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大学院医学系研究科（医学専攻等） 附属感染制御総合センター |
出身大学 【 表示 ／ 非表示 】
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-2011年07月
九江学院 医学部 臨床医学 卒業
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2015年04月-2019年03月
熊本大学 大学院医学教育部 微生物学講座（博士課程） 卒業
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2013年04月-2015年03月
熊本大学 大学院医学教育部 免疫学分野（修士課程） 卒業
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2007年09月-2012年07月
九江学院（大学） 医学部 卒業
出身大学院 【 表示 ／ 非表示 】
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2015年04月-2019年03月
熊本大学 医学系研究科 微生物学 博士課程 修了
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2013年04月-2015年03月
熊本大学 医学系研究科 免疫学 修士課程 修了
職務経歴（学内） 【 表示 ／ 非表示 】
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2025年04月-継続中
秋田大学 大学院医学系研究科（医学専攻等） 附属感染制御総合センター 助教
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2024年06月-2025年03月
秋田大学 感染統括制御・疫学・分子病態研究センター 助教
職務経歴（学外） 【 表示 ／ 非表示 】
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2024年06月-継続中
秋田大学 感染統括制御・疫学・分子病態研究センター 助教
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2022年10月-2024年05月
熊本大学 大学院生命科学研究部 微生物学講座 博士研究員
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2020年10月-2022年09月
独立行政法人日本学術振興会 外国人特別研究員
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2019年04月-2020年09月
熊本大学 大学院生命科学研究部 微生物学講座 博士研究員
研究分野 【 表示 ／ 非表示 】
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ライフサイエンス / 医化学
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ライフサイエンス / 免疫学
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ライフサイエンス / 免疫学
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ライフサイエンス / 医化学
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ライフサイエンス / 細菌学
研究等業績 【 表示 ／ 非表示 】
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Xiaoyan Li, Touya Toyomoto, Tianli Zhang, Chunyu Guo, Stephen Lindahl, Hiroyasu Tsutsuki, Ming Xian, Tomohiro Sawa
International immunology ( Oxford University Press (OUP) ) 36 ( 12 ) 641 - 652 2024年06月
研究論文（学術雑誌）
Interferons (IFNs) are cytokines produced and secreted by immune cells when viruses, tumor cells, and so forth, invade the body. Their biological effects are diverse, including antiviral, cell growth-inhibiting, and antitumor effects. The main subclasses of interferons include type-I (e.g., IFN-α and IFN-β) and type-II (IFN-γ), which activate intracellular signals by binding to type-I and type-II IFN receptors, respectively. We have previously shown that when macrophages are treated with supersulfide donors, which have polysulfide structures in which three or more sulfur atoms are linked within the molecules, IFN-β-induced cellular responses, including signal transducer and activator of transcription 1 (STAT1) phosphorylation and inducible nitric oxide synthase (iNOS) expression, were strongly suppressed. However, the subfamily specificity of the suppression of IFN signals by supersulfides and the mechanism of this suppression are unknown. This study demonstrated that supersulfide donor N-acetyl-L-cysteine tetrasulfide (NAC-S2) can inhibit IFN signaling in macrophages stimulated not only with IFN-α/β but also with IFN-γ. Our data suggest that NAC-S2 blocks phosphorylation of Janus kinases (JAKs), thereby contributes to the inhibition of phosphorylation of STAT1. Under the current experimental conditions, hydrogen sulfide (H2S) donor NaHS failed to inhibit IFN signaling. Similar to NAC-S2, carbohydrate-based supersulfide donor thioglucose tetrasulfide (TGS4) was capable of strongly inhibiting tumor necrosis factor-αproduction, iNOS expression, and nitric oxide production from macrophages stimulated with lipopolysaccharide. Further understanding of molecular mechanisms how supersulfide donors exhibit their inhibitory actions towards JAK/STAT signaling is necessary basis for development of supersulfide-based therapeutic strategy against autoimmune disorders with dysregulated IFN signaling.
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Regulation of innate immune and inflammatory responses by supersulfides.
Hiroyasu Tsutsuki, Tianli Zhang, Takaaki Akaike, Tomohiro Sawa
International immunology ( Oxford University Press (OUP) ) 36 ( 4 ) 143 - 154 2024年01月 [査読有り]
研究論文（学術雑誌）
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.
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Thioglucose-derived tetrasulfide, a unique polysulfide model compound.
Stephen Lindahl, Meg Shieh, Tianli Zhang, Chunyu Guo, Jerome R Robinson, Tomohiro Sawa, Ming Xian
Redox biology 70 103045 - 103045 2024年01月 [査読有り]
研究論文（学術雑誌）
Polysulfides have received increased interest in redox biology due to their role as the precursors of H2S and persulfides. However, the compounds that are suitable for biological investigations are limited to cysteine- and glutathione-derived polysulfides. In this work, we report the preparation and evaluation of a novel polysulfide derived from thioglucose, which represents the first carbohydrate-based polysulfide. This compound, thioglucose tetrasulfide (TGS4), showed excellent stability and water solubility. H2S and persulfide production from TGS4, as well as its associated antioxidative property were also demonstrated. Additionally, TGS4 was demonstrated to significantly induce cellular sulfane sulfur level increase, in particular for the formation of hydropersulfides/trisulfides. These results suggest that TGS4 is a useful tool for polysulfide research.
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腸管出血性大腸菌毒素SubABの病原性発現機構に関わるレドックスバイオロジー
津々木 博康, 張 田力, 澤 智裕
薬学雑誌 ( 公益社団法人 日本薬学会 ) 144 ( 1 ) 57 - 60 2024年01月
研究論文（学術雑誌）
<p>AB<sub>5</sub> toxins of pathogenic bacteria enter host cells and utilize the retrograde trafficking pathway to translocate to the cytoplasm and exert its pathogenesis. Cholera toxin and Shiga toxin reach the endoplasmic reticulum (ER), and the A subunit undergoes redox regulation by ER proteins to become active fragments, which pass through the ER membrane and translocate to the cytoplasm. By acting on molecular targets in the cytoplasm, the normal function of host cells are disrupted, causing diseases. ER chaperone proteins such as protein disulfide isomerase (PDI) and binding immunoglobulin protein (BiP) induce conformational changes triggered by the reduction of disulfide bonds in the A subunit. This is thought to be dependent on cysteine thiol-mediated redox regulation, but the detailed mechanism remains unclear. On the other hand, subtilase cytotoxin (SubAB), produced by enterohemorrhagic <i>Escherichia coli</i> (EHEC), localizes to the ER without translocating to the cytoplasm and cleaves BiP as a substrate. Therefore, it is thought that ER stress-based cytotoxicity and intestinal bleeding occur without translocating to the cytoplasm. We reported that PDI is involved in BiP cleavage through SubAB localization to the ER. Like other AB<sub>5</sub> toxins, this indicates the involvement of redox regulation <i>via</i> chaperone proteins in the ER, but also suggests that SubAB does not translocate to the cytoplasm because it cleaves BiP. Although there are few reports on the redox state of ER protein thiols, it is suggested that polysulfidation, which is discussed in this symposium, may be involved.</p>
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Waliul Islam, Hiroyasu Tsutsuki, Azizur Rahman, Ayaka Harada, Tianli Zhang, Katsuhiko Ono, Rayhanul Islam, Foysal Hossen, Takuro Niidome, Tomohiro Sawa, Jun Fang
ACS Applied Polymer Materials ( American Chemical Society (ACS) ) 5 ( 12 ) 10289 - 10302 2023年11月 [査読有り]
研究論文（学術雑誌）
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SIRT7 Is a Lysine Deacylase with a Preference for Depropionylation and Demyristoylation
Mohammad Golam Kibria, Tatsuya Yoshizawa, Tianli Zhang, Katsuhiko Ono, Tomoya Mizumoto, Yoshifumi Sato, Tomohiro Sawa, Kazuya Yamagata
International Journal of Molecular Sciences ( MDPI AG ) 26 ( 7 ) 3153 2025年03月
<jats:p>Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that remove acyl groups from lysine residues on target proteins, releasing nicotinamide. SIRT7 is associated with aging and a number of age-related diseases, but the enzymatic properties of SIRT7 are largely unknown. In the present study, we investigated the biochemical activity of SIRT7 by performing a series of in vitro kinetic studies in the presence of different acyl substrates. The binding affinity of SIRT7 for NAD+ was dependent on the acyl substrate, and SIRT7 showed a preference for depropionylation and demyristoylation. Nicotinamide, the end-product of the sirtuin reaction, inhibits the activity of SIRT1-6. We also found that the sensitivity of SIRT7 to nicotinamide inhibition also depended on the chain length of the acylated peptides and that nicotinamide was a poor inhibitor of SIRT7 with non-acetylated substrates. These findings may provide insights into the development of novel SIRT7 modulators for the treatment of age-related diseases.</jats:p>
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Supersulfides: A Promising Therapeutic Approach for Autoinflammatory Diseases
Tianli Zhang, Touya Toyomoto, Tomohiro Sawa, Takaaki Akaike, Tetsuro Matsunaga
Microbiology and Immunology ( Wiley ) 69 ( 4 ) 191 - 202 2025年02月
<jats:title>ABSTRACT</jats:title><jats:p>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.</jats:p>
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The Therapeutic Potential of Supersulfides in Oxidative Stress-Related Diseases
Yuexuan Pan, Tetsuro Matsunaga, Tianli Zhang, Takaaki Akaike
Biomolecules ( MDPI AG ) 15 ( 2 ) 172 2025年01月
<jats:p>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.</jats:p>
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システイン、ホモシステイン、グルタチオンパースルフィドの内因性メチル化体の細菌、植物、動物における同定
澤 智裕, 豊元 柊弥, 張 田力
日本毒性学会学術年会 ( 日本毒性学会 ) 52.1 ( 0 ) O-30 2025年
<p>チオール含有化合物のメチル化はホモシステインのメチル化によるメチオニンの生合成を含めて生体内で起こるプロセスである。またシステインやグルタチオンのメチル化体の生体内で検出されている。我々はこれまでにシステイン、ホモシステイン、グルタチオンなどの低分子チオール分子が生体内で過剰な硫黄原子が付加したパースルフィドやポリスルフィドとして存在すること、さらにはそれらが強い求核性、抗酸化性、抗炎症性を有することを明らかにしてきた。これらパースルフィドやポリスルフィドのメチル化体についてはこれまで解析がされていない。本研究ではこれらパースルフィドやポリスルフィドのメチル化体の高感度な解析系を構築した。その結果、細菌、植物、動物細胞においてメチル化されたシステインパースルフィド、ホモシステインパースルフィド、グルタチオンパースルフィド（S-MeS-SG）の検出に成功した。とくにニンニク鱗茎では通常のグルタチオンよりも高いレベルのS-MeS-SGが存在していた。S-MeS-SGは過酸化水素による酸化や、グルタチオン還元酵素によるジスルフィドの還元に抵抗性を示したことから、グルタチオンや酸化型グルタチオンとは異なる代謝の制御を受けることが予想された。今後、メチル化パースルフィド分子の生物機能やその生成機構についての研究が期待される。</p>
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カルバペネム耐性菌に対抗するキレート剤をベースとした新規MBL阻害剤の開発(Development of chelator based novel MBL inhibitors to combat carbapenem resistance bacteria)
豊元 柊弥, 張 田力, 上釜 綾夏, 津々木 博康, 澤 智裕
日本細菌学雑誌 ( 日本細菌学会 ) 79 ( 2 ) 119 - 119 2024年06月
◆原著論文【 表示 ／ 非表示 】
◆その他【 表示 ／ 非表示 】
科研費（文科省・学振）獲得実績 【 表示 ／ 非表示 】
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グルタチオン輸送に依存したNLRP3インフラマソーム制御の分子機構
特別研究員奨励費
研究期間: 2020年11月 - 2023年03月 代表者: 澤 智裕, ZHANG TIANLI
学会等発表 【 表示 ／ 非表示 】
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超硫黄化はNLRP3インフラマソームの活性化を調節する
張 田力
第35回日本生体防御学会 2024年09月 - 2024年09月
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Supersulfidation regulates NLRP3 inflammasome activation
Tianli Zhang
Gordon Research Conference 2024年07月 - 2024年07月
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NLRP3 supersulfidation modulates inflammasome activation in response to extracellular stimuli
Tianli Zhang
2024.05 第77回日本酸化ストレス学会 第23回日本NO学会 合同学術集会 2024年05月 - 2024年05月
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タンパク質超硫黄化によるNLRP3インフラマソーム活性化の内因性調節機構
張 田力
第76回日本細菌学会東北支部 2024年08月 - 2024年08月
メディア報道 【 表示 ／ 非表示 】
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食中毒を引き起こす細菌の毒素SubABが宿主免疫を抑制する仕組みを解明
2022年03月
熊本大学プレスリリース
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細菌における抗菌剤耐性の新しいメカニズムを発見
2021年04月
熊本大学プレスリリース・研究成果
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炎症反応を強力に抑える活性イオウ誘導体の開発に成功
2019年03月
熊本大学プレスリリース・研究成果
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熊本大・東北大・AMED、炎症反応を強力に抑える活性イオウ誘導体の開発に成功
2019年03月
日本経済新聞