residue in the propeptide autoinhibitory domain or so-called cysteine switch of proMMPs thus transforming proMMPs to their active conformation. Furthermore, we found a quite unique and novel MMP activation mechanism: Specifically, peroxynitrite-mediated MMP activation is remarkably potentiated by glutathione (GSH), in which nitrated GSH (NOィイD22ィエD2-GS) produced by peroxynitrite appears to be directly involved in the MMP activation. It is thus concluded that bacterial proteases and free radical species such as NO derived from host's inflammatory responses may contribute to the bacterial pathogenesis via activation of MMP activation particularly during bacterial intrusion into the host.

  90. Therapeutic application of NO scavenger and NO donor for endotoxin shock

    MAEDA Hiroshi, SAWA Tomohiro, AKAIKE Takaaki

    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: Kumamoto University

    1997 - 1999

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    It is now well conceivable that overproduction of nitric oxide (NO) contributes to the pathogenesis of various diseases. In endotoxic shock, for example, hypotension with decreased peripheral vascular resistance is now known to be mediated through excessive production of NO. In this context, it seems reasonable that inhibition of NO production or scavenging of NO will result in therapeutic effect of PTIO, an NO scavenger we developed previously, against endotoxin shock. In fact, PTIO can rescue such model animals in pathological condition. It is, however, found that PTIO was not necessarily stable in biological systems particularly when administered intravenously to the animals. In the present study, to overcome this drawback of PTIO, we first successfully prepared liposome-encapsulated PTIO, which can be applicable as a specific NO scavenger for the treatment of NO-related diseases including endotoxin shock. In contrast, it is now recognized that the role of NO in organ function is often dual with protective and injurious effects. These opposing functions of NO are also reported for endotoxin shock. We thus further invented a novel and potent NO donor to see the cytoprotective effect of NO in shock pathogenesis. For this purpose, αィイD21ィエD2-protease inhibitor (αィイD21ィエD2-PI), which is the most abundant serine protease inhibitor in human plasma known as an important defense-oriented acute phase protein, is S-nitrosylated under physiological conditions, yielding 100% S-nitrosylatedαィイD21ィエD2-PI (S-NO-αィイD21ィエD2PI). S-NO-αィイD21ィエD2PI thus obtained has multiple pharmacological functions, including potent antimicrobial activity and inhibition of cell apoptosis, and sustaining blood flow and organ functions. Also, it is of considerable importance that S-NO-αィイD21ィエD2PI shows a potent anti-neutrophil and anti-oxidant activities during ischemia-reperfusion injuries in rat livers. The present evidence, concerning the unique biological activities of S-NO-αィイD21ィエD2PI, may lead to further clinical application of S-NO-αィイD21ィエD2PI for treatment of various inflammatory and infectious diseases including endotoxin shock.

  91. 生体内ラジカル生成による発癌と抗ラジカル物質によるがん抑制

    前田 浩, 澤 智裕, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(A)

    Category: 特定領域研究(A)

    Institution: 熊本大学

    1998 - 1998

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    近年、細菌(ヘリコバクターピロリ)やウイルスの慢性感染が発癌促進効果をもたらしていることが指摘されている。本研究では、これら微生物感染に伴う炎症反応におけるフリーラジカル種、特にNO関連フリーラジカルと発癌との関連に焦点を当てて検討を行った。 その結果、(1) これまでに報告したインフルエンザウイルス、サルモネラ菌に加え、I型ヘルペス単純ウイルス(HSV)の脳炎発症モデルにおいても誘導型NO合成酵素(iNOS)の発現の増強が見られ、また電子スピン共鳴法からもNOの産生が亢進していることが示された。(2) HSV脳炎病巣において、NOとスーパーオキサイド(O_2^-)との反応産物であるパーオキシナイトライト(ONOO^-)などによりもたらされる生体内ニトロ化反応のマーカーであるニトロチロシンの生成が示唆された。(3) in vitroにおいてONOO^-と核酸との反応産物をHPLC法により解析した結果、ONOO-はDNA、RNAいずれに対してもグアニン残基の酸化(オクソグアニンの生成)とニトロ化(ニトログアニンの生成)をもたらした。DNA鎖中に生じたニトログアニンは加水分解により自発的に脱塩基反応を起こしたが、RNA鎖中のニトログアニンは安定に保持され、DNAとRNAとではニトログアニンは異なる作用を示すことが考えられた。(4) in vitroにおいてセンダイウイルス(変異を調べるためにマーカーとしてgreen fluorescent protein(GFP)をゲノムに組み込んである)を生理的濃度のONOO-(0.8μM)で処理すると有意にGFPの変異が上昇した。 以上の結果より、微生物感染に伴う炎症局所ではNOやO_2^-、さらにはONOO^-などの活性窒素酸化物が過剰に産生され、タンパクや遺伝子にニトロ化をもたらしていることが示唆された。また、ONOO^-は遺伝子の変異を促進し、その作用は宿主細胞のみならず、病原体に対しても影響していることが考えられた。

  92. 感染と炎症におけるメタロプロテアーゼの活性制御

    前田 浩, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(A)

    Category: 特定領域研究(A)

    Institution: 熊本大学

    1998 - 1998

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    昨年までの研究により、一酸化窒素(NO)と活性酸素(スーパーオキサイド、O_2^-)の反応生成物であるパーオキシナイトライト(ONOO^-)が、炎症の場において重要な生理活性を有するmatrix metalloproteinase前駆体(proMMP)を活性化し、さらにこの現象が、還元型グルタチオン(GSH)により調節されることを見出した。そこで本年度は、その活性化メカニズムの解析を行った。[^<35>S]GSHを種々の濃度のONOO^-と一定時間反応した後、精製した3種類のヒトproMMP(proMMP-8,-9,-1)と反応させ、その結合をfluorographyにより解析した。その結果、[^<35>S]GSHをproMMPとincubationするだけで両者は結合したが、活性化は見られなかった。これはdithithreitol(DTT)にて容易にはずれることから、単なるSS結合と思われた。一方、ONOO^-が存在する場合、proMMPの活性化がみられ、さらにその結合はDTTにては解離しないことから、SS結合以外の何らかの非可逆的な共有結合がおこっていることが示唆された。この結合はcysteine switchのanalogue peptide(PRCGVPD)により阻害されたことから、proMMPのcysteine switchを介して生じていることが示唆された。さらに、電子スピン共鳴法によりONOO^-とGSHにより反応性の高い分子種(活性型グルタチオン)が生成し、これがproMMPの不活性性に重要なCys残基(cysteine switch)に結合することで活性化を引き起こしているものと思われた。グルタチオンの新しい生理活性として、proMMPに非可逆的に結合することで、その生理活性を制御している可能性が示唆された。

  93. メタロプロテアーゼの炎症および組織リモデリングにおける作用メカニズム

    前田 浩, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1997 - 1997

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    マトリックスメタロプロテアーゼ(MMP)は、感染、炎症、あるいは固型腫瘍の進展・発育において組織破壊とその修復に関与する重要なプロテアーゼ群である。一方近年、感染・炎症の場において一酸化窒素(NO)が過剰に産生され、NO_2やN_2O_3、さらにはONOO^-(パーオキシナイトライト)などの反応性の高い窒素酸化物に変化し、多彩な生物活性を発揮することが知られている。我々はこれまで、MMPの活性化メカニズムを解明するため、ヒト好中球より精製したMMP前駆体(proMMP-8,好中球プロコラゲナーゼ)を用いて、反応性窒素酸化物NO_2およびONOO^-によるMMPの活性化について検討してきた。あわせて、細菌感染病態における組織破壊機構におけるMMPの役割を解析するため、各種細菌性プロテアーゼによるMMPの活性化についても検討した。その結果、ヒトproMMP-8は、μMレベルのNO_2とONOO^-により効率よく活性化され、これはproMMP-8のpropeptide domain(autoinhibitory domain)の一個のL-cys残基がNO_2やONOO^-により酸化されることでMMPの活性化がもたらされるものと思われた(Arch.Biochem.Biophys.342:261,1997)。さらに、本年度の研究により、ONOO^-によるMMPの活性化が、グルタチオン(GSH)により巧妙に調節されていることがわかった。すなわち、GSHはONOO^-と反応することにより、GSHチイールラジカルとなり、MMPのautoinhibitory domainに付加体を形成し、MMPを強く活性化することが明らかとなった(投稿準備中)。この知見は、生体内におけるNOの過剰生成がMMPの活性化を介して組織のリモデリングに関与することを示唆している。一方、細菌性プロテアーゼのうち、特にサーモライシンファミリーに属する細菌性プロテアーゼである緑膿菌エラスターゼとコレラ菌プロテアーゼが強いMMPの活性化を示し、これらプロテアーゼは、これまで全く報告のない全くユニークな部位でMMPを限定分解し、活性化していることがわかった(J.Biol.Chem.272:6059-6066,1997)。

  94. 腫瘍血管透過性亢進メディエーター制御による制癌剤の腫瘍選択的ターゲティングの増強

    前田 浩, 野口 陽一郎, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1996 - 1996

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    腫瘍血管においては血管透過性が亢進し、我々の提唱するEPR(enhanced permeability and reteention)効果の結果として、腫瘍局所に高分子制癌剤を有効にデリバーすることが可能である。今回は特に血管透過性亢進作用を発現する生体内メディエーターに焦点をあて、ブラジキニン(BK)、プロスタグランナディン(PG)、nitric oxide(NO)、等が血管透過性(高分子物質の腫瘍集積性)に与える影響について、それらメディエーターの合成酵素阻害剤、分解酵素阻害剤等を用いたin vivo実験系を行い検討を加えた。BKのアンタゴニストであるHOE 140、PG合成酵素阻害剤であるインドメタシンは、それぞれ血管透過性を減弱させ、BK分解酵素阻害剤であるtemocaprilは血管透過性を増強させた。これらの結果からBKおよびPGの生体内濃度を変化させることで有効に高分子制癌剤の腫瘍局所へのデータティング能を強化させるとが示唆された。また高分子物質の投与後早期のEPR効果を検討する目的で、水溶性ポリマーの分子量には依存せず、分子量20K以下のポリマーは速やかに腎排泄されるため、血中、腫瘍内濃度が時間と共に腫瘍集積性の急激な低下が生じるのに対し、分子量50K以上のポリマーや緩やかに腎排泄されるため、血中でも安定に存在し、回収系の不全な腫瘍組織では時間と共に腫瘍集積性が増加し、EPR効果(論文投稿準備中)が認められることが明らかになった。

  95. メタロプロテアーゼの炎症および組織リモデリングにおける作用メカニズム

    前田 浩, 野口 陽一郎, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1996 - 1996

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    マトリックスメタロプロテアーゼ(MMP)は、感染、炎症、あるいは固型腫瘍の進展・発育において組織破壊とその修復に関与する重用なプロテアーゼ群である。一方近年、生体内において非常に単純な無機ラジカルである一酸化窒素(NO)がつくられることが明らかとなった。NOは、特に感染・炎症の場において過剰に産生され、NO_2やN_2O_3、さらにはONOO^-(パーオキシナイトライト)などの反応性の高い窒素酸化物に変化し、多彩な生物活性を発揮することが知られている。そこで今回、我々はMMPの活性化メカニズムを解明するため、ヒト好中球より精製したMMP前駆体(proMMP-8,好中球プロコラゲナーゼ)を用いて、反応性窒素酸化物NO_2およびONOO^-によるMMPの活性化について検討した。あわせて、細菌感染病態における組織破壊機構におけるMMPの役割を解析するため、各種細菌性プロテアーゼによるMMPの活性化についても検討した。その結果、ヒトproMMP-8は、μMレベルのNO_2とONOO^-により効率よく活性化され、これはproMMP-8のpropeptidedomain(autoinhibitory domain)の一個のL-cys残基がNO_2やONOO^-により酸化されることでMMPの前駆体性が消失し、活性化がもたらされるものと思われた(Arch.Biochem.Biophys.1997,in press)。この知見は、生体内におけるNOの過剰生成がMMPの活性化を介して組織のリモデリングに関することを示唆している。さらに、細菌性プロテアーゼのうち、特にサーモライシンファミリーに属する細菌性プロテアーゼである緑膿菌エラスターゼとコレラ菌プロテアーゼが強いMMPの活性化を示し、これらプロテアーゼは、これまで全く報告のない全くユニークな部位でMMPを限定分解し、活性化していることがわかった(J.Biol.Chem.272:6059-6066,1997)。従って、病原細菌の産生するいくつかのプロテアーゼは、宿主のMMPを活性化することにより、細菌の生体内侵入を促し、病原性に寄与する可能性が示された。

  96. Viral Pathogenesis and Regulation Mechanism of Free Radicals in Host Responses : Role of Nitric Oxide

    AKAIKE Takaaki, NOGUCHI Youichiro, MAEDA Hiroshi

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    1995 - 1996

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    To date, importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized. Considerable attenstion is given to another type of simple inorganic radical nitric oxide (NO) in the host defense mechanism and pathogenesis of virus infection. It is now well documented that NO synthesis pathway in particular inducible isoform of NO synthase (iNOS) is expressed in different array of virus diseases via induction of proinflammatory cytokines such as interferon-gamma, and interleukin-1beta. Recent studies indicate that NO together with oxygen radicals particularly superoxide (O_2) produced excessively play an important role in inflammatory response of the host against various intruding microbes. A highly reactive nitrogen oxide species peroxynitrite is produced in biological systems through the reaction of NO with O_2. In this research project, role of NO in the pathogenesis of animal models of influenza virus and herpes simplex virus infections was investigated. As a results, we found a convincing evidence that formation of peroxynitrite is critically involved in the pathogenesis of influenza virus infection in mice. Thus, understanding of the role of NO in conjunction with oxygen radicals generated in virus infectionswill provide a new insight into the viral pathogenesis. More importantly, a novel therapeutic approach by regulating the free radical generation may be possible in various viral diseases in humans.

  97. Pathogenesis of Bacterial Proteases : Involvement of Bradykinin and Nitric Oxide Synthesis Pathway

    MAEDA Hiroshi, NOGUCHI Youichiro, AKAIKE Takaaki

    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: Kumamoto University

    1994 - 1996

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    A hall-mark event as the involvement of host protease is the activation of Hageman factor-prekallikrein-kinin cascade which can be coupled with blood coagulation cascade and complement activation. In our previous study, it is revealed that kinin (bradykinin) is generated as a result of kinin-generating cascade which can be activated by all microbial proteases at one or more steps. This cascade is also activated by negatively charged surface of both gram positive (teichoic acid) and negative (lipopolysaccharide) bacteria. Bradykinin is responsible for pain, edema, extravasation, bacterial translocation/dissemination, thrombus formation or DIC and multiple organ failure, hypotension and shock. Our results obtained by the present research indicate that tissuedestruction by microbial proteases can take place either directly or indirectly by activating matrix metalloproteases of the hosts. Moreover, importance of development of kinin receptor antagonists and potent protease inhibitors with broad antiprotease spectrum is now realized.

  98. 一酸化窒素合成酵素及びチトクロームP-450還元酵素の誘導による制癌剤感受性増強

    前田 浩, 野口 陽一郎, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1995 - 1995

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    一部の腫瘍細胞や固型腫瘍において恒常的に一酸化窒素合成酵素(NO synthae,NOS)が発現しNOを産生していることが知られている。このNOSはチトクロームP-450還元酵素に類似していることが知られており、本年はこのNOSに焦点を当てて、制癌剤感受性増強効果および固型腫瘍のNO産生動態とその意義について検討した。 (1)固型腫瘍局所にNO放出剤を投与して腫瘍血管の透過性を亢進させることにより、高分子制癌剤であるSMANCSのdrug delivery system (DDS)改善傾向を認めた。(2)またNOSの基質であるL-arginineの投与により固型腫瘍局所における内因性のNO産生を高める事により、腫瘍血管の透過性を更に亢進させることが明らかになった。(3)AH136B固型腫瘍のNO産生動態をelectro spin resonance (ESR)を使用して検討したところ、比較的多量のNO産生を認めた。(4)さらに増殖の速い腫瘍ほどNO産生量も増加する傾向を認めた。

  99. オキシラジカルによる発癌促進とラジカルスカベンジャーによる抑制-新しい立場から-

    甲木 孝人, 安武 律, 赤池 孝章, 前田 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1994 - 1994

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    近年、発癌機構における各種フリーラジカルの関与が明らかにされつつある。今回は、食物中の発癌誘発物質(carcinogen)によるフリーラジカル生成機構を検討するとともに、食物中に含まれるフリーラジカル消去物質による、主に、アルキルパーオキシラジカル(L00・)に対する消去活性について解析した。 その結果、食物中、特に、加熱、baking等の処理により生成するヘテロサイクリックアミンによるO_2^-等の酸素ラジカル生成機構にチトクロームP450 reductaseが深くかかわる可能性が示唆された。さらに、野菜、豆、芋、お茶類を現実の食生活に準じた条件で調理し、その煮汁のアルキルパーオキシラジカル(L00・)中和活性を測定したところ、特に野菜の水加熱(煮沸)により得られた煮汁中に、強いL00・消去活性が認められた。また、EBウイルスによるトランスフォームアッセイによっても、野菜煮汁中には強い抗プロモーター活性が認められた。これらは、同時に、L00・によるDNA切断をも強く抑制した。 以上の知見は、食物中にラジカル生成活性に基づく発癌促進物質と抑制物質が同時に含まれるものの、それらの成分の活性は、食物の調理法により大きく変動することを示している。 今後は、さらに、L00・をはじめとするフリーラジカルによるDNAの化学修飾作用と遺伝子の転写調節におよぼすラジカル種の作用機構を解析することにより、フリーラジカルのかかわる発癌機構を分子レベルで解明していく予定である。

  100. 一酸化窒素合成酵素を標的とした固型癌の診断と治療-とくにNOによる血管透過性亢進作用の制御に基づく-

    前田 浩, 野口 陽一郎, 赤池 孝章

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 重点領域研究

    Category: 重点領域研究

    Institution: 熊本大学

    1994 - 1994

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    マウス固型腫瘍S-180,Colon38,B-16,B-16F10,Lewis肺癌を移植し、腫瘍血管透過性に関して高分子制癌剤のモデルとなるエバンスブルーまたは[^<51>Cr]標識アルブミンを静脈注射し、これらの腫瘍内集積性をNOスカベンジャーであるPTIO投与群とPTIO非投与群で定量した。S-180,Colon38,B-16F10腫瘍では、PTIO投与群に腫瘍血管透過性亢進の抑制が25-40%認められたが、B-16,Lewis肺癌では抑制傾向は認められなかった。これらの結果からNOが腫瘍血管透過性亢進作用を有することが判明し、癌腫により血管透過性亢進作用に対するNOの関与に差異があることが明らかになった。この差異は、血管透過性亢進作用にNO以外の腫瘍血管透過性因子、ブラジキニン、プロスタグランジン等の他の生体内因子が総合的に関与しているためと考えられる。このPTIOによる抑制はNO合成酵素阻害剤であるL-NAMEとほぼ同等の効果であった。またキニンアンタゴニスト(HOE140)、インドメサシンさらにPTIOの併用により腫瘍血管透過性を約75%抑制した。今回使用したPTIOやL-NAME、あるいはHOE140やシクロオキシゲナーゼ阻害剤だけでなく腫瘍血管透過性因子のアンタゴニスト(又はその抗体)等を併用させることで、総合的に腫瘍血管透過性亢進を正常組織レベルまで抑制可能と考えられる。 次にラット固型腫瘍(AH136B)をラット足背部に作成し、腸骨動脈よりカニュレーションでNO放出剤であるSNAPおよび[^<51>Cr]標識アルブミンを投与し、標識アルブミンの腫瘍内集積量を検討した。その結果、全身の血圧を低下させない程度のSNAP投与量(0.1mg/kg)では、SNAP非投与群と比較して標識アルブミンの腫瘍内集積量で約50%の増加が認められた。またこの系にアンジオテンシンIIを併用し昇圧すると、さらにその集積性を増強できた。この結果は、NOを用いることで高分子制癌剤をより多く腫瘍へ集積し得ることを示唆している。

  101. ウイルス感染病態における一酸化窒素(NO)の役割についての研究

    赤池 孝章, 野口 陽一郎, 前田 浩

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 一般研究(C)

    Category: 一般研究(C)

    Institution: 熊本大学

    1994 - 1994

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    ウイルス感染病態における一酸化窒素(nitric oxide,NO)の役割を解析するため、マウスインフルエンザウイルス肺炎モデル、ラット狂犬病ウイルス/単純ヘルペス脳炎モデルを作製し、各ウイルス感染病巣におけるNOの過剰生成を解析し、NO合成阻害剤であるN^G-monomethyl-L-arginine(L-NMMA)を投与し、生体内のNO合成を制御することで、ウイルス感染病態がどのように修飾されるかを検討した。 その結果、マウス、ラットの肺、および脳内において、ウイルス感染に伴い誘導型NO合成酵素(NOS)が強く誘導されることが、誘導型NOSのcDNAプローブを用いたRT-PCR/Sourthern blot法、およびNorthern blot法により明らかとなった。また、ウイルス感染局所におけるNO生成を電子スピン共鳴(electron spin resonance,ESR)法により、110Kにて解析したところ、過剰に産生したNOに由来するNO-ヘモグロビンアダクトの有意な生成が認められ、これは、NOS阻害剤であるL-NMMAを動物に投与することにより著明に抑制された。さらに、L-NMMA投与により、インフルエンザウイルス感染マウスの生存率が有意に改善(100%致死率→50%生存)した。 以上の知見より、マウスインフルエンザウイルスをはじめとする各種ウイルス感染の病原性発現機構において、NOが重要な増悪因子として作用していることが明らかとなった。

  102. Involvement of virus infection in the pathogenesis of pulmonary fibrosis

    AKAIKE Takaaki, ANDO Masayuki, MAEDA Hiroshi

    Offer Organization: Japan Society for the Promotion of Science

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

    Category: Grant-in-Aid for General Scientific Research (C)

    Institution: Kumamoto University

    1992 - 1993

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    Free radicals such as superoxide anion(O_2) and nitrite oxide were found generated markedly in influenza virus infected mouse lung, and these molecular species were identified as the potent pathogenic principle. This finding has many important implications for understanding of the viral pathogenesis : namely, the direct viral cytotoxicity referred cytopahtic effect is only a fraction of several types of events induced by virus infection. The toxicity and reactivity of oxygen radicals, which are presumably generated in excess amount by the over reaction of host's immune response against the virus replicating organs, may explain the mechanism of tissue injuries observed not only in infuluenza virus infection in mice but also in other types of virus diseases, especially those viruses with less acute but with longer incubation period, in which immunological interactions are usually involved. Research focused more on the role of host-derived factors may shed new light on the understanding of viral pathogenesis in the lung as wel as other pulmonary disorders with uncertain etiology, such as idiopathic interstitial pneumonia/pulmonary fibrosis.

  103. Molecular pathogenesis of influenza virus infection : involvement of free radicals and bradykinin

    MAEDA Hiroshi, ANDO Masayuki, AKAIKE Takaaki

    Offer Organization: Japan Society for the Promotion of Science

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

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

    Institution: Kumamoto University

    1991 - 1993

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    Our findings obtained in this reseach leveal the importance of host-derived pathogenic agents, e. g., endogenous proteases, kinins, oxygen radicals, in the pathogenesis of influenza virus infections, indicating that the direct cytotoxicity by viral infection in the host's cells is only a fraction of the pathological events of influenza virus infection in the lung. Furthermore, it was found that mite proteases as environmental factors showed a potent enhancement of influenza virus replication in mice lungs as well as nasopharynged cavity of ferrets, In addition, mite proteases in human habitation could activate all the step of kinin generating cascade and also generate C5a and C3a in complement systems. These results indicate the improtant role of mite proteases as environmental factors in the pathogenensis and transmission of influenza virus infection in humans. Research focused on the mode of interactions between host-derived factors, environmental factor, and multiple factors thereof should shed new light on the understanding of viral pathogenesis of influenza virus and other viruses.

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Media Coverage 18

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    昭和大学プレスリリース・研究成果

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  3. 京都大学と東京都健康長寿医療センターとの共同研究によりNOと活性酸素のシグナル分子ニトロｃGMPが記憶形成に必要であることを解明

    東北大学医学部ニュース

    2024/03/06

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    京都大学薬学研究科 柿澤 昌准教授、東京都健康長寿医療センター研究所 遠藤 昌吾研究部長、石神 昭人副所長、東北大学大学院医学系研究科 赤池 孝章教授らの研究グループは、悪玉因子、活性酸素が記憶形成に必要であることを解明しました。 本研究成果は、2024年2月1日にオランダの国際学術誌「Redox Biology」にオンライン掲載されました。

  4. 「超硫黄分子」の寿命延長効果を発見 ～新たなサプリメントや健康法の開発に期待～

    東北大学プレスリリース・研究成果

    2024/01/19

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    奈良先端科学技術大学院大学（学長：塩﨑一裕）先端科学技術研究科 バイオサイエンス領域の西村 明 助教（兼・研究推進機構）、研究推進機構の髙木博史 特任教授、東北大学大学院医学系研究科の赤池孝章 教授らの共同研究グループは、「超硫黄分子（注1）」が、酵母の寿命を制御していることを発見しました。今回、明らかになった酵母に対する寿命の制御機構は、ヒトを含む高等生物に広く保存されていると予想されることから、超硫黄分子の利用が老化予防や健康寿命の延長などに貢献すると期待されます。 本研究成果は、2024年1月3日付けで国際学術誌Redox Biologyに掲載されました。

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  6. 超硫黄分子による心機能の制御メカニズムを解明 虚血性心疾患や難治性心不全などの診断・治療への応用に期待 Myself

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    2023/08/21

  7. 超硫黄分子によるウイルスと慢性肺疾患の制御法を開発 ミラクル分子・超硫黄による病気のコントロールで未来型呼気医療を展開へ

    東北大学プレスリリース・研究成果

    2023/08/04

  8. 咳の流量2倍で約100倍の微小なエアロゾルが発生!? ～咳による体内のエアロゾル発生をコンピュータシミュレーションで再現～

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  9. ヒューマニエンス 40億年のたくらみ

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    Type: TV or radio program

  10. 結核菌が宿主の免疫応答を抑制するメカニズムの一端を解明 ～新たな結核治療薬の開発に繋がる可能性～

    東北大学医学部ニュース

    2022/01/28

  11. ボールウェーブ、東北大学、豊田合成が新型コロナウイルスの高速センサを共同開発 ―エアロゾル中のウイルス直接検出を目指す―

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  12. 細菌における抗菌剤耐性の新しいメカニズムを発見

    東北大学プレスリリース・研究成果

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  13. 息を用いた新型コロナ検査法を開発 -呼気オミックスによる未来型呼気医療への展開-

    東北大学プレスリリース・研究成果

    2020/10/16

  14. 活性硫黄によるタンパク質劣化防止機構の発見 -タンパク質の劣化を防いで老化防止・健康長寿の可能性-

    東北大学プレスリリース・研究成果

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  15. サルモネラが持つ巧妙な生き残り戦術を解明 〜硫黄代謝経路をターゲットとした新たな抗菌薬の開発が可能に〜

    東北大学プレスリリース・研究成果

    2018/10/03

  16. 世界初：哺乳類における「硫黄呼吸」を発見 - 酸素に依存しないエネルギー代謝のメカニズムを解明 -

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  17. 動脈硬化症を促進する新しい病原体を発見～動脈硬化症関連疾患の新しい予防・治療法の開発に期待～

    東北大学プレスリリース・研究成果

    2014/04/16

  18. 活性酸素の強力な消去物質を発見～酸化ストレス関連疾患の予防・診断・治療に期待～

    東北大学プレスリリース・研究成果

    2014/04/15

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