Updated on 2024/10/07

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写真a

 
YAMASHITA TOMOHIRO
 
Organization
Faculty of Pharmaceutical Sciences Department of Pharmaceutical Health Care and Sciences Lecturer
Title
Lecturer
Contact information
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Profile
・慢性疼痛および慢性掻痒のメカニズム解析および治療薬の探索 ・グリーンファルマ研究
Homepage
  • http://www.phar.kyushu-u.ac.jp/library-screening/

    九州全域のアカデミアが有する有望なシーズをもとに、三大死因疾患(慢性的な痛みと痒み、心循環、炎症・がん等)などのアンメット・ニーズの高い疾患を対象にグリーンファルマを基盤にした創薬オープンイノベーションを推進しています

External link

Degree

  • Ph.D.

Research History

  • なし   

    なし

  • なし   

Research Interests・Research Keywords

  • Research theme: ・Drug discovery for pain and itch. ・Greenpharma research.

    Keyword: drug screening, neuropathic pain, itch, MRGPR, DRG neuron, microglia, ATP receptors

    Research period: 2018.4

Papers

  • Construction of a screening system for lipid-derived radical inhibitors and validation of hit compounds to target retinal and cerebrovascular diseases. Reviewed International journal

    Ryota Mori, Masami Abe, Yuma Saimoto, Saki Shinto, Sara Jodai, Manami Tomomatsu, Kaho Tazoe, Minato Ishida, Masataka Enoki, Nao Kato, Tomohiro Yamashita, Yuki Itabashi, Ikuo Nakanishi, Kei Ohkubo, Sachiko Kaidzu, Masaki Tanito, Yuta Matsuoka, Kazushi Morimoto, Ken-Ichi Yamada

    Redox biology   73   103186 - 103186   2024.7   ISSN:2213-2317

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Redox Biology  

    Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.

    DOI: 10.1016/j.redox.2024.103186

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  • Inhibition of G protein-coupled receptor 68 using homoharringtonine attenuates chronic kidney disease-associated cardiac impairment. Reviewed International journal

    Yuya Yoshida, Kohei Fukuoka, Miyu Sakugawa, Masayuki Kurogi, Kengo Hamamura, Keika Hamasaki, Fumiaki Tsurusaki, Kurumi Sotono, Takumi Nishi, Taiki Fukuda, Taisei Kumamoto, Kosuke Oyama, Takashi Ogino, Akito Tsuruta, Kouta Mayanagi, Tomohiro Yamashita, Hiroyuki Fuchino, Nobuo Kawahara, Kayo Yoshimatsu, Hitomi Kawakami, Satoru Koyanagi, Naoya Matsunaga, Shigehiro Ohdo

    Translational research : the journal of laboratory and clinical medicine   269   31 - 46   2024.2   ISSN:1931-5244 eISSN:1878-1810

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Translational Research  

    Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD.

    DOI: 10.1016/j.trsl.2024.02.004

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  • Inhibition of tumor-derived CCL2 expression attenuates tactile allodynia in NCTC 2472 fibrosarcoma-inoculated mice. Reviewed International journal

    #Marie Taniguchi, #Sai Yasukochi, #Wakaba Yamakawa, @Yuya Tsurudome, @Akito Tsuruta, @Michiko Horiguchi, @Kentaro Ushijima, @Tomohiro Yamashita, @Naoya Shindo, @Akio Ojida,@ Naoya Matsunaga, @Satoru Koyanagi, @Shigehiro Ohdo

    Molecular pharmacology   104 ( 2 )   73 - 79   2023.6   ISSN:0026-895X eISSN:1521-0111

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Molecular pharmacology  

    Neuropathic pain associated with cancers is caused by tumor growth compressing and damaging nerves, which would also be enhanced by inflammatory factors through sensitizing nociceptor neurons. One troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, a condition known as "tactile allodynia" which is often refractory to NSAIDs and opioids. The involvement of chemokine CCL2 (monocyte chemoattractant protein-1) in cancer-evoked neuropathic pain is well established, but opinions remain divided as to whether CCL2 is involved in the production of tactile allodynia with tumor growth. In this study, we constructed Ccl2 knockout NCTC2472 (Ccl2-KO NCTC) fibrosarcoma cells and conducted pain behavioral test using Ccl2-KO NCTC-implanted mice. Implantation of naïve NCTC cells around the sciatic nerves of mice produced tactile allodynia in the inoculated paw. Although the growth of Ccl2 KO NCTC-formed tumors was comparable to that of naïve NCTC-formed tumors, Ccl2-KO NCTC-bearing mice failed to show tactile pain hypersensitivity, suggesting the involvement of CCL2 in cancer-induced allodynia. Subcutaneous administration of controlled-release nanoparticles containing CCL2 expression inhibitor NS-3-008 significantly attenuated tactile allodynia in naïve NCTC-bearing mice accompanied by a reduction of CCL2 content in tumor masses. Our present findings suggest that inhibition of CCL2 expression in cancer cells is useful strategy to attenuate tactile allodynia induced by tumor growth. Development of a controlled release system of CCL2 expression inhibitor may be a preventive option for the treatment of cancer-evoked neuropathic pain. Significance Statement The blockade of chemokine/receptor signaling, particularly for C-C motif chemokine ligands 2 (CCL2) and its high-affinity receptor CCR2, has been implicated to attenuate cancer-induced inflammatory and nociceptive pain. This study demonstrated that continuous inhibition of CCL2 production from cancer cells also prevents the development of tactile allodynia associated with tumor growth. Development of controlled release system of CCL2 expression inhibitor may be a preventative option for management of cancer-evoked tactile allodynia.

    DOI: 10.1124/molpharm.123.000690

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  • GPR55 contributes to neutrophil recruitment and mechanical pain induction after spinal cord compression in mice. Reviewed International journal

    #Teruaki Ono, @Tomohiro Yamashita, #Ryota Kano, Mariko Inoue, #Shota Okada, Koki Kano, @Schuichi Koizumi, @Kazuhisa Iwabuchi, @Yoshio Hirabayashi,@ Ichiro Matsuo, @Yasuharu Nakashima, @Hiroyuki Kamiguchi, @Yuta Kohro, @Makoto Tsuda

    Brain, behavior, and immunity   110   276 - 287   2023.3   ISSN:0889-1591 eISSN:1090-2139

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Brain, Behavior, and Immunity  

    Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3+ T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis.

    DOI: 10.1016/j.bbi.2023.03.008

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  • Combinatorial screening for therapeutics in ATTRv amyloidosis identifies naphthoquinone analogues as TTR-selective amyloid disruptors. Reviewed

    Ryoko Sasaki, Mary Ann Suico, Keisuke Chosa, Yuriko Teranishi, Takashi Sato, Asuka Kagami, Shunsuke Kotani, Hikaru Kato, Yuki Hitora, Sachiko Tsukamoto, @Tomohiro Yamashita, Takeshi Yokoyama, Mineyuki Mizuguchi, Hirofumi Kai, Tsuyoshi Shuto

    Journal of pharmacological sciences   151 ( 1 )   54 - 62   2023.1   ISSN:1347-8613 eISSN:1347-8648

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    Hereditary ATTR amyloidosis is caused by the point mutation in serum protein transthyretin (TTR) that destabilizes its tetrameric structure to dissociate into monomer. The monomers form amyloid fibrils, which are deposited in peripheral nerves and organs, resulting in dysfunction. Therefore, a drug that dissolves amyloid after it has formed, termed amyloid disruptor, is needed as a new therapeutic drug. Here, we first established a high throughput screening system to find TTR interactors from the LOPAC1280 compound library. Among the hit compounds, thioflavin T-based post-treatment assay determined lead compounds for TTR amyloid disruptors, NSC95397 and Gossypol, designated as B and R, respectively. Because these compounds have naphthoquinone-naphthalene structures, we tested 100 naphthoquinone derivatives, and found 10 candidate compounds that disrupted TTR amyloid. Furthermore, to determine whether these 10 compounds are selective for TTR amyloid, we evaluated them against beta-amyloid (Aβ1-42). We found two compounds that were selective for TTR and did not disrupt Aβ-derived amyloid. Therefore, we succeeded in identifying TTR-selective amyloid disruptors, and demonstrated that naphthoquinone compounds are useful structures as amyloid disruptors. These findings contribute to the on-going efforts to discover new therapeutic tools for TTR amyloidosis.

    DOI: 10.1016/j.jphs.2022.11.004

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  • ATTRvアミロイドーシスの治療薬に対するコンビナトリアルスクリーニングによるナフトキノン類似体のTTR選択的アミロイド攪乱物質としての同定(Combinatorial screening for therapeutics in ATTRv amyloidosis identifies naphthoquinone analogues as TTR-selective amyloid disruptors)

    Sasaki Ryoko, Suico Mary Ann, Chosa Keisuke, Teranishi Yuriko, Sato Takashi, Kagami Asuka, Kotani Shunsuke, Kato Hikaru, Hitora Yuki, Tsukamoto Sachiko, Yamashita Tomohiro, Yokoyama Takeshi, Mizuguchi Mineyuki, Kai Hirofumi, Shuto Tsuyoshi

    Journal of Pharmacological Sciences   151 ( 1 )   54 - 62   2023.1   ISSN:1347-8613

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    LOPAC1280化合物ライブラリからトランスサイレチン(TTR)インタラクタを探索するハイスループットスクリーニング(HTS)系を確立した。このHTS系でヒットした化合物の中から、チオフラビンT基盤アッセイによりTTR-アミロイド攪乱物質(AD)として2種類の化合物、NSC95397とGossypolをリード化合物として選定した。これらの化合物はナフトキノン(NQ)-ナフタレン構造を持つため、100種類のNQ誘導体を試験して、10種類のTTR-AD候補化合物を特定した。これら10化合物のTTRアミロイドに対する選択性をβアミロイド(Aβ1-42)で評価し、TTRに選択的で、Aβ由来アミロイドを破壊しない2種類の化合物を見出した。このHTS系はTTR-ADを同定し、NQ化合物はADとして有用な構造であった。

  • Compound screening identified gossypetin and isoquercitrin as novel inhibitors for amyloid fibril formations of Vλ6 proteins associated with AL amyloidosis. Reviewed International journal

    @Daisuke Takahashi, #Eri Matsunaga , @Tomohiro Yamashita, @Jose M M Caaveiro , Yoshito Abe, @Tadashi Ueda

    Biochem. Biophys. Res. Commun.   596 ( March 12 )   22 - 28   2022.3   ISSN:0006-291X eISSN:1090-2104

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Biochemical and Biophysical Research Communications  

    AL amyloidosis is a life-threatening disease characterized by the deposition of amyloidogenic immunoglobulin light chain secreted from clonal plasma cells. Here we established an in-vitro screening system of amyloid inhibition of a variable domain in λ6 light chain mutant (Vλ6), Wil, and screened a food-additive compound library to identify compounds inhibiting the fibril formation. We found gossypetin and isoquercitrin as novel inhibitors. NMR analysis showed that both compounds directly interacted with natively-folded Wil, and proteolysis experiments demonstrated that these compounds conferred proteolytic resistance, suggesting that the compounds enhance the kinetic stability of Wil. Since gossypetin and isoquercitrin specifically interacted with the protein at micromolar concentrations, these compounds could be used as lead to further develop inhibitors against AL amyloidosis.

    DOI: 10.1016/j.bbrc.2022.01.066

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  • New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth Reviewed International journal

    #Akiko Sagara, @Kohei Nakata,@Tomohiro Yamashita, Weiyu Guan, Pingshan Zhong, Sokichi Matsumoto, Sho Endo, Chika Iwamoto, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, @Kenoki Ohuchida , @Kazuhiro Mizumoto, @Masafumi Nakamura

    Pancreatology   2021.4

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  • New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1 beta Release: An Involvement in its Alleviating Effect on Neuropathic Pain Reviewed International journal

    @Yamashita, Tomohiro; #Kamikaseda, Sawako; #Tanaka, Aya; @Tozaki-Saitoh, Hidetoshi; @Caaveiro, Jose M. M.; @Inoue, Kazuhide; @Tsuda, Makoto

    CELLS   10 ( 2 )   2021.2

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    DOI: 10.3390/cells10020434

  • Synthesis of DFGH-Ring Derivatives of Physalins via One-Pot Construction of GH-Ring and Evaluation of Their NF-kappa B-Inhibitory Activity Reviewed International journal

    @Yoritate, Makoto; #Morita, Yuki; Gemander, Manuel; @Morita, Masaki; @Yamashita, Tomohiro; @Sodeoka, Mikiko; @Hirai, Go

    ORGANIC LETTERS   22 ( 22 )   8877 - 8881   2020.11

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    DOI: 10.1021/acs.orglett.0c03255

  • Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1 Reviewed

    Ryoko Igarashi, Shun-Ichi Yamashita, Tomohiro Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Takeo Fukuchi, Tomotake Kanki

    Scientific reports   10 ( 1 )   1465   2020.1

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    Mitophagy plays an important role in the maintenance of mitochondrial homeostasis. PTEN-induced kinase (PINK1), a key regulator of mitophagy, is degraded constitutively under steady-state conditions. During mitophagy, it becomes stabilized in the outer mitochondrial membrane, particularly under mitochondrial stress conditions, such as in treatment with uncouplers, generation of excessive mitochondrial reactive oxygen species, and formation of protein aggregates in mitochondria. Stabilized PINK1 recruits and activates E3 ligases, such as Parkin and mitochondrial ubiquitin ligase (MUL1), to ubiquitinate mitochondrial proteins and induce ubiquitin-mediated mitophagy. Here, we found that the anticancer drug gemcitabine induces the stabilization of PINK1 and subsequent mitophagy, even in the absence of Parkin. We also found that gemcitabine-induced stabilization of PINK1 was not accompanied by mitochondrial depolarization. Interestingly, the stabilization of PINK1 was mediated by MUL1. These results suggest that gemcitabine induces mitophagy through MUL1-mediated stabilization of PINK1 on the mitochondrial membrane independently of mitochondrial depolarization.

    DOI: 10.1038/s41598-020-58315-w

  • Involvement of exchange protein directly activated by cAMP and tumor progression locus 2 in IL-1β production in microglial cells following activation of β-adrenergic receptors Reviewed

    Hidetoshi Tozaki-Saitoh, Izumi Sasaki, Tomohiro Yamashita, Masako Hosoi, Takahiro A. Kato, Makoto Tsuda

    Journal of Pharmacological Sciences   2020.1

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    Endogenous noradrenaline (NA) has multiple bioactive functions and, in the central nervous system (CNS), has been implicated in modulating neuroinflammation via β-adrenergic receptors (β-ARs). Microglia, resident macrophages in the CNS, have a central role in the brain immune system and have been reported to be activated by NA. However, intracellular signaling mechanisms of the AR-mediated proinflammatory responses of microglia are not fully understood. Using a rapid and stable in vitro reporter assay system to evaluate IL-1β production in microglial BV2 cells, we found that NA and the β-AR agonist isoproterenol upregulated the IL-1β reporter activity. This effect was suppressed by β-AR antagonists. We further examined the involvement of EPAC (exchange protein directly activated by cAMP) and TPL2 (tumor progression locus 2, MAP3K8) and found that inhibitors for EPAC and TPL2 reduced AR agonist-induced IL-1β reporter activity. These inhibitors also suppressed NA-induced endogenous Il1b mRNA expression and IL-1β protein production. Our results suggest that EPAC and TPL2 are involved in β-AR-mediated IL-1β production in microglial cells, and extend our understanding of its intracellular signaling mechanism.

    DOI: 10.1016/j.jphs.2020.03.004

  • Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes Reviewed

    Kazuhiro Nishiyama, Takuro Numaga-Tomita, Yasuyuki Fujimoto, Tomohiro Tanaka, Chiemi Toyama, Akiyuki Nishimura, Tomohiro Yamashita, Matsunaga Naoya, Koyanagi Satoru, Yasu Taka Azuma, Yuko Ibuki, Koji Uchida, Shigehiro Ohdo, Motohiro Nishida

    British Journal of Pharmacology   176 ( 18 )   3723 - 3738   2019.9

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    Background and Purpose: Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. Experimental Approach: We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key Results: Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and Implications: These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

    DOI: 10.1111/bph.14777

  • Evidence for detection of rat P2X4 receptor expressed on cells by generating monoclonal antibodies recognizing the native structure Reviewed

    Tatsuhiro Igawa, Shuhei Kishikawa, Yoshito Abe, Tomohiro Yamashita, Saki Nagai, Mitsunori Shiroishi, Chinatsu Shinozaki, Hiroyuki Tanaka, Hidetoshi Saitoh, Tsuda Makoto, Kazuhide Inoue, Tadashi Ueda

    Purinergic Signalling   2019.1

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    P2X purinergic receptors are ATP-driven ionic channels expressed as trimers and showing various functions. A subtype, the P2X4 receptor present on microglial cells is highly involved in neuropathic pain. In this study, in order to prepare antibodies recognizing the native structure of rat P2X4 (rP2X4) receptor, we immunized mice with rP2X4’s head domain (rHD, Gln111–Val167), which possesses an intact structure stabilized by S-S bond formation (Igawa and Abe et al. FEBS Lett. 2015), as an antigen. We generated five monoclonal antibodies with the ability to recognize the native structure of its head domain, stabilized by S-S bond formation. Site-directed mutagenesis revealed that Asn127 and Asp131 of the rHD, in which combination of these amino acid residues is only conserved in P2X4 receptor among P2X family, were closely involved in the interaction between rHD and these antibodies. We also demonstrated the antibodies obtained here could detect rP2X4 receptor expressed in 1321N1 human astrocytoma cells.

    DOI: 10.1007/s11302-019-09646-5

  • New pharmacological effect of fulvestrant to prevent oxaliplatin-induced neurodegeneration and mechanical allodynia in rats Reviewed International journal

    Shota Yamamoto, Tomohiro Yamashita, Mayu Ito, Jose Manuel Martinez Caaveiro, Nobuaki Egashira, Hidetoshi Saitoh, Tsuda Makoto

    International Journal of Cancer   2018.12

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    Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose-limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small-molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high-throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin-induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin-induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin-induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin-induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy.

    DOI: 10.1002/ijc.32043

  • Green Pharma A New Strategy for Drug Discovery in Academia by Targeting Glial Cells and ATP Receptors Reviewed

    Tomohiro Yamashita, Tsuda Makoto, Hidetoshi Saitoh, Kazuhide Inoue

    Yakugaku Zasshi   138 ( 8 )   1027 - 1031   2018.1

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     Neuropathic pain associated with cancer, diabetic neuropathy, and postherpetic neuralgia is a type of intractable chronic pain characterized by mechanical allodynia and abnormal pain hypersensitivity evoked by innocuous stimuli. However, this disorder has no specific treatment. We previously showed that the purinergic receptor P2X4 (P2X4R), a subtype of ATP-gated nonselective cation channels, is highly upregulated in spinal microglia after peripheral nerve injury, and blocking the function of P2X4R reverses mechanical allodynia. In the present study, we screened a chemical library of 1979 clinically approved compounds (a gift from the Drug Discovery Initiative at the University of Tokyo) aimed at achieving "Eco-Pharma," which refers to seeking new effects of existing drugs. We demonstrated that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rat and human P2X4R. In rat primary cultured microglial cells, duloxetine also inhibited P2X4R-mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain reversed nerve injury-induced mechanical allodynia. Based on those results, we suggest that the inhibition of P2X4R expressed in microglial cells may be involved in the antiallodynic effect of duloxetine in neuropathic pain. Furthermore, in this review, we discuss a new strategy for drug discovery called "Green Pharma" (a merger of "Eco-Pharma" and "Green chemistry" and referring to the development of eco-friendly pharmaceuticals).

    DOI: 10.1248/yakushi.17-00211-1

  • P2Y12 receptors in primary microglia activate nuclear factor of activated T-cell signaling to induce C–C chemokine 3 expression Reviewed

    Hidetoshi Saitoh, Hiroyuki Miyata, Tomohiro Yamashita, Katsuyuki Matsushita, Tsuda Makoto, Kazuhide Inoue

    Journal of Neurochemistry   141 ( 1 )   100 - 110   2017.4

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    Microglia are widely accepted as surveillants in the central nervous system that are continually searching the local environment for signs of injury. Following an inflammatory situation, microglia alter their morphology, extend ramified processes, and undergo cell body hypertrophy. Extracellular nucleotides are recognized as a danger signal by microglia. ADP acting on P2Y12 receptors induce process extension of microglia thereby attracting microglia to the site of adenosine tri-phosphate/ADP leaking or release. However, the question whether ADP/P2Y12 receptor signaling directly stimulates the production or release of inducible factors such as cytokines remains unclear. In this study, we found that CC chemokine ligand 3 (CCL3) is induced by ADP-treated primary microglia. Pharmacological characterization using pertussis toxin, a P2Y12 receptor inhibitor, and a calcium chelator revealed that CCL3 induction was caused by P2Y12 receptor-mediated intracellular calcium elevation. Next, nuclear factor of activated T-cell dephosphorylation and nuclear translocalization were observed. Calcineurin, an inhibitor for nuclear factor of activated T cell, suppressed CCL3 induction. These data indicate that microglial P2Y12 receptors are utilized to trigger an acute inflammatory response in microglia via rapid CCL3 induction after ADP stimulation. (Figure presented.).

    DOI: 10.1111/jnc.13968

  • Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease Reviewed

    Matsunaga Naoya, Eriko Ikeda, Keisuke Kakimoto, Miyako Watanabe, Naoya Shindo, Akito Tsuruta, Hisako Ikeyama, Kengo Hamamura, Kazuhiro Higashi, Tomohiro Yamashita, Hideaki Kondo, Yuya Yoshida, Masaki Matsuda, Takashi Ogino, Kazutaka Tokushige, Kazufumi Itcho, Yoko Furuichi, Takaharu Nakao, Kaori Yasuda, Atsushi Doi, Toshiaki Amamoto, Hironori Aramaki, Tsuda Makoto, Kazuhide Inoue, Akio Ojida, Koyanagi Satoru, Shigehiro Ohdo

    EBioMedicine   13   262 - 273   2016.11

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    Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

    DOI: 10.1016/j.ebiom.2016.10.008

  • Duloxetine inhibits microglial P2X4 receptor function and alleviates neuropathic pain after peripheral nerve injury Reviewed

    Tomohiro Yamashita, Shota Yamamoto, Jiaming Zhang, Miho Kometani, Daisuke Tomiyama, Keita Kohno, Hidetoshi Saitoh, Kazuhide Inoue, Tsuda Makoto

    PLoS One   11 ( 10 )   2016.10

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    P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge. In the present study, we screened a chemical library of clinically approved drugs and show for the first time that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rodent and human P2X4R. In primary cultured microglial cells, duloxetine also inhibited P2X4R-, but not P2X7R-, mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain produced a reversal of nerve injury-induced mechanical allodynia, a cardinal symptom of neuropathic pain. In rats that were pretreated with a serotonin-depleting agent and a noradrenaline neurotoxin, the antiallodynic effect of duloxetine was reduced, but still remained. Based on these results, we suggest that, in addition to duloxetine's primary inhibitory action on serotonin and noradrenaline transporters, an inhibitory effect on P2X4R may be involved at least in part in an antiallodynic effect of intrathecal duloxetine in a model of neuropathic pain.

    DOI: 10.1371/journal.pone.0165189

  • A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain Reviewed

    Yuta Matsumura, Tomohiro Yamashita, Atsushi Sasaki, Eriko Nakata, Keita Kohno, Takahiro Masuda, Hidetoshi Saitoh, Toshiyasu Imai, Yasushi Kuraishi, Tsuda Makoto, Kazuhide Inoue

    Scientific Reports   6   2016.8

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    Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect). Furthermore, in a mouse model of herpetic pain, P2X4R upregulation in the spinal cord exclusively occurred in microglia, and intrathecal NP-1815-PX suppressed induction of mechanical allodynia. This model also showed K+/Cl- cotransporter 2 (KCC2) downregulation, which is implicated in dorsal horn neuron hyperexcitability; this downregulation was restored by intrathecal treatment with NP-1815-PX or by interfering with brain-derived neurotrophic factor (BDNF) signaling, a P2X4R-activated microglial factor implicated in KCC2 downregulation. Taken together, the newly developed P2X4R antagonist NP-1815-PX produces anti-allodynic effects in chronic pain models without altering acute pain sensitivity, suggesting that microglial P2X4R could be an attractive target for treating chronic pain.

    DOI: 10.1038/srep32461

  • Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury Reviewed

    Ryoichi Tashima, Satsuki Mikuriya, Daisuke Tomiyama, Miho Shiratori, Tomohiro Yamashita, Yuta Koro, Hidetoshi Saitoh, Kazuhide Inoue, Tsuda Makoto

    Scientific Reports   6   2016.3

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    Accumulating evidence indicates that peripheral nerve injury (PNI) activates spinal microglia that are necessary for neuropathic pain. Recent studies using bone marrow (BM) chimeric mice have reported that after PNI, circulating BM-derived cells infiltrate into the spinal cord and differentiate into microglia-like cells. This raises the possibility that the population of spinal microglia after PNI may be heterogeneous. However, the infiltration of BM cells in the spinal cord remains controversial because of experimental adverse effects of strong irradiation used for generating BM chimeric mice. In this study, we evaluated the PNI-induced spinal infiltration of BM-derived cells not only by irradiation-induced myeloablation with various conditioning regimens, but also by parabiosis and mice with genetically labelled microglia, models without irradiation and BM transplantation. Results obtained from these independent approaches provide compelling evidence indicating little contribution of circulating BM-derived cells to the population of spinal microglia after PNI.

    DOI: 10.1038/srep23701

  • Preparation and characterization of a monoclonal antibody against the refolded and functional extracellular domain of rat P2X4 receptor Reviewed

    Tatsuhiro Igawa, Sadayuki Higashi, Yoshito Abe, Takatoshi Ohkuri, Hiroyuki Tanaka, Satoshi Morimoto, Tomohiro Yamashita, Tsuda Makoto, Kazuhide Inoue, Tadashi Ueda

    Journal of Biochemistry   153 ( 3 )   275 - 282   2013.3

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    The P2X4 purinergic receptor is a key molecule in neuropathic pain, particularly in the allodynia after peripheral nerve injury. We therefore sought to establish an anti-P2X4 receptor monoclonal antibody that would be useful for detection and characterization of the P2X4 receptor. We first prepared the refolded extracellular domain of the rat P2X4 receptor expressed in Escherichia coli. Then, we established a B-cell hybridoma producing the monoclonal antibody for the head domain of the rat P2X4 receptor with strict recognition, including S-S bond formation. In addition, we succeeded in the detection and immune precipitation of rat P2X4 receptor molecules on cultured cells. As the antibody specifically binds to the rat P2X4 receptor molecule, it is expected that the established monoclonal antibody will be applicable as a tool for detecting increasing expression levels of the P2X4 receptor molecule accompanied with increasing intensity of neuropathic pain.

    DOI: 10.1093/jb/mvs143

  • CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia Reviewed

    Emika Toyomitsu, Tsuda Makoto, Tomohiro Yamashita, Hidetoshi Saitoh, Yoshitaka Tanaka, Kazuhide Inoue

    Purinergic Signalling   8 ( 2 )   301 - 310   2012.6

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    P2X4 receptors (P2X4Rs), a subtype of the purinergic P2X family, play important roles in regulating neuronal and glial functions in the nervous system. We have previously shown that the expression of P2X4Rs is upregulated in activated microglia after peripheral nerve injury and that activation of the receptors by extracellular ATP is crucial for maintaining nerve injury-induced pain hypersensitivity. However, the regulation of P2X4R expression on the cell surface of microglia is poorly understood. Here, we identify the CC chemokine receptor CCR2 as a regulator of P2X4R trafficking to the cell surface of microglia. In a quantitative cell surface biotinylation assay, we found that applying CCL2 or CCL12, endogenous ligands for CCR2, to primary cultured microglial cells, increased the levels of P2X4R protein on the cell surface without changing total cellular expression. This effect of CCL2 was prevented by an antagonist of CCR2. Time-lapse imaging of green fluorescent protein (GFP)-tagged P2X4R in living microglial cells showed that CCL2 stimulation increased the movement of P2X4R-GFP particles. The subcellular localization of P2X4R immunofluorescence was restricted to lysosomes around the perinuclear region. Notably, CCL2 changed the distribution of lysosomes with P2X4R immunofluorescence within microglial cells and induced release of the lysosomal enzyme β-hexosaminidase, indicating lysosomal exocytosis. Moreover, CCL2-stimulated microglia enhanced Akt phosphorylation by ATP applied extracellularly, a P2X4R-mediated response. These results indicate that CCL2 promotes expression of P2X4R protein on the cell surface of microglia through exocytosis of P2X4R-containing lysosomes, which may be a possible mechanism for pain hypersensitivity after nerve injury.

    DOI: 10.1007/s11302-011-9288-x

  • Antidepressants inhibit P2X4 receptor function A possible involvement in neuropathic pain relief Reviewed

    Kenichiro Nagata, Toshiyasu Imai, Tomohiro Yamashita, Tsuda Makoto, Hidetoshi Saitoh, Kazuhide Inoue

    Molecular Pain   5   2009.4

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    Background: Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. Results: Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. Conclusion: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.

    DOI: 10.1186/1744-8069-5-20

  • Reduced pain behaviors and extracellular signal-related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet-activating factor receptor Reviewed

    Tsuda Makoto, Satoshi Ishii, Takahiro Masuda, Shigeo Hasegawa, Koji Nakamura, Kenichiro Nagata, Tomohiro Yamashita, Hidemasa Furue, Hidetoshi Saitoh, Megumu Yoshimura, Schuichi Koizumi, Takao Shimizu, Kazuhide Inoue

    Journal of Neurochemistry   102 ( 5 )   1658 - 1668   2007.9

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    Peripheral tissue injury causes the release of various mediators from damaged and inflammatory cells, which in turn activates and sensitizes primary sensory neurons and thereby produces persistent pain. The present study investigated the role of platelet-activating factor (PAF), a phospholipid mediator, in pain signaling using mice lacking PAF receptor (pafr-/- mice). Here we show that pafr-/- mice displayed almost normal responses to thermal and mechanical stimuli but exhibit attenuated persistent pain behaviors resulting from tissue injury by locally injecting formalin at the periphery as well as capsaicin pain and visceral inflammatory pain without any alteration in cytoarchitectural or neurochemical properties in dorsal root ganglion (DRG) neurons and a defect in motor function. However, pafr-/- mice showed no alterations in spinal pain behaviors caused by intrathecally administering agonists for N-methyl-d-aspartate (NMDA) and neurokinin1 receptors. A PAFR agonist evoked an intracellular Ca2+ response predominantly in capsaicin-sensitive DRG neurons, an effect was not observed in pafr-/- mice. By contrast, the PAFR agonist did not affect C- or Aδ-evoked excitatory post-synaptic currents in substantia gelatinosa neurons in the dorsal horn. Interestingly, mice lacking PAFR showed reduced phosphorylation of extracellular signal-related protein kinase (ERK), an important kinase for the sensitization of primary sensory neurons, in their DRG neurons after formalin injection. Furthermore, U0126, a specific inhibitor of the ERK pathway suppressed the persistent pain by formalin. Thus, PAFR may play an important role in both persistent pain and the sensitization of primary sensory neurons after tissue injury.

    DOI: 10.1111/j.1471-4159.2007.04796.x

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Presentations

  • Therapeutic Approach for the Treatment of Neuropathic Pain by the Inhibition of Microglial P2X7 Receptors by Approved Drugs Invited International conference

    @Tomohiro Yamashita, #Sawako Kamikaseda, #Aya Tanaka, @Hidetoshi Tozaki-Saitoh, @Jose M. M. Caaveiro, @Kazuhide Inoue, @Makoto Tsuda

    Purines 2021  2021.6 

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    Event date: 2021.6

    Language:English   Presentation type:Symposium, workshop panel (public)  

    Venue:オンライン(Braziil)   Country:Japan  

  • Drug discovery technologies to achieve pain relief through drug repositioning approaches(ドラッグリポジショニングによる疼痛緩和を達成するための創薬技術) Invited

    @山下智大

    第92回日本薬理学会年会  2019.3 

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    Event date: 2019.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大阪   Country:Japan  

  • Microglial ATP receptors in neuropathic pain Invited International conference

    @Tomohiro Yamashita

    PURINES 2018  2018.6 

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    Event date: 2018.6

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Foz do Iguacu, Brazil   Country:Brazil  

    Neuropathic pain is a debilitating pain state, which is often caused by peripheral nerve injury (PNI) by autoimmune disease, diabetes, cancer or physical injury. The hallmark symptom of neuropathic pain is tactile allodynia (pain hypersensitivity to innocuous light touching). Tactile allodynia is refractory to available medicines such as non-steroidal anti-inflammatory drugs and opioids. The mechanism of the neuropathic pain was still largely unknown. We found that activated spinal microglia of dorsal horn over-expressed P2X4 receptors(P2X4R)which cause to release brain-derived neurotrophic factor (BDNF) after the stimulation of ATP. BDNF evokes a collapse of their transmembrane anion gradient in the secondary neurons of dorsal hone resulting in tactile allodynia (Tsuda et al. Nature 424, 778-783, 2003; Coull et al. Nature, 438, 1017-1021, 2005). Now we know that various molecules in microglia play important roles in the relation to the neuropathic pain. We examined what regulates the expression of these molecules and found that the transcription factor interferon-regulatory factor 8 (IRF8) is a critical regulator of the gene expression of these molecules in microglia. Recently, we also have found the important role of IRF5-IRF8 for the expression of P2X4R in microglia (Masuda et al. Nat Commun.5:3771, 2014). ATP is released from primary afferent neurons of spinal dorsal horn (SDH) and various glia cells. We found that not microglia nor astrocytes but SDH inhibitory interneurons that express vesicular nucleotide transporter (VNUT) are a candidate source of the ATP (Masuda, et al. Nat. Commun. 7:12529, 2016; Inoue & Tsuda Nature Rev Neurosci, 19, 138-152, 2018).
    The role of purinergic P2X4R function in microglia in the mechanisms of neuropathic pain provides exciting insights in its pathogenesis, and suggests P2X4R inhibitors may be potential candidates for new medicines against neuropathic pain. We are finding such inhibitors from already approved medicines as the drug-developing system namely “Eco-Pharma” for providing benefits of science to patients as soon as possible. We will present some examples of Eco-Pharma in the symposium.

  • 化合物スクリーニングによって発見した新たなMRGPRA3アゴニストは非ヒスタミン性のかゆみを誘発する

    山下 智大,#伊藤 麻結, #川浪 侑華, @古賀 啓祐, #兼久 賢章, #藤井 志織, 津田 誠

    日本薬学会第144年会  2024.3 

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    Event date: 2024.3

    Language:Japanese  

    Country:Japan  

  • BINDS九州大学拠点が実施する化合物スクリーニング支援と高度化 Invited

    山下智大

    徳島大学・九州大学BINDS合同シンポジウム  2023.10 

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    Event date: 2023.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  • 九大薬が取り組む「グリーンファルマ研究」とは?

    山下智大

    令和5年度九州大学薬学研究院公開講座  2023.10 

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    Event date: 2023.10

    Language:Japanese  

    Country:Japan  

  • A newly discovered MRGPRA3 agonist by high-throughput screening induces scratching behaviors

    @Tomohiro Yamashita, Mayu Ito, Yuka Kawanami, Keisuke Koga, Kensho Kanehisa, Shiori Fujii, @Jose M. M. Caaveiro, @Makoto Tsuda.

    第95回日本薬理学会年会  2022.3 

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    Event date: 2022.3

    Language:English  

    Venue:福岡   Country:Japan  

  • グリーンファルマという新たな創薬システムを成功させるために九州大学が取り組む包括的な支援 Invited

    @山下智大

    長崎大学BINDS利用セミナー  2021.11 

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    Event date: 2021.11

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:オンライン   Country:Japan  

    アカデミアで発見した有望な創薬標的分子に対して薬理作用を発揮する既承認薬を見出し、さらにその既存の薬をもとに新薬を創製する新たな創薬システム「グリーンファルマ」を成功させるため、九州大学では化合物スクリーニング、ヒット化合物の最適化、動物での動態解析さらには疾患モデルでの解析などの包括的な支援を実施する。本セミナーではグリーンファルマの仕組みおよび支援体制について具体的な成果事例を交えて紹介する。

  • Discovery of a new MrgprA3 agonist and evaluation of its effect for itch sensation 新規MrgprA3アゴニストの発見およびかゆみ感覚に対するその評価

    @Tomohiro Yamashita, #Mayu Ito, #Yuka Kawanami, @Keisuke Koga, #Kensho Kanehisa, #Shiori Fujii, @Miho Shiratori-Hayashi, @Makoto Tsuda

    第93回日本薬理学会年会(誌上開催)  2020.3 

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    Event date: 2020.3

    Language:English  

    Venue:誌上開催   Country:Japan  

  • アカデミアが実践するニューロンおよびグリア細胞を標的とした疼痛治療戦略

    @山下智大

    第72回日本薬理学会西南部会  2019.11 

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    Event date: 2019.11

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:那覇   Country:Japan  

  • グリーンファルマ研究が切り拓くアカデミアにおける新たな創薬戦略 Invited

    @山下智大

    薬物動態談話会 第42年会  2019.11 

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    Event date: 2019.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:浜松   Country:Japan  

  • オキサリプラチン誘発末梢神経障害に対する乳がん治療薬フルベストラントの保護効果

    @山下智大, @山本将大, #伊藤麻結, @カアベイロホセ, @江頭伸昭, @齊藤秀俊, @津田誠

    第13回日本緩和医療薬学会年会  2019.6 

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    Event date: 2019.5 - 2019.6

    Language:Japanese  

    Venue:千葉   Country:Japan  

  • New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury International conference

    @Tomohiro Yamashita,#Sawako Kamikaseda,#Aya Tanaka,@Hidetoshi Tozaki-Saitoh,@Makoto Tsuda,@Kazuhide Inoue

    Young Pharmacologist Mixer  2018.7 

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    Event date: 2018.7

    Language:English  

    Venue:Kyoto   Country:Japan  

  • New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury International conference

    @Tomohiro Yamashita,#Sawako Kamikaseda,#Aya Tanaka,@Hidetoshi Tozaki-Saitoh,@Makoto Tsuda,@Kazuhide Inoue

    WCP2018 KYOTO  2018.7 

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    Event date: 2018.7

    Language:English  

    Venue:Kyoto   Country:Japan  

  • グリア細胞およびATP受容体を標的としたアカデミア創薬の実現に向けた「グリーンファルマ研究」の取り組み

    @山下智大,@齊藤秀俊,@津田誠,@井上和秀,

    薬学会137年会  2017.3 

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    Event date: 2017.3

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:仙台   Country:Japan  

  • デュロキセチンによるミクログリアに発現するP2X4受容体の阻害作用および末梢神経損傷に伴う神経障害性疼痛に対する改善効果

    @山下智大, #山本将大, #張佳明,@齊藤秀俊,@津田誠,@井上和秀

    第90回日本薬理学会年会  2017.3 

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    Event date: 2017.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:長崎   Country:Japan  

  • Searching for analgesics targeted at P2X4 receptors by screening of well-established drugs. International conference

    @Tomohiro Yamashita, @Makoto Tsuda, @Hidetoshi Tozaki-Saitoh, @Kazuhide Inoue

    Purines 2014  2014.7 

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    Event date: 2014.7

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Bonn   Country:Germany  

  • デュロキセチンによるミクログリアに発現するP2X4受容体の阻害作用および末梢神経損傷に伴う神経障害性疼痛に対する改善効果

    山下 智大

    第90回日本薬理学会年会  2017.3 

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    Language:Japanese  

    Country:Other  

  • グリア細胞およびATP受容体を標的としたアカデミア創薬の実現に向けた「グリーンファルマ研究」の取り組み

    山下 智大

    薬学会137年会  2017.3 

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    Language:Japanese  

    Country:Other  

  • New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury International conference

    山下 智大

    Purines 2018  2018.6 

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    Country:Other  

    New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury

  • Microglial ATP receptors in neuropathic pain Invited International conference

    山下 智大

    Purines 2018  2018.6 

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    Country:Other  

    Microglial ATP receptors in neuropathic pain

  • New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury WCP2018 International conference

    山下 智大

    WCP2018  2018.7 

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    Country:Other  

    New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury WCP2018

  • GPR55は脊柱管狭窄に伴う下肢痛の発症と好中球の浸潤に寄与する

    大野 瑛明, 山下 智大, 狩野 航輝, 岩渕 和久, 平林 義雄, 松尾 一郎, 上口 裕之, 中島 康晴, 津田 誠

    Journal of Spine Research  2023.4  (一社)日本脊椎脊髄病学会

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    Language:Japanese  

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MISC

  • エコファーマによる新規神経障害性疼痛治療薬の探索

    #山下智大

    ファルマシア55巻03号   2019.3

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    Language:Japanese  

Professional Memberships

  • 日本薬学会

  • 日本薬理学会

  • 日本緩和医療薬学会

Academic Activities

  • Screening of academic papers

    Role(s): Peer review

    2022

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:2

  • Screening of academic papers

    Role(s): Peer review

    2021

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:2

  • Screening of academic papers

    Role(s): Peer review

    2020

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:2

  • 不明

    日本薬理学会 次世代の会  ( Japan ) 2019.4 - 2020.3

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    Type:Competition, symposium, etc. 

  • Screening of academic papers

    Role(s): Peer review

    2018

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:2

  • Screening of academic papers

    Role(s): Peer review

    2017

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:1

  • Screening of academic papers

    Role(s): Peer review

    2016

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:2

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Research Projects

  • かゆみの伝達および慢性化にかかわるMRGPRsの多様性解明と新たな治療薬の創出

    Grant number:24K10034  2024 - 2026

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    山下 智大

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    Authorship:Principal investigator  Grant type:Scientific research funding

    本研究では、Mas関連Gタンパク質共役型受容体(MRGPRs)ファミリーを薬理学的に制御することで、かゆみなどの感覚伝達にどのような影響を及ぼすかを検証する。さらに、慢性掻痒時における各種MRGPRsの発現変化および役割を調査する。各種MRGPRsがかゆみの伝達や慢性化にどのように関与するかを明らかにすることで、多様なMRGPRsの機能や役割を解明し、新たなかゆみ治療薬や研究ツールの開発を目指す。

    CiNii Research

  • オートファジー依存性がん抗原放出機構の解明および免疫提示システムの強化改変

    Grant number:23K27673  2023.4 - 2026.3

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

    仲田 興平, 山下 智大, 肥川 和寛, 池永 直樹, 森崎 隆

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    Grant type:Scientific research funding

    膵癌ではがん抗原が少なく、樹状細胞によるCD8陽性T細胞への抗原提示能が抑制されているため免疫チェックポイント阻害剤(ICB)の効果が乏しいといわれている。一方で、マイクロサテライト不安定性(MSI)が高い膵癌患者ではがん抗原が増加し、ICBに反応することが報告されており、ICBに対する効果が期待されている。腫瘍免疫サイクルの初期段階のメカニズムにAutophagyが関与していると仮説をたて、解明することで免疫提示システムを強化改変、MSI-H膵癌患者で見られる様なICBの効果を一般化する。また、薬剤スクリーニングから同定した新規Autophagy抑制剤を用い、ICBと併用した新規治療法を開発する。

    CiNii Research

  • オートファジー依存性がん抗原放出機構の解明および免疫提示システムの強化改変

    Grant number:23H02982  2023 - 2025

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • グリーンファルマ創薬構造解析による支援高度化の推進

    2022 - 2026

    AMED 創薬等ライフサイエンス研究支援基盤事業

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    Authorship:Coinvestigator(s)  Grant type:Contract research

  • Development of cancer immunotherapy using non-receptor type immune checkpoint inhibitor targeting PTPN3

    Grant number:22K08715  2022 - 2024

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    中山 和典, 大西 秀哉, 山下 智大, 藤村 晶子, 大薗 慶吾

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

    我々は先行研究により、①Protein tyrosine kinase non-receptor type3 (PTPN3)が活性化リンパ球で発現亢進し,②PTPN3が活性化リンパ球では免疫チェックポイント分子として作用しておりPTPN3発現抑制によりリンパ球活性化(増殖能、運動能および細胞傷害活性)が更に亢進することを新たに見出した。本研究の目的は、PTPN3を標的とする非抗体型免疫チェックポイント阻害剤(低分子化合物)を用いた難治性固形癌に対する新規癌免疫治療を創生することである。

    CiNii Research

  • Improvement of protein expression by Escherichia coli based on the structure of anti-P2X4 antibody Fab and development of its additional function.

    Grant number:21K06517  2021 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    阿部 義人, 山下 智大

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

    低分子化抗体Fabは安定性、抗原親和性が優れており、抗体医薬品の次世代フォーマットとして期待されている。Fabは大腸菌発現から得られたリコンビナントが医薬品にも使われているが、リコンビナントFabは各抗体依存的に発現量が少ないものも多い。そこで我々は大腸菌発現系で調製した可溶性抗P2X4抗体Fabのアミノ酸変異を行い、大腸菌発現量の理論的な改良を目指す。さらに調製したFab を利用し、痛みのターゲット分子であるP2X4受容体の機能抑制を目標とした酵素とのコンジュゲート抗体の調製および評価を行う。また抗体医薬品において問題となっている凝集抑制を目的とした糖鎖付加法の開発を行う。

    CiNii Research

  • かゆみ伝達に対するMRGPRの包括的研究および創薬シーズの探索

    Grant number:21K06804  2021 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    山下 智大

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    Authorship:Principal investigator  Grant type:Scientific research funding

    本研究では,既承認薬,天然化合物,薬用植物エキス,海洋微生物そしてペプチドなどの多種多様な資材やライブラリーを利用することで,主に末梢神経系に発現する各種Mas関連Gタンパク質共役受容体(MRGPR)の機能を特異的に制御する化合物やペプチドを見出し,その薬効を評価することで各種MRGPRのかゆみ伝達メカニズムを包括的に明らかにする。さらには慢性的・難治性のかゆみを止める画期的な創薬シーズの探索を目指す。

    CiNii Research

  • 非天然α-アミノ酸を用いた中分子ペプチド医薬品創成

    2021 - 2023

    AMED 創薬基盤推進研究事業

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    Authorship:Coinvestigator(s)  Grant type:Contract research

  • Elucidation of abnormal functioning of neuronal circuits underlying neuropathic pain and its application for drug discovery

    Grant number:19H05658  2019 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (S)

    津田 誠, 八坂 敏一, 山下 智大

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

    がんや糖尿病,脳梗塞などに伴う神経系の障害により,モルヒネにも抵抗性を示す神経障害性疼痛が発症する。特に,触刺激で誘発される激烈な痛み(アロディニア)の治療は困難で,多くの患者が苦しんでいるが,「なぜ触覚が痛覚に変わるのか」という根源的な問いは未解明である。本研究では,代表者らがこれまで構築した疼痛・グリア研究基盤と,最近確立した技術(新規アロディニア評価法,神経サブセット特異的機能制御法)を融合させ,アロディニアに直結する神経回路とその動作異常を特定し,触から痛への転換メカニズムを解明する。そして,アロディニアの発症メカニズムの理解を深め,画期的な創薬シーズの発見に繋げる。

    CiNii Research

  • 制御化合物から紐解くかゆみ伝達におけるMrgprの役割そして創薬への応用

    Grant number:19K16502  2019 - 2021

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Early-Career Scientists

    山下 智大

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    Authorship:Principal investigator  Grant type:Scientific research funding

    本研究課題では,ハイスループットスクリーニング技術により,化合物ライブラリーの中からMas関連Gタンパク質共役受容体(Mrgpr)ファミリーに分類されるMrgprA3を活性化する化合物および各種Mrgprの機能を抑制する化合物を同定する。そしてすでに発見したMrgprA3を活性化する化合物Xおよび新たに探索する制御化合物を切り口としてMrgprが関わるかゆみの発症や維持メカニズムを紐解き,さらには画期的な創薬シーズの発見につなげる。

    CiNii Research

  • P2X4に対する高親和性抗体を利用した痛みを抑制する誘導体化抗体の開発

    Grant number:18K06597  2018 - 2020

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • グリーンファルマを基盤にした創薬オープンイノベーションの推進

    2017 - 2021

    AMED 創薬等ライフサイエンス研究支援基盤事業

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    Authorship:Coinvestigator(s)  Grant type:Contract research

  • オートファジーによるミトコンドリアDNA分解の分子機構と生理的意義の解析

    Grant number:17K15088  2017 - 2018

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists(A)or(B)

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Scientific research funding

  • ミクログリアに起因する慢性炎症を制御する新規治療薬の探索研究

    Grant number:17K17947  2017 - 2018

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

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 慢性疼痛における糖脂質シグナルの作動機序解明と創薬に向けた研究

    2016 - 2021

    AMED 革新的先端研究開発支援事業

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    Authorship:Coinvestigator(s)  Grant type:Contract research

  • 免疫アレルギー疾患等実用化研究事業, 分担, 皮膚バリアに影響する一次求心性神経由来シグナル分子の特定

    2016 - 2018

    AMED 免疫アレルギー疾患等実用化研究事業

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    Authorship:Coinvestigator(s)  Grant type:Contract research

  • オートファジーによって分解されるミトコンドリアの形態制御機構の解明

    Grant number:15K18501  2015 - 2016

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists(A)or(B)

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Scientific research funding

  • ミトコンドリアオートファジー関連薬物の探索

    Grant number:25560414  2013 - 2014

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Exploratory Research

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

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Class subject

  • 創薬化学

    2023.6 - 2023.8   Summer quarter

  • 薬理基礎理論

    2022.10 - 2023.3   Second semester

  • 医療系薬学英語講義

    2021.10 - 2022.3   Second semester

  • 薬理・疾患治療

    2021.10 - 2022.3   Second semester

FD Participation

  • 2023.11   Role:Participation   Title:第2回部局FD講演会「機関間連携」

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2023.8   Role:Participation   Title:令和5年度4部局合同男女共同参画FD

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2022.11   Role:Participation   Title:第4回創薬産学官連携セミナー(アカデミア創薬)

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2022.4   Title:学生の多様性に対応した教育とは:障害学生への合理的配慮を中心に

  • 2022.3   Role:Participation   Title:第3回創薬産学官連携セミナー(感染症研究拠点WG共催)

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2021.9   Title:JST 次世代研究者挑戦的研究プログラム 説明会

  • 2021.5   Role:Participation   Title:第2回創薬産学官連携セミナー

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2021.2   Role:Participation   Title:創薬産学官連携セミナー

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2019.9   Role:Participation   Title:外国人研究者・留学生受け入れ、貨物輸出と技術の提供に関して

    Organizer:[Undergraduate school/graduate school/graduate faculty]

  • 2018.10   Role:Participation   Title:M2B/Moodleに関するFD

    Organizer:[Undergraduate school/graduate school/graduate faculty]

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Social Activities

  • 不明

    令和5年度九州大学薬学研究院公開講座  九州大学コラボ・ステーションⅠ 視聴覚ホール  2023.10

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    Audience:General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture